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by M. Böhm, J . -C. Rei l , and F. Cus todi s , Germany

Michael BÖHM, MD, PhD
Jan-Christian REIL, MD
Florian CUSTODIS, MD
Internal Medicine Clinic III University Clinic of Saarlandes Homburg
Saar, GERMANY

Elevated heart rate and atherosclerosis: pathophysiology and clinical outcomes

A high heart rate is associated with an elevated mortality rate both in the general population as well as populations with hypertension or established cardiovascular disease like coronary artery disease (CAD) and heart failure. In view of this epidemiological background, it has been suggested that pharmacological heart rate reduction might improve cardiovascular complications. This pharmacological approach became available after the development of the I_f channel inhibitor ivabradine. Ivabradine reduces heart rate by depressing the phase of spontaneous depolarization of the sinus node. The sinus node activity of the drug is specific, and therefore no cardiodepressant effects on atrioventricular conduction or inotropy are induced. In experimental models of atherosclerosis, ivabradine was able to reduce endothelial dysfunction and inhibit plaque formation. In the large outcome trial, BEAUTIFUL (morBidity-mortality EvAlUaTion of the I_f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), ivabradine was able to reduce ischemia-related outcomes like reinfarction or the necessity for coronary revascularization in patients with known CAD after myocardial infarction. Furthermore, ivabradine has an established role in the symptomatic treatment of CAD and angina syndromes to reduce myocardial ischemia—alone, and even in the presence of β-blockers. A trial of ivabradine in chronic heart failure, the end stage of CAD, is currently being performed (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial; SHIFT). The data of this large outcome trial will establish whether the beneficial effects in experimental models might translate into a reduction of hard clinical end points in clinical practice in patients with advanced CAD or heart failure.

Heart rate is highly variable, and acts as the predominant driving force for cardiovascular regulation in mammals, including humans. Heart rate contributes closely to myocardial work and energy requirements, thus influencing the balance of cardiac performance and economy. It seems plausible that, via myocardial mechanical and metabolic stimulation, heart rate could impose stress on the myocardium and may therefore play an important role in determining life expectancy as well as lifespan in all individuals. This biological background is supported by many studies and investigations.¹ The myocardium with compromised function shows a significant rightward shift of the normal physiological pressurevolume curves (Figure 1). The external work is greatly decreased, whereas much more internal energy is generated, which consequently decreases efficiency.^2,3 These energy considerations are in line with the specific interrelation between heart rate and life expectancy (Figure 2). It is striking that mammals with the highest heart rates at rest have the shortest lifespan. The opposite holds true for those mammals with the lowest heart rates (Figure 2). Lowering heart rate reduces the ischemic threshold of diseased hearts, reduces heart work, and thus might be a potential therapeutic target of treatment in heart disease. According to detailed calculations, heart rate reduction of 10 beats per minute (bpm) can save about 5 kg of adenosine triphosphate per lifetime in humans.⁴

Figure 1. Panel A: normal pressure-volume relationship in the healthy heart.

Panel B: pressure-volume loop of a heart with severe diastolic and systolic heart failure (arrows).

An increase in sympathetic activity and a decrease in parasympathetic activity increases heart rate. Stimulation of the sympathetic nervous system can cause myocardial apoptosis as well as sudden cardiac death.^5,6

Consequently, it is difficult to distinguish between the influence on life expectancy of increased heart rate itself (metabolic demand), and the potential imbalance between sympathetic and parasympathetic neuroendocrine regulation. Experimentally, the pharmacological reduction of heart rate with cardiac glycosides like digitalis has been found to cause a 30% prolongation of survival time in healthy mice (Figure 3, page 358).⁷ This may support the notion that reduction of heart rate could itself prolong survival time in mammals, at least in part independently of the activity of the autonomic nervous system. The open question is whether these effects of heart rate modulation primarily act on the vessels or on the myocardium.

Figure 2. Inverse linear relationship between heart rate and life expectancy in different species. Bpm, beats per minute.

Heart rate and survival in healthy and hypertensive individuals

Epidemiological studies investigating approximately 30 000 individuals in total over a time period of between 5 and 36 years have revealed an inverse relationship between heart rate and survival time.^8-13 The risk for total mortality, coronary artery disease (CAD), stroke, and death caused by noncardiovascular diseases significantly increased in an age- and gender- independent manner with higher heart rates (Figure 4).¹¹

Figure 3. Comparison of survival time in normal mice and mice treated with digitalis.

Figure 4. Relationship between heart rate and the incidence of total mortality, coronary heart disease (CHD), cancer, other deaths, and stroke. Bpm, beats per minute.

More specifically, by comparing data on individuals with a heart rate lower than 60 bpm to that of individuals with a heart rate of 90 to 99 bpm, it was estimated that there is a threefold increased mortality risk associated with the higher heart rate.¹¹ According to the CArdiovascular Study in the ELderly (CASTEL), this relationship is especially true for patients older than 65 years.¹⁴ In clinical practice, it can be assumed that high heart rate is correlated with an increase in mortality caused by CAD, and is associated with an increased risk of sudden cardiac death.^9,12,15 Maximal heart rate developed during exercise, the difference between this heart rate value and the resting heart rate, and the time course of the heart rate returning to normal values after exercise are risk factors for sudden cardiac death if abnormal.^16,17 Compared with resting heart rates of about 60 to 65 bpm, resting heart rates of about 88 to 99 bpm are associated with a five- to sixfold increase in the risk of sudden cardiac death in men and a twofold increase in women.^9,10,15 The total mortality rate doubles with a rise in heart rate of about 40 bpm.^15,18,19 This correlation is strengthened when further risk factors like older age, hypertension, diabetes mellitus, and high body mass index are present. The association between heart rate and the development of arterial hypertension was first demonstrated in soldiers after their return from the First World War.²⁰ Follow-up in these individuals revealed a significant correlation between heart rate and the development of hypertension, cardiovascular disease, and chronic renal failure. These findings were supported by the prospectively designed Hypertension and Ambulatory Recording VEnetia STudy (HARVEST),²¹ which showed a link between high heart rates and a further increase in blood pressure in stage 1 hypertensive individuals. Additionally, Gillum et al demonstrated that patients with arterial hypertension have higher heart rates compared with healthy individuals.²² Complications of cardiovascular disease as well as total mortality double as heart rate increases by 40 bpm.^23,24 Heart rate therefore appears to be associated with vascular risk factors like hypertension.

Atherosclerotic heart disease – heart rate and mechanisms of atherosclerosis

Experimentally, in vitro studies have demonstrated that the stretching of human smooth muscle cells enhances the release of angiotensin II in a frequency-dependent manner and thereby stimulates the production of collagen in the vessel wall. This effect can be antagonized by angiotensin receptor 1 antagonists.²⁵ Corresponding to this result, the stiffness of the arterial vessel wall rises with increasing heart rates. This close correlation has especially been revealed in individuals suffering from hypertension. The combination of increased blood pressure with repetitive pressure changes caused by higher heart rates imposes an additional mechanical load on the vessel wall, potentially increasing the risk of clots.²⁶ Mangioni et al demonstrated that tachycardic pacemaker stimulation increases the stiffness of carotid arteries.²⁷ In monkeys, a strong correlation was shown between an increased hemo- dynamic stress index (heart rate multiplied by mean arterial blood pressure) and the development of atherosclerosis in the aorta or iliac vessels.²⁸

Figure 5. Atherosclerotic lesions in the aortic sinus (upper panels) and the
ascending aorta (lower panels) in ApoE knockout mice treated with vehicle and ivabradine.

Experimental heart rate reduction

Heart rate reduction caused by sinus note ablation in monkeys fed with a cholesterol-rich diet was found to be associated with a decrease in coronary atherosclerotic lesions.²⁹ Additionally, in young patients with myocardial infarction, there is a strong positive relationship between higher heart rates and the extent of atherosclerotic coronary lesions.³⁰ Pharmacological inhibition of heart rate was possible after the development of the I_f channel inhibitor ivabradine. In ApoE knockout mice, cholesterol-induced atherosclerosis was inhibited by heart rate reduction with ivabradine.³¹ Heart rate reduction of 10% led to a 40% decline in plaque load of the aortic sinus and a 70% decline in plaque load in the ascending aorta (Figure 5). Mechanistically, a reduction in NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide production—and thus in oxidative stress—might be involved (Figure 6). In earlier stages of atherosclerosis, a reduction in endothelial dysfunction was observed with heart rate reduction by ivabradine.³² Presumably, therefore, mechanical load on the vessel wall caused by higher heart rates might lead to endothelial dysfunction, increased oxidative stress, and enhanced plaque formation, which can be reversed or prevented by the inhibition of I_f channels and consecutive heart rate reduction with ivabradine.^31,32

Figure 6. Panel A: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity; Panel B: superoxide anion production; Panel C: lipid hydroperoxidase; and Panel D: dehydroetidium (DHE) fluorescent staining, in ApoE KO mice treated with vehicle or ivabradine.

Coronary artery disease and myocardial infarction

Events in patients with stable CAD are correlated with resting heart rate.³³ Diaz et al investigated 24 913 patients and demonstrated that total mortality rate, the mortality rate for cardiovascular diseases, as well as the rate of cardiovascular rehospitalization increases with increasing heart rate.³⁴ Patients with a resting heart rate of more than 83 bpm had an increased relative risk of 1.23 and an elevated cardiovascular mortality risk of 1.31 compared with the control group. Kaplan et al demonstrated a reduced progression of atherosclerosis in monkeys fed with a cholesterol-rich diet, as a result of heart rate lowering with propranolol.³⁵ A high heart rate could additionally impair the stability of coronary plaques through enhanced mechanical stress caused by repetitive pressure changes. Myocardial infarction develops when coronary plaques rupture and thrombosis occludes the vessel. The probability of plaque rupture depends on the stability of the fibrous cap covering the plaque shoulder, as well as the mechanical stress imposed on it. An increased mechanical load has been shown to provoke rupture of the plaque.³⁶ Furthermore, Lee et al found that rupture of explanted human aortic plaques was augmented with increased heart rates.³⁷ This effect was supported by the work of Heidland and Strauer, who studied 106 patients who underwent two coronary angiography procedures within 6 months.³⁸ All patients had only smooth stenosis on initial observation. The group with higher heart rates (>80 bpm) developed significantly more plaque ruptures compared with the group with the lower heart rates. Regression analysis identified heart rate as an independent risk factor for development of plaque rupture.

Figure 7. Comparison of mortality in patients with myocardial infarction according to heart rate. Bpm, beats per minute.

Several trials have demonstrated the relevance of heart rate regarding the prognosis of patients after myocardial infarction. According to a study by Hjalmarson et al, the heart rate of patients with myocardial infarction was significantly higher than that of controls.³⁹ Furthermore, higher heart rates in myocardial infarction patients at hospital discharge correlate with an increase in mortality rate after 1 year (Figure 7). Meta-analyses of the GISSI-2 and GISSI-3 trials (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico), which included about 20 000 patients, demonstrated that in-hospital mortality rates of patients after myocardial infarction rise from 3.3% for patients with a heart rate <60 bpm on admission to 10.1% for patients with a heart rate >100 bpm.⁴⁰

The GISSI trials showed that even myocardial infarction patients without heart failure who had an elevated heart rate had a worse long-term survival prognosis.⁴⁰ The relevance of heart rate after myocardial infarction is supported by results from β-blocker trials. Heart rate reduction by â-blockers is associated with a decrease in total mortality and sudden cardiac death.^41-44 Accordingly, heart rate–reducing verapamil- like calcium antagonists have beneficial effects in terms of prognosis of patients after myocardial infarction in the absence of heart failure.⁴⁵ In contrast, dihydropyridinetype calcium antagonists have detrimental effects on survival because of reflex tachycardia.

Taken together, heart rate reduction is correlated with an improvement in the long-term survival of patients with myocardial infarction, which has been best demonstrated by β-blocker trials.

Effects of heart rate reduction on outcome

The role of I_f channel inhibition on cardiovascular events in patients with CAD and reduced left ventricular function was studied in BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).^46,47 The BEAUTIFUL investigators studied patients with known CAD who also presented with left ventricular dysfunction. In the epidemiological part of the trial,⁴⁷ it was shown that patients had an adverse prognosis if heart rate was above 70 bpm (Figure 8). This held true for hospitalizations for heart failure, coronary revascularization, and cardiovascular death. Treatment with ivabradine⁴⁶ resulted in a reduction of ischemia-related end points like myocardial infarction and cardiovascular revascularization in patients with a heart rate above 70 bpm. The combined end point was not significantly affected by the treatment with ivabradine. It thus seems apparent that atherosclerosis, and in particular atherosclerotic events, are favorably influenced by a reduction in heart rate. This is not self-evident, because in a reduced heart rate, other mechanisms like higher daily levels of exercise, fewer comorbidities, and less obesity might be involved.⁴⁸ Nevertheless, further trials will have to establish the role of I_f channel inhibition, possibly in other conditions associated with high heart rates such as heart failure or renal damage in high-risk hypertensive individuals.^49,50

Figure 8. Relation between heart rate and ischemia-related end points (upper Panel A) and cardiovascular end points (upper Panel B) as well as Kaplan-Meier curves (lower Panel A and B) in BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).
HF, heart failure.

Future perspectives: heart failure

As with the conditions hypertension and CAD, heart failure, in particular in the decompensated state, is accompanied by high heart rates. This is brought about by activation of the sympathetic nervous system as one component of neuroendocrine activation. It is also known that in this condition, elevated heart rate is associated with a poor outcome. Heart rate reduction has been discussed as being one of the mechanisms by which β-blockers mediate an improvement of outcome in heart failure. Interestingly, there is discussion that in heart failure, there may be energy depletion, which is improved by heart rate reduction. Furthermore, in the failing heart, the positive force frequency relationship turns into a negative inverted relationship that results in a decline in the force of contraction when heart rate is increased (impaired Bowditch-effect). It is therefore tempting to speculate that heart rate reduction might also be beneficial to reduce heart failure–related events.

However, in BEAUTIFUL, heart failure hospitalizations were not significantly reduced. It is noteworthy that heart rate in BEAUTIFUL was rather low. It was therefore extremely important to carry out a trial specifically in patients with heart failure and neuroendocrine activation, and therefore higher heart rates. In Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial (SHIFT), patients with heart failure who are Haron standard medication are being investigated. These patients are receiving ivabradine as an add-on therapy. The average heart rate in SHIFT is higher than in BEAUTIFUL. Therefore, this trial will give a definite answer as to whether there is a reduction in heart failure outcome with heart rate reduction in this high-risk population. Furthermore, it will provide proof of the pathophysiological concept that along the cardiovascular continuum, events are dependent on heart rate and can be targeted by heart rate–lowering therapies (Figure 9). All patients are randomized in SHIFT and the results can be expected at the end of 2010.

Figure 9. Clinical and experimental evidence for the potential role of heart rate along the cardiovascular continuum. In patients with high heart rates, there is a high risk of the development of atherosclerosis. A high heart rate leads to ischemia and remodeling of the heart and vessels, and contributes to comorbidities in hypertension and chronic heart failure. Inhibition of the If channel might reduce heart rate, and therefore cardiovascular events, following treatment with ivabradine.

Conclusion

Heart rate is an independent risk factor for patients with cardiovascular disease, in particular arterial hypertension, myocardial infarction, CAD, and heart failure. This relationship is supported by a large number of animal studies that have shown detrimental effects of increased heart rate on the function and structure of the cardiovascular system, in particular in atherosclerosis. Whether pharmacological heart rate reduction might be beneficial in other conditions, such as for prevention of atherosclerotic disease or heart failure, must be the subject of future clinical trials. _

References

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17. Jouven X, Empana J-P, Schwartz PJ, Desnos M, Courbon D, Ducimetière P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352:1951-1958.
18. Mensink GB, Hofmeister H. The relationship between resting heart rate and all-cause cardiovascular and cancer mortality. Eur Heart J. 1997;18:1404-1410.
19. Benetos A, Rucnichi A, Thomas F, Safar M, Guize L. Influence of heart rate on mortality in a French population: role of age, gender and blood pressure. Hypertension. 1999;33:44-52.
20. Levy RL, White PD, Stroud WD. Transient tachycardia: prognostic significance alone and in association with transient hypertension. JAMA. 1945;129:585-588.
21. Palatini P, Casiglia E, Pauletto P. Relation between physical training and ambulatory blood pressure in stage I hypertensive subjects. Results of the Haron vest Trial. Circulation. 1994;90:2870-2872.
22. Gillum R. The epidemiology of resting heart rate in a national sample of men and women: association with hypertension, coronary heart disease, blood pressure, and other cardiovascular risk factors. Am Heart J. 1988;116:163-174.
23. Gillman M, Kannel W, Belanger A. Influence of heart rate on mortality among persons with hypertension. The Framingham study. Am Heart J. 1993;125: 1148-1154.
24. Habib GB. Reappraisal of heart rate as a risk factor in the general population. Eur Heart J. 1999;(suppl H):H2.
25. Stanley AG, Patel H, Knight AL. Mechanical strain-induced human vascular matrix synthesis: the role of angiotensin II. J Renin Angiotensin Aldosterone Syst. 2000;1:32-35.
26. Benetos A, Adamopoulos C, Bureau J-M. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation. 2002;105:1202-1207.
27. Mangioni AA, Mircoli L, Giannattasio C. Heart rate dependence of arterial distensibility in vivo. J Hypertens. 1996;14:897-901.
28. Bassiouny HS, Zarins CK, Kadowaki MH, Glagov S. Hemodynamic stress and experimental aortoiliac atherosclerosis. J Vasc Surg. 1994;19:426-434.
29. Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984;226:180-182.
30. Perski A, Hamsten A, Lindvall K, Theorell T. Heart rate correlates with severity of coronary atherosclerosis in young postinfarction patients. Am Heart J. 1988;116:1369-1373.
31. Custodis F, Baumhäkel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E deficient mice. Circulation. 2008;117:2377-2387.
32. Drouin A, Gendron ME, Thorin E, et al. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154:749-757.
33. Perski A, Olsson G, Landou C, de Faire U, Theorell T, Hamsten A. Minimum heart rate and coronary atherosclerosis: independent relations to global severity and rate of progression of angiographic lesions in men with myocardial infarction at a young age. Am Heart J. 1992;123:609-616.
34. Diaz A, Bourassa GM, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
35. Kaplan RJ, Manuck BS, Adams MR, Weingand KW, Clarkson TB. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987;76:1364-1372.
36. Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941-944.
37. Lee RT, Gordzinsky AJ, Frank EH, Kamm RD, Schoen JF. Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques. Circulation. 1991;83:1764-1770.
38. Heidland EU, Strauer EB. Left ventricular muscle mass and elevated heart rate are associatedwith coronary plaque disruption. Circulation. 2001;104:1477-1482.
39. Hjalmarson A, Gilpin E, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.
40. Zuanetti G, Hernándes-Bernal F, Rossi A, Comerio G, Paolucci G, Maggioni AP. Relevance of heart rate as a prognostic factor in myocardial infarction: the GISSI experience. Eur Heart J. 1999;1(suppl H):H52-H57.
41. Gundersen T, Groettum P, Pedersen T, Kjekshus J; Norwegian Timolol Multicenter Study Group. Effect of timolol on mortality and reinfarction after acute myocardial infarction: prognostic importance of heart rate at rest. Am J Cardiol. 1986;58:20-24.
42. Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J. Beta-blockers and sudden cardiac death. Ann Intern Med. 1995;123:358-367.
43. Hjalmarson A. Effects of beta blockade on sudden cardiac death during acutemyocardial infarction and the postinfarction period. Am J Cardiol. 1997;80:35J-39J.
44. Beta-blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. Mortality results. JAMA. 1982; 247:1707-1714.
45. Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II (DAVIT II). Am J Cardiol. 1990;66:770-785.
46. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo controlled trial. Lancet. 2008;372:807-816.
47. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction: a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
48. Reil JC, Böhm M. BEAUTIFUL results—the slower, the better? Lancet. 2008; 372:779-780.
49. Böhm M, Reil JC, Danchin N, et al. Association of heart rate with microalbuminuria in cardiovascular risk patients: data from I-SEARCH. J Hypertens. 2008; 26:585-592.
50. Reil C, Böhm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol. 2007;96:585-592.

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by P. G. Steg and G. Ducrocq, France

Philippe Gabriel STEG, MD
Gregory DUCROCQ, MD
Centre Hospitalier Bichat- Claude Bernard, Assistance Publique, Hôpitaux de Paris
Université Paris 7 – Paris, FRANCE

Is heart rate optimally controlled in patients with coronary artery disease in clinical practice?

Coronary artery disease remains a major global public health problem. Treatment includes drugs to control anginal symptoms and myocardial ischemia, and treatment to improve clinical outcomes. The latter includes not only recommended lifestyle changes and drugs to control risk factors, but also a series of drugs with established efficacy in preventing adverse cardiac outcomes, such as antithrombotic agents, statins, renin-angiotensin system blockers, and β-blockers. Ivabradine is a specific inhibitor of the I_f current, whose action produces selective heart rate reduction in patients with elevated heart rate, without adverse hemodynamic side effects. It has established efficacy in preventing or limiting anginal symptoms and myocardial ischemia, and in head to head comparisons, yields comparable efficacy to that of atenolol on exercise-induced ischemia. A recent trial, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the I_f Current Inhibitor ivAbradine with a beTa-blockEr), demonstrated that when added to chronic treatment with β-blockers, ivabradine further reduces heart rate and improves exercise capacity while being well tolerated. Ivabradine has also now been tested in a large outcome trial, BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), in patients with stable coronary artery disease and left ventricular dysfunction. While it did not affect the primary composite end point of cardiovascular death and hospitalization for acute myocardial infarction or heart failure, it did, in a prespecified subset analysis, reduce coronary events in patients with a baseline heart rate

Coronary artery disease is a major public health problem worldwide

Cardiovascular disease is currently, and is anticipated to remain in the next 10 years, the leading cause of mortality worldwide. Despite a continuous decline in industrialized countries, a genuine epidemic of cardiovascular mortality is affecting low and middle-income countries worldwide, due to major epidemiologic transition in these countries that is related to westernization of lifestyle, with increased smoking, diabetes, and obesity. Even today, cardiovascular disease is the single most frequent cause of death in these countries.¹ Among cardiovascular diseases, coronary artery disease (CAD) is itself the most frequent cause of mortality and morbidity. Just as an example of the public health burden associated with CAD, it is estimated that in the USA alone, every 26 seconds somebody will suffer from an acute coronary event, and every minute someone will die from one.² Even among patients with stable CAD receiving modern therapy for secondary prevention, the rate of major adverse cardiac events remains high: data from the recent REduction of Atherothrombosis for Continued Health (REACH) registry have shown that the yearly rate of cardiovascular death, myocardial infarction, and stroke is approximately 4.5%, and that an additional 10% of these patients require hospitalization for cardiovascular reasons every year.³

Treatment for coronary artery disease

_ General therapeutic measures
Modern therapy for patients with CAD aims to control anginal symptoms, thereby improving exercise capacity and quality of life. But it also aims to prevent adverse cardiovascular events and improve outcomes. Such treatment includes lifestyle modifications (encouraging patients to quit smoking, to be physically active, and to maintain a healthy diet and a normal body mass index) and drug treatments to control risk factors such as hypertension, dyslipidemia, and diabetes.^4,5

_ Treatment to improve clinical outcomes
In addition to strict control of risk factors, four categories of agents have established benefits on clinical outcomes in the treatment of patients with CAD: antiplatelet agents (such as aspirin or thienopyridines), statins, angiotensin-converting enzyme (ACE) inhibitors (and angiotensin receptor blockers after acute myocardial infarction), and, to a lesser extent, â-blockers, which have been shown, beyond their ability to prevent anginal symptoms and minimize myocardial ischemia, to impact favorably on clinical outcomes after acute myocardial infarction.⁶

_Treatment to control anginal symptoms and prevent myocardial ischemia
There are a host of pharmacologic agents that have been demonstrated to exert antianginal effects and either prevent or delay the occurrence of anginal symptoms on exertion. In addition to β-blockers, calcium channel blockers, long-acting nitrates, potassium channel agonists, metabolic agents (such as trimetazidine and ranolazine), and ivabradine all have established efficacy against angina (usually measured by the number of anginal attacks or the use of rapid acting nitrate preparations) and myocardial ischemia (generally reflected by duration of exercise without either ST-segment depression or anginal symptoms on a stress test). However, despite such efficacy, most of these agents have little demonstrated effectiveness in preventing adverse cardiovascular outcomes.

Nicorandil is one of the few agents that has been tested in a modern randomized trial and has demonstrated an impact on clinical outcomes: in the Impact of Nicorandil in Angina (IONA) trial, the use of nicorandil on top of usual therapy reduced the combination of deaths from coronary heart disease, myocardial infarction, and unplanned hospitalization for chest pain in patients with stable angina.⁷ Most other agents have not been studied in large randomized outcome trials in the context of stable CAD.

Myocardial revascularization, using either percutaneous coronary intervention or coronary artery bypass grafting, is often used to control anginal symptoms or myocardial ischemia in patients with CAD. While remarkably effective at improving outcomes in the context of acute coronary syndromes,^6,8 it has little impact, if any, on clinical outcomes in patients with stable CAD.⁹ In fact, the recent Clinical Outcomes Utilizing Revascularization And aGgressive drug Evaluation (COURAGE) trial found no additional benefit of an initial strategy of routine revascularization on top of optimal medical therapy compared with medical therapy alone.¹⁰

Ivabradine: an antianginal agent

Ivabradine (Procoralan®) is an agent that inhibits the If current of the sinus node, thereby specifically slowing the heart rate of patients in sinus rhythm. Because of the importance of heart rate in myocardial oxygen consumption, reductions in heart rate are associated with a potent anti-ischemic and antianginal effect.

Since ivabradine is a pure heart rate–reducing agent, it has no negative effect on inotropy, preserves left ventricular relaxation, does not lead to coronary vasoconstriction, preserves atrioventricular and intraventricular conduction, and has no effect on blood pressure.^11-13 In addition, ivabradine can be added to other antianginal agents and has excellent tolerability and safety. The principal side effect is rare, minor, and reversible visual disturbances, because some retinal cells also harbor the I_f current.

Figure 1. Efficacy of ivabradine versus atenolol on exercise tolerance test parameters at trough of drug activity in the INternatIonal TriAl on the Treatment of angIna with iVabradinE versus atenolol (INITIATIVE).

Clinical trials have established the potent antianginal effects of ivabradine. In randomized trials, compared with placebo, ivabradine demonstrated dose-dependent improvements in exercise tolerance and prevention of exercise-induced ischemia.¹⁴ In the INternatIonal TriAl on the Treatment of angIna with iVabradinE versus atenolol (INITIATIVE), ivabradine was compared with â-blocker therapy with atenolol, an established treatment for prevention of exercise-induced angina, using stress tests, in 939 patients. In that study, ivabradine at the dose of 5 mg produced essentially similar effects to those of 50 mg atenolol on total exercise duration when tested at the trough of drug activity.¹⁵ Likewise, after 4 months of treatment, 10 mg of ivabradine were “noninferior” to 100 mg of atenolol, with in fact, a strong trend toward superiority of ivabradine. Indeed, in that trial, when 7.5 mg ivabradine twice daily was compared with 100 mg atenolol four times daily, all the parameters of the exercise treadmill test (ie, exercise duration, time to limiting angina, time to anginal onset, and time to 1-mm ST-segment depression) fulfilled criteria for noninferiority with ivabradine compared with atenolol (Figure 1). In addition, when examining the increase in exercise capacity (measured by increase in total exercise duration) provided by each beat reduction in heart rate, the “efficiency” of heart rate reduction with ivabradine was greater than that achieved by atenolol (increase in total exercise duration of 10.1 vs 5.6 seconds).

A recent trial, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr), examined the effects of ivabradine in patients with chronic stable angina pectoris receiving â-blocker therapy. In this double-blind trial, 889 patients who were all on 50 mg of atenolol daily were randomly assigned to additional treatment with either ivabradine up to 7.5 mg twice daily or placebo. Patients were then studied using exercise treadmill tests at the trough of drug activity 2 and 4 months later. Compared with placebo, and in these patients who were already on atenolol, ivabradine treatment led to improved total exercise duration on all parameters of the exercise test at 2 and 4 months (Figure 2). In addition, treatment was well tolerated, with only 1% of patients stopping drug therapy because of bradycardia. Minor reversible visual effects (phosphenes and blurred vision) were reported in 2% of ivabradine-treated patients and 0.9% of the placebo-treated patients.¹⁶ Thus, it had already been established that ivabradine is an effective and well-tolerated antianginal agent, alone or in combination with other drugs. ASSOCIATE now also demonstrates that when added to chronic treatment with β-blockers, ivabradine further reduces heart rate and improves exercise capacity, while being well tolerated.

Figure 2. Anti-ischemic efficacy of ivabradine in combination with β-blockers.

_ Impact of ivabradine on clinical outcomes in patients with coronary artery disease
In order to assess whether treatment with ivabradine was associated not only with symptomatic benefits, but also with improvement in clinical outcomes, several trials have been initiated in patients with CAD. The first of these trials is BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction). This is a large international, double-blind, randomized clinical trial of ivabradine versus placebo on top of optimal medical therapy, in patients with stable CAD, a baseline heart rate of at least 60 beats per minute (bpm), and left ventricular dysfunction (defined as a left ventricular ejection fraction of <40%). The primary end point was a composite of cardiovascular death and hospitalization for acute myocardial infarction or heart failure. Almost 11 000 patients were enrolled in 33 countries. After a median follow-up of 19 months, ivabradine did not affect the primary end point in the overall trial (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.85- 1.10; P=0.94) nor in a prespecified subgroup of patients with a heart rate of 70 bpm or greater (HR, 0.91; 95% CI, 0.81- 1.04; P=0.17).17 It did, however, reduce secondary end points in that subset: admission to hospital for fatal and nonfatal myocardial infarction (HR, 0.64; 95% CI, 0.49-0.84; P=0.001) and coronary revascularization (HR, 0.70; 95% CI, 0.52-0.93; P=0·016) (Table, Figure 3).

Figure 3. Heart rate as a predictor of cardiovascular death.

Importantly, these results were achieved despite the fact that patients were receiving excellent background medical therapy, with high rates of the use of antithrombotics, statins, and renin-angiotensin system blockers, and more importantly, with 87% of the patients on β-blockers. It is important to put these results into perspective using the analysis done in the placebo group of the same trial, looking at the impact of heart rate at baseline on clinical outcomes.18 In that analysis, it was apparent that heart rate is a strong prognostic factor in patients with CAD and left ventricular dysfunction, and that in fact, an elevated heart rate (≥70 bpm) identifies those at increased risk of cardiovascular outcomes, with a differential effect on outcomes associated with heart failure and outcomes associated with coronary events: the risk of mortality and heart failure increased continuously with increasing heart rate, whereas the impact of heart rate on coronary events appeared to increase above the threshold of 70 bpm. This suggests that the value of 70 bpm is probably a key threshold in CAD, which deserves consideration in making decisions regarding treatment of these patients (Figures 4-6).

Figure 4. Heart rate as a predictor of hospitalization for heart failure.

Figure 5. Heart rate as a predictor of hospitalization for myocardial infarction (MI).

Figure 6. Ivabradine reduces fatal and nonfatal myocardial infarction

These findings have two important implications: first, from a pathophysiologic standpoint, the fact that a drug that specifically slows the heart rate without affecting any of the other determinants of oxygen consumption or any other hemodynamic parameter would affect clinical outcomes, demonstrates that the relationship between elevated heart rate and adverse cardiovascular outcomes that has been demonstrated in several important observational studies^19-22 is not solely an association, but is at least in part, causal, since ivabradine has no other hemodynamic action other than slowing sinus rhythm. In addition, from a clinical standpoint, they provide evidence of a benefit of ivabradine far beyond the mere control of anginal symptoms. It now belongs to the small number of drugs that have established prognostic benefits on hard clinical outcomes in patients with CAD, even when such patients receive excellent background medical therapy. This indicates that ivabradine should now be considered for the management of patients with CAD, left ventricular dysfunction, and a heart rate of 70 bpm. It is plausible that these benefits may extend to a similar patient population but who are without left ventricular dysfunction, but this deserves to be tested in a second trial, which is indeed ongoing.

Conclusion

Given the burden that CAD imposes on global public health, it is important to find new treatments that are able to improve clinical outcomes in patients with CAD. Ivabradine is a new treatment that selectively slows the heart rate and is associated with established efficacy against angina and exerciseinduced myocardial ischemia. It has comparable efficacy to that of atenolol, an established treatment for angina, but also provides additional efficacy when added to β-blockers (as recently demonstrated in ASSOCIATE) or to other antianginal background therapy.

BEAUTIFUL showed that in addition to symptomatic improvement, treatment with ivabradine also yields improved clinical outcomes in terms of prevention of fatal or nonfatal myocardial infarction or the need for myocardial revascularization in patients with a baseline heart rate ≥70 bpm when added to modern background therapy. Both prevention of myocardial infarction and reduction of the need for myocardial revascularization are likely to have a substantial impact on global health and health costs. Ivabradine (Procoralan®) therefore has an important role in the management of patients with stable CAD. _

References
1. Anderson GF, Chu E. Expanding priorities—confronting chronic disease in countries with low income. N Engl J Med. 2007;356:209-211.
2. Rosamond W, Flegal K, Furie K, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics 2008 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117: 25-146.
3. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297:1197-1206.
4. Fox K, Garcia MA, Ardissino D, et al; Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341-1381.
5. Gibbons RJ, Abrams J, Chatterjee K, et al; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159-168.
6. Van de Werf F, Bax J, Betriu A, et al; Task Force on the Management of STSegment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur Heart J. 2008;29:2909-2945.
7. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;359:1269-1275.
8. Bassand JP, Hamm CW, Ardissino D, et al; Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007;28: 1598-1660.
9. Katritsis DG, Ioannidis JP. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation. 2005;111:2906-2912.
10. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.
11. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676-H682.
12. Colin P, Ghaleh B, Monnet X, et al. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236-240.
13. Simon L, Ghaleh B, Puybasset L, et al. Coronary and hemodynamic effects of S16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275:659-666.
14. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
15. Tardif J-C, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
16. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
17. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
18. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817- 821.
19. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
20. Kannel WB, Kannel C, Paffenbarger RSJR, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494.
21. Jouven X, Empana JP, Schwartz PJ, et al. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352:1951-1958.
22. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008; 29:1327-1334.

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by C. Daly, Ireland

Caroline DALY MB, PhD, MRCPI
CREST Unit St James’s Hospital
Dublin, IRELAND

Myocardial oxygen demand is primarily controlled by heart rate, which also controls myocardial oxygen supply, and an elevated heart rate can trigger myocardial ischemia. Furthermore, emerging evidence suggests that as an independent cardiovascular risk factor, heart rate may be comparable in importance to smoking, dyslipidemia, or hypertension, yet this is often overlooked. Data on the control of heart rate in clinical practice is scarce, and that which do exist, ie, in registries of acute coronary syndromes and post–myocardial infarction populations, suggest that elevated resting heart rate is common. A resting heart rate of >75 beats per minute, the level above which the risk of cardiac events begins to increase, is found in a substantial proportion of patients post–myocardial infarction—up to one third of women and one quarter of men. Observational data from studies of preoperative β-blockade, and meta-analysis of the effect of preoperative β-blockade on mortality reduction, point to considerable inter-patient variability in heart rate response to β-blockade. There are also indications that a substantial proportion of patients fail to achieve target heart rates (over 25%) and that attainment of target heart rate is necessary to achieve cardioprotection with β-blockade. Data from the Euro Heart Survey of Angina suggest that heart rate control is not optimal in the stable angina setting, despite its proven benefits with regard to reducing ischemia, with multiple factors including comorbidity affecting the use of β-blockers.

Heart rate and ischemia

Heart rate is the primary determinant of myocardial oxygen demand, and it also controls myocardial oxygen supply.¹ Experimental studies indicate that increased heart rate is associated with increased myocardial oxygen demand through the combined effects of increased cardiac work and myocardial oxygen consumption, and reduced diastolic perfusion time and subendocardial perfusion.^2-4

Numerous experimental studies have shown that elevated heart rate triggers most episodes of myocardial ischemia.^5-7 Data published in the early 1990s gathered by the Angina and Silent Ischemia Study (ASIS) Group from a sample of 50 coronary artery disease (CAD) patients treated with a â-blocker, calcium channel blocker, or placebo, suggest that most episodes of ambulatory ischemia (>80%) are associated with preceding increases in heart rate, and that the likelihood of ischemia development is directly related to baseline resting heart rate. Myocardial ischemia was more than twice as likely in patients with a baseline heart rate of ≥80 beats per minute (bpm) rather than <60 bpm, and the anti-ischemic activity of each type of medication was related chiefly to each drug’s ability to reduce heart rate.⁵

A considerable amount of the available data regarding the effect of elevated heart rate on ischemia was published over 15 years ago, and although guidelines for the management of angina emphasize the need to achieve target heart rates to control ischemia,^8,9 the significance of raised resting heart rate as a major prognostic indicator and target for treatment has only become more widely realized in the clinical community in recent times.^1,10 Despite its simplicity, heart rate may be comparable in importance as an independent cardiovascular risk factor to smoking, dyslipidemia, or hypertension, yet this is often overlooked.

Heart rate and prognosis

There have been several large observational studies showing elevated heart rate to be associated with adverse outcome in both the coronary disease population and the general population.^11,12 A key study in this regard showed resting heart rate to be a predictor of total and cardiovascular mortality in nearly 25 000 patients with CAD.¹³ Patients from the Coronary Artery Surgery Study registry were followed up for a median 14.7 years, and those with a resting heart rate of ≥83 bpm had significantly increased risks of total mortality (hazard ratio [HR] 1.32; P<0.0001) and cardiovascular mortality (HR 1.31; P<0.0001), after adjustment for other clinical variables.¹³ In BEAUTIFUL (morBidity-mortality EvAlUaTion of the I_f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), a large study of CAD patients with left ventricular systolic dysfunction, patients with a heart rate of ≥70 bpm had a 34% increased risk of cardiovascular death (P=0.0041), a 53% higher risk of admission to hospital for heart failure (P<0.0001), a 46% greater risk of admission to hospital for myocardial infarction (P=0.0066), and a 38% higher risk of coronary revascularization (38%; P=0.037).¹⁴ The INternational VErapamil SR/Trandolapril study (INVEST), which included over 22 000 patients with stable CAD and hypertension randomized to verapamil or atenolol, demonstrated a similar linear increase in the risk of cardiovascular events with increasing resting heart rate, with risk increasing significantly at a heart rate of approximately 75 bpm.¹⁵ And the effects of heart rate on outcome are evident across the spectrum of coronary presentations. A recent report on prognostic indicators in a low risk population presenting with acute coronary syndromes (ACS; n=15 000) selected heart rate at presentation as an important clinical indicator of the likelihood of freedom from events, with lower heart rates associated with fewer events during follow-up.¹⁶

Treatment of heart rate

Heart rate reduction has been associated with clinically important benefits in various subtypes of coronary heart disease.¹ Pooled data from 8 randomized, double-blind studies of β-blockade revealed that during the evolution of myocardial infarction (ie, within 12 hours of symptom onset), a decrease in heart rate of ≥14 bpm was linked to a 25% to 30% decrease in infarct size.¹⁷ Moreover, in large-scale, pooled analyses of post-infarct patients, a mean heart rate decrease of approximately 10 bpm was associated with reduced risks of approximately 20% to 25% in total mortality, cardiac death, and nonfatal reinfarction.^17,18 In specific studies of angina and silent myocardial ischemia prevention, the most marked efficacy has been documented for agents with the most sustained decreases in heart rate. For instance, during 24-hour ambulatory echocardiographic monitoring in ASIS in patients with stable CAD, β-blockade significantly reduced the mean number of asymptomatic ischemic episodes by 57% (P<0.0001), and the mean duration of ischemia by 87% (P<0.0001).¹⁹ The American College of Cardiology and American Heart Association now recommend a target resting heart rate of 60 bpm for β-blocker–treated patients
with stable angina.⁸

Heart rate lowering in practice

Despite the proven benefits of heart rate reduction in reducing ischemia and angina, and the association of lower heart rates with improved prognosis, only relatively limited data exist on the attainment of heart rate targets in clinical practice or the use of pharmacological therapies to achieve target heart rate. The vast majority of studies on pharmacological therapies or revascularization in CAD populations do not even report resting heart rate at baseline, even when blood pressure is reported. The analogy may be drawn between this and earlier scant reporting of either cholesterol levels or the use of antilipid or antiplatelet therapies. Resting heart rate and heart rate during follow-up are reported in a handful of studies that have looked at management of ischemia in stable angina, such as Total Ischaemic Burden European Trial (TIBET), a study using atenolol,²⁰ and Angina Prognosis Study In Stockholm (APSIS), a study using metoprolol,²¹ as well as more recent trials such as the aforementioned INVEST and BEAUTIFUL. But accurate data regarding the actual heart rates routinely encountered in “real world” patients are rare.

_ Acute coronary syndromes and myocardial infarction
The Global Registry of Acute Coronary Events (GRACE) was designed to reflect an unbiased population of patients with ACS, irrespective of geographical region. More than 120 hospitals located in 14 countries in North and South America, Europe, Australia, and New Zealand contributed patients who had been admitted with a presumptive diagnosis of ACS (that is, had symptoms consistent with acute ischemia), and had at least one of the following: electrocardiogram (ECG) changes consistent with ACS, serial increases in serum biochemical markers of cardiac necrosis, and documentation of CAD. In this population (n=15 757), the median heart rate (interquartile range) was 76 bpm (65-90 bpm). In those free of events, the median heart rate was 75 bpm (64-88 bpm), and in those who went on to die or develop further myocardial infarction or revascularization, it was 83 bpm (70-100 bpm).¹⁶

Table. Heart rate and associated risk of mortality in the GISSIPrevenzione
study.

In the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin) registry of ACS, only limited data were presented regarding heart rate at baseline; median heart rate was 72 bpm (63-80 bpm), but heart rate was significantly associated with clinical events during follow-up, with the effect greater for myocardial infarction than for unstable angina (Figure, page 367).²² The GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico)-Prevenzione study collected data on almost 12 000 patients who had suffered a myocardial infarction in the previous 3 months, and found that a quarter of men and one third of women had a heart rate >75 bpm (Table), which in this study was also associated with an increased risk of subsequent mortality.²³

Even when published, for the most part, data from registries of ACS and myocardial infarction patients regarding the resting heart rates encountered in clinical practice are relatively limited. In particular, there is limited information regarding the interrelationship between anti-ischemic and chronotropic medications such as β-blockers or calcium antagonists and the measured heart rate, and no published data on the relationship between resting heart rate and comorbid conditions such as chronic respiratory disease, diabetes, or peripheral vascular disease. Even more importantly, there is no data on the influence of heart rate on subsequent management, the effect of pharmacological interventions on follow-up heart rates, or the effect, if any, of successful heart rate modification on mortality or other outcomes. In effect, there is little data on the control of heart rate in clinical practice.

_ Perioperative heart rate lowering
An exception and important data source on this topic is the literature surrounding β-blockade for the prevention of perioperative cardiac events in vascular surgery patients. Patients undergoing vascular surgery have a high risk of suffering major postoperative cardiac events. This risk can be modified by perioperative β-blockade, although there has been debate in recent years as to the universal benefit of β-blockade in such patients.²⁴

Preoperative myocardial ischemia as detected by Holter monitoring identifies a high-risk subgroup of patients in whom postoperative ischemia, similarly detected, heralds major cardiac events. In one study, Holter monitoring was used to select patients for β-blockade, and it was shown that systematic, patient-specific postoperative heart rate control with β-adrenergic blocker therapy can decrease the incidence of postoperative ischemia among high-risk vascular surgery patients.²⁵ A total of 26 of 150 patients due to undergo elective vascular surgery who were monitored preoperatively by 24-hour Holter monitoring were found to have significant myocardial ischemia defined by ST-segment depression. The ischemic threshold was defined as the minimal heart rate at which this ST-segment depression occurred. These 26 patients were then randomized to receive continuous intravenous βblockade with esmolol or placebo plus usual medical therapy, with the aim of reducing the postoperative heart rate to 20% below the ischemic threshold. All patients were monitored for 48 hours postoperatively. Postoperative Holter readings were analyzed for the incidence of ischemia and for the number of hours during which heart rate was controlled below the ischemic threshold. A total of 15 patients were randomized to receive esmolol, and 11 were randomized to receive placebo. The two groups were comparable with respect to clinical characteristics and incidence and duration of preoperative ischemia. Ischemia persisted in the postoperative period in 8 of 11 placebo patients (73%), but only 5 of 15 esmolol patients (33%) (P<0.05). Of the 15 esmolol patients, 9 had mean heart rates below the ischemic threshold, and all 9 patients had no postoperative ischemia. A total of 4 of 11 placebo patients had mean heart rates below the ischemic threshold, and 3 out of the 4 had no postoperative ischemia. There were two postoperative cardiac events among patients who had postoperative ischemia (one placebo, one esmolol) and whose mean heart rates exceeded the ischemic threshold. These data suggest that patient- specific, strict heart rate control aimed at a predefined target based on the individual preoperative ischemic threshold was associated with a significant reduction and frequent elimination of postoperative myocardial ischemia among highrisk patients.

Figure. Data from the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin) registry of ACS.

In a more recent observational cohort study, 272 vascular surgery patients were preoperatively screened for cardiac risk factors and â-blocker dose, with β-blocker dose expressed as a percentage of the maximum recommended therapeutic dose, and the effect of higher â-blockade and lower heart rate were evaluated.26 β-Blocker dose was converted to a percentage of the maximum recommended therapeutic dose according to the Food and Drug Administration’s Center for Drug Evaluation and Research database. The maximum recommended therapeutic dose for atenolol was 3.330 mg/kg (body weight) per day, for bisoprolol it was 0.330 mg/kg (body weight) per day, for metoprolol 6.670 mg/ kg (body weight) per day, for carvedilol 0.417 mg/kg (body weight) per day, for propranolol 10.700 mg/kg (body weight) per day, and for labetalol 40.700 mg/kg (body weight) per day. Heart rate and ischemic episodes were recorded by continuous 12-lead electrocardiography, starting 1 day before to 2 days after surgery, and serial troponin T levels were measured after surgery. Of the 272 patients, myocardial ischemia was detected in 85 patients (31%) and troponin T release in 44 patients (16.2%). Higher doses of â-blockers were significantly associated with lower heart rates during 12-lead ECG monitoring (78.8 ±11.8, 73.1 ±11.1, and 68.0 ±10.9 bpm in patients with no dose, low-dose, and highdose â-blockers, respectively, P<0.0001), and nonsignificantly associated with lower absolute heart rate change (11.3 ±8.8, 9.6 ±7.2, and 8.5 ±9.7 bpm in patients with no dose, low-dose, and high-dose â-blockers, respectively, P=0.092). In multivariate analysis, higher preoperative heart rates during ECG monitoring (per 10-bpm increase) were significantly associated with an increased incidence of myocardial ischemia (HR, 2.49; 95% CI, 1.79 to 3.48), troponin T release (HR, 1.53; 95% CI, 1.16 to 2.03), and long-term mortality (HR, 1.42; 95% CI, 1.14 to 1.76), with similar patterns observed for intraoperative and postoperative heart rates. This study confirmed that tight heart rate control is associated with reduced perioperative myocardial ischemia, and it further expanded findings by showing that reduced heart rate is also associated with reduced troponin T release and improved long-term outcome in vascular surgery patients.

Following on from such studies, a recent meta-analysis sought to determine the part played by tight heart rate control in the efficacy of perioperative â-blockade. Previous meta-analyses of trials assessing the efficacy of perioperative â-blockade failed to show a consistent reduction in postoperative morbidity and mortality, but showed sizeable heterogeneity of effect, and found that the influence of tight heart rate control had not been considered. The current meta-analysis included 2176 patients from 10 studies, and grouped the trials on the basis of maximal heart rate.27 Trials in which the estimated maximal heart rate was <100 bpm were associated with cardioprotection (odds ratio [OR], 0.23; 95% CI, 0.08-0.65; P=0.005), whereas trials in which the estimated maximal heart rate was >100 bpm did not demonstrate cardioprotection (OR, 1.17; 95% CI, 0.79- 1.80; P=0.43), suggesting that effective heart rate control is important in achieving cardioprotection. Importantly, in the context of the question of heart rate control in clinical practice, 25% of patients receiving â-blockers had episodes during which their heart rate was over 100 bpm, demonstrating that administration of â-blockers does not reliably decrease heart rate in all patients. Furthermore this meta-analysis highlighted the risks of increased side effects, including bradycardia, supporting the judicious use of combination therapy with other drugs to achieve effective postoperative control of heart rate.

_ Heart rate control in stable angina
The area in which data on the control of heart rate in clinical practice is particularly sparse—despite its relevance—is stable angina. Specific questions include those relating to the resting heart rate patterns of patients with stable angina both on and off medication to reduce heart rate, the effects of heart rate on clinical decisions made by cardiologists who are treating patients with stable angina and the clinical scenarios that mediate against tight control of heart rate, the appropriateness of the use of available agents to reduce heart rate, and the effect of appropriate heart rate control on outcome. Studies are emerging, however, that offer to cast light on this important issue.

The Euro Heart Survey on Angina was a prospective, observational, cohort study of patients with stable angina presenting to cardiology services for the first time. Consecutive outpatients with a clinical diagnosis made by a cardiologist were enrolled, and 3779 patients were included in the analysis.28 Patients with stable angina caused by myocardial ischemia secondary to coronary disease were included. The survey was carried out in community-based, ambulatory individuals newly presenting to a cardiologist. The majority of patients had been referred by their primary care physician, with under 10% being self referrals, and the remainder having been referred by general physicians or accident and emergency physicians. Enrolment took place at 197 centers in 36 countries in Europe and the Mediterranean basin.

Although there was marked regional heterogeneity in prescribing patterns, overall, after initial assessment by a cardiologist, 67% of patients were taking (or were recommended to take) a β-blocker, 61% a nitrate, and 27% a calcium channel blocker.²⁹ Most patients (59%) received two or more antianginal drugs, and only 13% received no antianginal therapy. Despite approximately a third of patients taking β-blockers at baseline, the overall mean resting heart rate was 73 bpm.³⁰ Other important points that have been highlighted by this survey are the fact that resting heart rate is affected by comorbid conditions such as chronic respiratory disease and diabetes, with higher resting heart rates recorded in patients with these conditions. β-Blockers are less fre quently prescribed in patients with chronic respiratory disease or diabetes, and crucially, the doses of â-blockade used by both primary physicians and cardiologists were found to be subtherapeutic. These findings clearly point to concern regarding the potential for side effects.

Current treatment options to reduce heart rate chiefly comprise β-blockers and calcium channel blockers,^8,9 although selective If channel inhibitors such as ivabradine are a newer addition to the armamentarium.³¹ Ivabradine was not available at the time of the Euro Heart Survey. While β-blockers are widely prescribed, there are important differences in their pharmacokinetics and pharmacodynamics as well as their side-effect profiles, which will have important effects on tolerability and the maximum prescribed dose,³² all of which need to be considered when targeting heart rate control. The use of combination therapy needs to be judicious and guided by the results of clinical trials, rather than clinical trial and error. The results of the recently published ASSOCIATE trial (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the I_f Current Inhibitor ivAbradine with a beTablockEr), a large trial in over 880 patients, demonstrated that the addition of ivabradine 7.5 mg twice daily to atenolol at the commonly-used dosage in clinical practice in patients with chronic stable angina pectoris, produced additional heart rate reduction. The average heart rate reduction of 9 bpm was significant, allowing the patients to reach the recommended heart rate level of less than 60 bpm. This heart rate reduction was associated with a significant further improvement on all exercise testing parameters, with no untoward effects on safety or tolerability.³³

Conclusion

The evidence for targeted heart rate lowering is growing, and there is emerging evidence that a gap exists between guidelines and practice in managing heart rate in the CAD population. The challenge to the cardiology community is twofold: (i) to refine our current knowledge regarding the effect of heart rate lowering on clinical events according to the agents used, the optimal doses, and the specific different clinical presentations of CAD; and (ii) to rapidly translate this evidence into practice. _

References
1. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830.
2. Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236-240.
3. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676-H682.
4. Collins P, Fox KM. Pathophysiology of angina. Lancet. 1990;335:94-96.
5. Andrews TC, Fenton T, Toyosaki N, et al; Angina and Silent Ischemia Study Group (ASIS). Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. Circulation. 1993;88:92-100.
6. Kop WJ, Verdino RJ, Gottdiener JS, O’Leary ST, Bairey Merz CN, Krantz DS. Changes in heart rate and heart rate variability before ambulatory ischemic events. J Am Coll Cardiol. 2001;38:742-749.
7. Krittayaphong R, Biles PL, Christy CG, Sheps DS. Association between angina pectoris and ischemic indexes during exercise testing and ambulatory monitoring. Am J Cardiol. 1996;78:266-270.
8. Gibbons RJ, Abrams J, Chatterjee K, et al; Committee on the Management of Patients With Chronic Stable Angina. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2003;107:149-158.
9. Fox K, Garcia MA, Ardissino D, et al; Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Guidelines on the management of stable angina pectoris: executive summary. Eur Heart J. 2006; 27:1341-1381.
10. Graham I, Atar D, Borch-Johnsen K, et al; Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice: full text. Eur J Cardiovasc Prev Rehabil. 2007; 14(suppl 2):S1-S113.
11. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112:736-749.
12. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study. Am Heart J. 1991;121: 172-177.
13. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J.2005;26:967-974.
14. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
15. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008; 29:1327-1334.
16. Brieger D, Fox KA, Fitzgerald G, et al. Predicting freedom from clinical events in non-ST-elevation acute coronary syndromes. The Global Registry of Acute Coronary Events. Heart. 2009, February 25. Epub ahead of print.
17. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
18. Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
19. Stone PH, Gibson RS, Glasser SP, et al; ASIS Study Group. Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. Circulation. 1990;82:1962- 1972.
20. Dargie HJ, Ford I, Fox KM; TIBET Study Group. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. Eur Heart J. 1996;17:104-112.
21. Rehnqvist N, Hjemdahl P, Billing E, et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J. 1996;17:76-81.
22. Boersma E, Pieper KS, Steyerberg EW, et al; PURSUIT Investigators. Predictors of outcome in patients with acute coronary syndromes without persistent STsegment elevation. Results from an international trial of 9461 patients. Circulation. 2000;101:2557-2567.
23. Marchioli R, Avanzini F, Barzi F, et al. Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J. 2001;22:2085-2103.
24. London MJ. Quo vadis, perioperative beta blockade? Are you “POISE’d” on the brink? Anesth Analg. 2008;106:1025-1030.
25. Raby KE, Brull SJ, Timimi F, et al. The effect of heart rate control on myocar dial ischemia among high-risk patients after vascular surgery. Anesth Analg. 1999;88:477-482.
26. Feringa HH, Bax JJ, Boersma E, et al. High-dose beta-blockers and tight heart rate control reduce myocardial ischemia and troponin T release in vascular surgery patients. Circulation. 2006;114(1 suppl):I344-I349.
27. Beattie WS, Wijeysundera DN, Karkouti K, McCluskey S, Tait G. Does tight heart rate control improve beta-blocker efficacy? An updated analysis of the noncardiac surgical randomized trials. Anesth Analg. 2008;106:1039-1048.
28. Daly CA, Clemens F, Sendon JL, et al. The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina. Eur Heart J. 2005;26: 996-1010.
29. Daly CA, Clemens F, Sendon JL, et al. The initial management of stable angina in Europe, from the Euro Heart Survey: a description of pharmacological management and revascularization strategies initiated within the first month of presentation to a cardiologist in the Euro Heart Survey of Stable Angina. Eur Heart J. 2005;26:1011-1022.
30. Daly C, Tavazzi L, Fox K; Euro Heart Survey of Angina Investigators. Inadequate control of heart rate in patients with stable angina: results from the European Heart Survey. European Society Of Cardiology Congress 2008. Munich, Germany. Eur Heart J. 2008;29(suppl)204-205. Abstract.
31. Diaz A, Tardif JC. Heart rate slowing versus other pharmacological antianginal strategies. Adv Cardiol. 2006;43:65-78.
32. Stoschitzky K, Stoschitzky G, Brussee H, Bonelli C, Dobnig H. Comparing betablocking
effects of bisoprolol, carvedilol and nebivolol. Cardiology. 2006;106:
199-206.
33. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.

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Guy G. DE BACKER MD, PhD
Department of Cardiology – University Hospital Ghent and Department of Public Health – Ghent University – Ghent, BELGIUM

The coronary heart disease (CHD) epidemic has been extremely dynamic over the last half century, with marked variation in its characteristics among different regions of the world—both between neighboring nations and even regions within a country. In the USA and most countries of the European Union, the age-standardized CHD mortality rates have decreased significantly; this may lead paradoxically to an increase in the prevalence of CHD in these countries—indeed, better survival of CHD patients and demographic changes have resulted in more elderly people suffering from CHD. In other parts of the world, the incidence of CHD is still on the increase, and it is estimated that in the coming years the number of CHD patients will increase substantially, especially in developing and transitional countries. Recent developments in the epidemic in the USA and Europe additionally suggest that the spectacular decline in CHD in the last half of the 20th century may have halted, especially in younger subjects. CHD is also an important source of disability, which can be translated into disability-adjusted life years (DALYs). The CHD burden in terms of DALYs is also projected to rise in the coming years, especially in countries in transition. There are also important regional differences in CHD burden within countries. If these differences are well understood, lessons can be learned and the knowledge applied in order to reduce the burden in less well-off communities.
Medicographia. 2009;31:343-348 (see French abstract on page 348)

“Coronary heart disease (CHD) is now the leading cause of death worldwide; it is on the rise and has become a true pandemic that respects no borders.” This statement, made in 2009, can be found on the Web site of the World Health Organization,¹ and is not that different from the warning issued in 1969 by the executive board of the World Health Organization: “Mankind’s greatest epidemic: coronary heart disease has reached enormous proportions striking more and more at younger subjects. It will result in coming years in the greatest epidemic mankind has faced unless we are able to reverse the trend by concentrated research into its cause and prevention.”²

This may give the wrong impression that nothing has changed over the last 40 years. On the contrary, the epidemic of CHD has been, and still is, extremely dynamic and influenced by environmental factors, resulting in rises and falls in morbidity and mortality over relatively short time periods. Furthermore, during the last 40 years, results from observational and intervention studies have clearly shown that CHD is partial- ly preventable. Knowledge of this has been implemented in some populations more than in others, which may explain the heterogeneous changes that have taken place in CHD incidence and mortality among different places around the world.

The underlying pathology of most clinical manifestations of CHD is atherosclerosis; this is a slowly progressive process that starts in the young. Despite the progress that has been made toward prevention and cure of CHD, it appears that our actual abilities are limited to a retardation of atherosclerosis and a postponement of CHD to older age; given the demographic changes that are taking place in most communities, one has to expect a further increase in the absolute number of people with CHD.

The purpose of this article is to describe aspects of the CHD epidemic in relation to time, place, age, and gender. From this, one can learn lessons about how to prevent CHD, or at least how to reduce the number of premature deaths and improve quality of life, thus prolonging life expectancy in good health and reducing the number of disability-adjusted life years (DALYs).

The burden of coronary heart disease at the global level

CHD has received great attention because its epidemic development after World War II initially struck the industrialized countries. Nowadays, however, the burden of CHD involves the whole world; the age-standardized death rates for CHD are declining in many developed countries but are increasing in developing and transitional countries—partly as a result of demographic changes, urbanization, and lifestyle changes. Today, approximately 3.8 million men and 3.4 million women worldwide die each year from CHD.¹ According to the Global Burden of Disease Study,³ the developing countries contributed 3.5 million of the 6.2 million global deaths from CHD in 1990. The projections estimate that these countries will account for 7.8 million of the 11.1 million deaths due to CHD in 2020.

But there is more to these numbers when they are translated into health care and community costs. In 2003, the economic impact of cardiovascular disease (CVD) on health care costs in the enlarged European Union (EU) was estimated to be 169 billion euros,⁴ which is an average of 3724 euros per capita per year. A total of 62% of this sum was related to direct costs and 21% to productivity loss. The latter is particularly important in developing countries; indeed, given the demographic composition of the populations of developing countries and the changes that will take place in age distribution, not only is the increase in CVD alarming in itself, but also the fact that this increase in the coming decades will manifest itself mainly in the economically active part of societies.

In 1990, 47% of all CVD-related deaths in developing countries occurred before the age of 70 years, in contrast with only 23% in high-income industrialized countries. This has a consequence in that there is a difference in the number of DALYs resulting from CVD; the burden of CVD expressed in DALYs from 1990 to 2020 was estimated for different populations in the Global Burden of Disease Study.³ In India and China, a spectacular rise in the number of DALYs is expected in the coming years—from a figure of less than 25 million DALYs in each country in 1990, to 30 million and 35 million in India and China, respectively, in 2020. By contrast, a decline from around 20 million to 15 million DALYs is expected in established market economies. The gap between industrialized countries and developing countries will significantly increase, and the increasing burden of CVD in terms of DALYs will clearly mostly affect developing countries in the next two decades. In different parts of the world, the dynamics of the CHD epidemic are also very different in terms of pattern, magnitude, and timing.⁵

The burden of coronary heart disease in the USA

CHD mortality in the USA began to decline in the mid 1960s. Age-adjusted CHD mortality rates continued to fall throughout the 1990s, although crude mortality rates changed more modestly, with CHD being postponed and manifesting itself at an older age. Because of this, CHD remains the largest single cause of death and disability in the USA.⁶ In 2005, CHD caused approximately 1 of every 5 deaths in the USA.7 It is the largest major killer of both American men and women. Approximately 37% of people who develop a coronary event in a given year will die from it.

Results from the Framingham study⁸ based on observations from 1950 until 1999 demonstrate that CHD death rates decreased by 59% during this time period. This favorable trend was seen in men and women. From 1995 to 2005, the death rate from CHD declined by 34.3%. In 2005, the overall CHD death rate was 144.4 per 100 000 population. For white males it was 187.7 and for black males it was 213.9 per 100 000, and for white females the rate was 110.0 and for black females 140.9 per 100 000.⁹

According to data from the National Registry of Myocardial Infarction, the in-hospital mortality rate for an acute myocardial infarction declined from 11.2% in 1990 to 9.4% in 1999.¹⁰ Analysis of CHD mortality data among US adults aged 35 to 54 years showed that the annual percentage change in (age-adjusted) mortality rates slowed markedly from 1980 to 2002 in both men and women. Particularly noteworthy is that the mortality rate among women aged 34 to 44 years of age has been increasing on average by 1.3% per year since 1997.¹¹

With regard to incidence, data from the Atherosclerosis Risk In Communities (ARIC) and Cardiovascular Health Study indicate that annually, 785 000 Americans have a new coronary attack and 470 000 have a recurrent attack; in addition, approximately 195 000 silent myocardial infarctions occur each year. This assumes that 21% of the 935 000 first and recurrent myocardial infarctions are silent.^12,13 On the basis of results from the Framingham study, it is estimated that CHD accounts for more than half of all cardiovascular events in men and women under 75 years of age.¹² The lifetime risk of developing CHD after the age of 40 years is 49% in men and 32% in women.¹⁴ The total incidence of CHD in women lags behind men by 10 years.³

The burden of coronary heart disease in Europe

_ Mortality burden
CHD by itself is the single most common cause of death in Europe and the EU. Between 1 in 5 and 1 in 7 women die from CHD in Europe and the EU, and in men, it accounts for between 1 in 4 and 1 in 6 of all deaths.¹⁵ One could argue that this is the fate of communities that are growing to very old ages. This may be part of the explanation. In 2005, the mean life expectancy at the age of 50 years for men and women in all 25 EU countries was 28.6 and 33.5 years, respectively.¹⁶ Therefore, dying before the age of 75 years in an EU country may be considered as premature. In Figure 1, EU deaths under the age of 75 years are given by cause for men and women. CHD was the cause of 15% and 10% of all premature deaths in men and women, respectively.¹⁵ In other parts of Europe, CHD strikes even more: in Europe as a whole, CHD causes 20% of all male deaths before the age of 75 years and 18% of all female deaths before the same age.¹⁵

In the economically active work force of Europe (ie, those below the age of 65 years), CHD was found to be the cause of death in 16% and 12% of men and women, respectively. Age-standardized and gender-specific CHD mortality rates have significantly decreased during recent decades in many countries in the north, west, and south of Europe. However, the decline has been less apparent, or indeed absent, in Central and Eastern Europe. So based on the mortality statistics, one may conclude that the epidemic of CHD in Europe has been extremely diverse in pattern, magnitude, and timing. The decreases in the standardized CHD mortality rates are the result of great efforts made in preventive cardiology, but there are limitations: in fact, the crude CHD mortality rates remain stable or are even on the increase because of aging of the population. Therefore the total CHD burden remains high, and it may appear paradoxical that as a result of prevention, the total number of CHD deaths could even increase. New therapeutic options for prevention and treatment of CVD have resulted in an increasing number of patients who survive a cardiovascular event; in developed countries, the burden has shifted from the middle aged to the elderly, and the prevalence of CVD increases exponentially with age.

Figure 1. Causes of death in the European Union in males and
females under the age of 75 years.

_ Morbidity
At present there is no standardized source of worldwide or Europe-wide coronary artery disease (CAD) morbidity data. Hospital discharge data can be used, but this provides only part of the picture and the validity of such data in some countries is open to question. The results from the multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) project¹⁷ are still the best available source of information, although they are now more than 15 years old. Some MONICA centers have continued their registers and have reported more recent results.

The cross-sectional data from MONICA revealed age-standardized annual event rates for fatal and nonfatal coronary events in men aged 35 to 64 years covering a 12-fold range; from 915 per 100 000 for North Karelia, Finland to 76 per 100 000 for Beijing, China. For women, rates covered an 8.5- fold range, from 256 per 100 000 for Glasgow, UK to 30 per 100 000 for Catalonia, Spain.¹⁸

Twenty-eight-day case fatality rates ranged in men from 37% to 81% and in women from 31% to 91%. From1985 to 1990, overall 28-day case fatality was halved for hospitalized events (compared with all events), and was nearly halved for hospitalized 24-hour survivors. Because approximately twothirds of 28-day CHD deaths occurred before individuals reached the hospital, opportunities for reducing case fatalities through improved in-hospital care are limited.

Figure 2. Rates of acute coronary events in Ghent, Belgium, in
the male population aged 25-69 years during the periods 1983-
1987, 1988-1992, and 1996-2001.

Over the decade studied, CHD mortality rates as defined by MONICA criteria fell annually by an average 2.7% in men (range –8.0% to +4.2%) and by an average 2.1% in women (range –8.5% to +4.1%). Changes in nonfatal rates were smaller (–2.1%; range –6.5% to +2.8%).19 There were, however, important regional differences in all of these changes; countries from the same geographical area have experienced very different time trends in terms of the CHD epidemic. For example, incidence rates for men living in North Karelia, Finland, fell by 6.5% per year from 1983 to 1996, but rose by 1.2% per year for men of the same age living in Kaunas, Lithuania. For women, the incidence fell by 5.1% per year in North Karelia, but rose by 2.7% per year in Kaunas in women of similar age.¹⁷

MONICA was partly established to investigate how much of the reported decline in CHD mortality is attributable to improvements in case fatality, and how much is attributable to declines in CHD incidence. The project concluded that, “contribution to changing CHD mortality varied, but in populations in which mortality decreased, coronary event rates contributed two thirds and case fatality one third.”¹⁷

Patterns of CHD incidence and case fatality across Europe may have changed since the mid 1990s. Some MONICA centers have been able to continue their registers until now, but in comparing time trends over a longer time period, one has to consider possible differences in the definition of coronary events following the introduction of troponin estimations. In Ghent, Belgium, the register continued, and the MONICA methodology to identify and define acute coronary events was kept identical. In Figure 2, results are given from the register of acute myocardial infarction in the population aged less than 70 years in the city of Ghent. Attack rates are presented for the male population; when comparing the period 1983-1986 with the period 1996-2001, a decline of almost 40% was observed.

In Figure 3, the most recent results from the register up to 2005 are given; since 1999, the study population has been extended up to the age of 74 years. In the figure, attack rates are given for the male and female populations; results are given both for all events and only nonfatal events, the latter meaning only those patients who survived for at least 28 days. The curves have now become very flat; statistically there was no change observed from 1999 to 2005.

This confirms results published from the US, where agespecific mortality rates for CHD have been found to be leveling off in younger adults.¹¹ These observations are also consistent with results from a population-based autopsy study of non-natural deaths, suggesting that temporal declines in the grade of CHD at autopsy have ended.²⁰ All this necessitates continuous and careful monitoring of an epidemic that continues to change over relatively short time periods—indicating the importance of environmental influences—with the use of valid and comparable methods that allow accurate surveillance of the epidemic dynamics.

_ Quality of life
CHD is not only the leading cause of death, but is also an important source of disability that translates into DALYs. In 2002, CHD was the cause of 11% of all DALYs in Europe, comparable to that caused by all cancers. All CVD taken together was, however, responsible for 23% of all DALYs, and was thus the most important cause.¹⁵ CVD is responsible for 10% of DALYs lost in low and middle income countries, and 18% in high income countries. The CHD burden is projected to rise from around 47 million DALYs globally in 1990 to 82 million DALYs in 2020.¹

Figure 3. Age-standardized rates (per 10 000 patients) of acute
myocardial infarction in men and women in Ghent, Belgium.

The burden of coronary heart disease at the national level

Looking solely at the burden of CHD at the international level may hide important regional differences. In 2005, male life expectancy at the age of 50 years in the 25 countries of the EU varied from 21.3 years in Latvia to 30.4 years in Italy16; for women, the variation between countries was 6.1 years. The healthy life expectancy (HLY) varied even more: the range in HLY at age 50 years was 14.5 years in men and 13.7 years in women. Death rates from CAD are generally higher in Central and Eastern Europe than in Northern, Western, and Southern Europe. For example, the death rate for men aged less than 65 years living in Ukraine is 14 times higher than in France, and for women it is 25 times higher. Likewise, Western Europe has generally higher death rates than Southern Europe: for example, in Ireland, the death rate for men aged less than 65 years is 1.6 times higher than in Italy, and for women it is 1.8 times higher. In Figure 4, the age-standardized mortality rates for CHD in the year 2000 are given for populations aged 45 to 74 years in different European countries; the figures vary from 0.65 to 4.61 per 1000, illustrating that there is still a clear North-East to South-West gradient in CHD mortality within Europe.²¹

The Institut des Sciences de la Santé carried out a study examining CHD mortality changes in the EU population in individuals less than 75 years of age between 1990/91 and 2000/02. Age-standardized CHD mortality fell in all countries, but not equally across the EU. CHD mortality declined by almost a half in the Czech Republic, the UK, Ireland, and Finland. Elsewhere, rates fell by about one fifth to one third; the only exceptions were Latvian men and Polish women, in whom the improvements were just over 10%.²²

But even within countries, significant regional variation in CHD mortality has been observed. In Germany, for example, there was found to be an East-West gradient, with a twofold increased risk of dying from CHD in the state with the highest mortality rate compared with the lowest mortality.²³ In Great Britain, a North-South gradient has been observed, with CHD mortality rates being higher in the north.²⁴ In France, the mortality from CHD also shows a North-South gradient, with very low figures in the south-west region.²⁵ In Belgium, large differences in CHD incidence and mortality have been observed, with higher rates in Wallonia compared with Flanders.²⁶ All these regional differences are partly explained by variations in classical risk factors and in socioeconomic factors.

Conclusion

The burden of CHD remains high across Europe and the rest of the world. CHD continues to be the main cause of death and a major cause of morbidity and loss of quality of life. The decline in age-standardized mortality rates and in the incidence of CHD in many countries illustrates the potential for prevention of premature deaths and for prolonging healthy life expectancy. However, one should realize that this will paradoxically increase the prevalence of patients with CHD, especially in old age. This is a challenge for modern cardiology; specific attention needs to be given to the development of guidelines in elderly patients. For policy makers, it is also important to know whether major contributors to morbidity and mortality such as CHD are tracking up or down. A valid and actual description of the epidemic by place, by time, and by personal characteristics is continuously needed to guide and support appropriate health policies. _

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Jeffrey S. BORER, MD
Division of Cardiovascular Medicine, Cardiovascular Translational Research Institute
Howard Gilman Institute for Heart Valve Disease – State University of New York
New York, NY USA

Heart rate:
from risk marker to risk factor
in coronary artery disease

Several clinical/biological “markers” can aid in detection of patients likely to develop clinical evidence of coronary artery disease and its major sequelae. Thesemay also help guide efforts directed at prevention of cardiovascular events. Heart rate is a well-known risk marker in patients with coronary artery disease, and it is an important component in the generation of ischemia in such patients. Experimental data and clinical observations support a role for heart rate in the pathophysiology of atherosclerosis and plaque rupture. A growing body of evidence points to high resting heart rate as being more than simply a risk marker, but in fact, a risk factor, for adverse outcomes in various populations including those with coronary disease, as heart rate reduction now seems to beneficially alter certain outcomes. The relationship between resting heart rate and cardiovascular mortality is strong, graded, and independent of other factors such as blood pressure and physical activity. The results of the recent BEAUTIFUL (morBidity-mortality EvAl- UaTion of the I_f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study underline the importance of heart rate reduction in managing stable coronary disease. Prospective analysis of data from the placebo arm of this study demonstrated that a resting heart rate of ≥70 bpm is a strong independent predictor of clinical outcome. Consistent with these data, ivabradine significantly improved coronary outcomes in patients with a heart rate of ≥70 bpm. Thus, emerging data suggest that heart rate has joined the list of risk factors for coronary artery disease, importantly altering management strategies for affected patients. Heart rate has already appeared in European guidelines for the prevention of cardiovascular events, and should seriously be considered in future guidance documents for patients with coronary artery disease.

Coronary artery disease (CAD) is a highly prevalent condition and has potentially life-threatening consequences. It affects a large proportion of the general population over the age of 60 years, and according to the Framingham Heart Study,¹ the lifetime risk of developing CAD in individuals aged 40 years is 48% in men and 31% in women. CAD thus represents an important public health problem that is both costly for society and responsible for relatively high mortality and morbidity levels in affected patients. Therefore, there is a clear medical need for guidance on efforts directed at preventing disease progression and associated clinical sequelae. Much of our current understanding of risk markers that identify those like- ly to develop clinically evident disease comes from observational studies and randomized trials; additionally, such investigations have further defined those risk markers that can be modified to achieve clinical benefit—so-called “risk factors.”^2,3 The major risk factors for CAD and the first to be identified, aside from sex and age, were total cholesterol, systolic and diastolic blood pressures, smoking, and diabetes. Other less predictive risk factors include obesity, physical inactivity, and a family history of CAD (particularly in young individuals). Among the more recently recognized markers of CAD risk are resting heart rate and the metabolic syndrome. It is the aim of this article to present and assess the accumulating evidence in support of the evolution of heart rate—an easily measured clinical parameter—from risk marker, to risk factor in CAD mortality and morbidity.

Table. Epidemiological studies on the relationship between heart rate and cardiovascular mortality in the general and hypertensive populations.

Difference between risk marker and risk factor

Risk markers and risk factors are both identified from correlations between the presence of the factor and subsequent development of the disease. A risk marker can be considered a risk factor if intervention to modulate this factor also results in a parallel modulation of risk—provided that the analysis demonstrating the risk modulation also accounts for possible confounding factors. For example, systemic arterial hypertension is well established as a risk factor for CAD and its sequelae, and also for stroke,⁴ not only because it identifies patients at risk for cardiovascular events, but because many studies with many different agents have demonstrated that in hypertensive individuals, risk is reduced when blood pressure is reduced.^5-8 The demonstration of the benefits of blood pressure reduction with many different agents is important: some antihypertensives, including the angiotensinconverting enzyme inhibitors ramipril and perindopril, reduce events through pharmacological effects that appear to be in addition to the benefits of the antihypertensive action itself.^5,6 Several criteria have been developed in order to allow one to validate a risk marker as a risk factor, and these are detailed later in this article.

Resting heart rate and prognosis in the general population

Several epidemiological studies support the predictive value of resting heart rate regarding total and cardiovascular mortality (Table).⁹ The Chicago Peoples Gas Company Study (including 1233 men followed for 15 years), the Chicago Western Electric Company Study (including 1899 men followed for 17 years), and the Chicago Heart Association Detection Project (including 5784 men followed for 5 years), reported together in 1980, were among the earliest studies to demonstrate the prognostic importance of resting heart rate for allcause mortality in large populations.⁸ Indeed, multivariate analysis using age, blood pressure, total blood cholesterol, smoking, and body weight as covariates, found heart rate to be an independent predictor both of sudden cardiac death and of noncardiovascular mortality in 2 out of the 3 cohorts studied. A 30-year follow-up of the Framingham study, reported in 1987, demonstrated a significant relationship between heart rate, cardiovascular mortality, coronary heart dis- ease, and sudden coronary death in both men and women.¹⁰ Paralleling these findings, a study of 19 386 “white collar” employees in France followed over a period of 20 years found that resting heart rate was a significant predictor of noncardiovascular mortality in both men and women.¹¹ In men, the risk of cardiovascular death was lowest among those with a heart rate of <60 beats per minute (bpm); in comparison with this group, the relative risks among men with a resting heart rate of 60-80 bpm, 81-100 bpm, and >100 bpm were 1.35, 1.44, and 2.18, respectively (all statistically significant). Cardiovascular deaths were primarily and predominantly due to coronary events, and not to cerebrovascular accidents. In men, the predictive value of heart rate was independent of age, hypertension, total cholesterol, body mass index, smoking status, and exercise activity. In women, heart rate did not influence cardiovascular mortality.

Parallel results were reported from the MATISS Project (Malattie cArdiovascolari aTerosclerotiche, Istituto Superiore di Sanità), which included 2533 men aged 40 to 69 years. With 24 457 subject-years of follow-up, heart rate was found to independently predict total mortality, cardiovascular mortality, and noncardiovascular mortality.¹² In another French cohort study that included 5713 asymptomatic apparently healthy working men aged between 42 and 53 years at study entry, a 23-year follow-up demonstrated a significant association between resting heart rate and both sudden and myocardial infarction–related death.¹³ The study found that compared with a resting heart rate of <60 bpm, a resting heart rate of >75 bpm defined a relative risk of 3.92 for sudden death. A recently published study undertaken in a French population of 5139 healthy men found that resting heart rate and the change in resting heart rate over 5 years were both predictors of death, independent of the conventional risk factors.¹⁴ After adjustments were made for confounding factors including baseline heart rate at rest, and results were compared with subjects with an unchanged heart rate, those whose heart rate decreased during the 5 years had a 14% lower mortality risk (P=0.05), whereas men whose heart rate increased over the 5 years had a 19% higher mortality risk (P<0.012).

Resting heart rate and prognosis in patients with coronary artery disease

Hjalmarson et al¹⁵ demonstrated that in patients with acute myocardial infarction (AMI), inhospital mortality and post-discharge mortality increased with increasing heart rate on admission. Total mortality was 15% for patients whose heart rate on admission ranged between 50 and 60 bpm, 41% for those with a heart rate of >90 bpm, and 48% for a heart rate of >110 bpm. Mortality after hospital discharge up to 1 year was also related to the maximal heart rate observed in the coronary care unit and heart rate at discharge. The prognostic significance of heart rate was also assessed in 8915 patients with AMI in GISSI-2 (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico–2), who were treated with fibrinolytic therapy.¹⁶ Increased heart rate on admission was associated with a progressive increase in hospital mortality (from 7.1% for a heart rate of <60 bpm to 23.4% for a heart rate >100 bpm). In addition, a progressive increase in 6- month mortality was noted with increasing heart rate at discharge (from 0.8% for a heart rate <60 bpm to 14.3% for a heart rate >100 bpm).Tardif and colleagues¹⁷ investigated 24 913 men and women with suspected or proven CAD who were followed for an average of 14.1 years, and found that resting heart rate was an independent risk marker for total and cardiovascular mortality. The prognostic value of heart rate persisted when analysis was adjusted for hypertension, diabetes, and smoking status, as well as for left ventricular ejection fraction and the number of diseased coronary vessels. Patients with a heart rate ≥83 bpm also had a significantly higher risk of hospital admission for cardiovascular causes than those with a heart rate ≤62 bpm (Figure 1).

Figure 1. The risk of death progressively increases with increasing heart rate.
Data are from the Coronary Artery Surgery Study, including 24 913 men and women with suspected or proven coronary artery disease, with 14.7 years of follow-up. Based on data from reference 17. Bpm, beats per minute.

In the INternational VErapamil SR/trandolapril STudy (INVEST), the relationship between resting heart rate at baseline and follow-up and adverse outcomes (all-cause death, nonfatal myocardial infarction, and nonfatal stroke) was evaluated in 22192 patients with hypertension and CAD treated either with verapamil or with atenolol. Resting heart rate was found to be directly associated with adverse events, and heart rate on receiving treatment was even more predictive than baseline heart rate,18 consistent with the concept that heart rate is a risk factor.

The BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) investigators have added substan- tially to current knowledge concerning the prognostic value of heart rate. They carried out a prospective analysis of data from the placebo arm of BEAUTIFUL (comprising a relatively large, well-treated population [n=5438] with stable CAD and left ventricular dysfunction) to assess the association between heart rate and clinical outcome.19 The results showed that compared with a heart rate of 60 to 69 bpm, resting heart rate _70 bpm is a significant predictor of adverse outcome (including mortality and major CAD morbidity) in patients with stable CAD and left ventricular dysfunction. This held true even after results were adjusted for all variables that differed between the two groups at baseline, including â-blocker intake and other background therapy. Compared with those whose heart rate was <70 bpm, those with a heart rate of _70 bpm were 34% more likely to die from cardiovascular causes (hazard ratio [HR], 1.34; 95% confidence interval [CI] 1.10-1.36; P=0.0041), 53% more likely to be hospitalized for new or worsening heart failure (HR, 1.53; 95% CI, 1.25-1.88; P<0.0001), 46% more likely to suffer fatal and nonfatal myocardial infarction (HR, 1.46; 95% CI, 1.11-1.91; P=0.0066) and 38% more likely to undergo coronary revascularization (HR, 1.38; 95% CI, 1.02-1.86; P=0.037) (Figure 2). The BEAUTIFUL placebo data were also analyzed regarding the effect of incremental increases in resting heart rate on cardiovascular outcomes. In fact, for all outcomes, the risk increased with heart rate values >65 bpm. For ischemia-related outcomes (fatal and nonfatal myocardial infarction, revascularization, etc.), risk tended to plateau as heart rate exceeded 70 bpm. By contrast, for heart failure, events continued to increase as heart rate rose. In another analysis in which baseline heart rate was treated as a continuous variable, there were substantial increases in risk with every 5-bpm heart rate incremental increase, and these were highly significant for both hospitalization for heart failure (16%; HR, 1.16; 95% CI, 1.11-1.21; P<0.0001) and cardiovascular death (8%; HR, 1.08; 95% CI, 1.03-1.12; P=0.0005). Though less striking, each 5- bpm increase in heart rate was also associated with an 8% increase in the likelihood of coronary revascularization (HR, 1.08; 95% CI, 1.01-1.16; P=0.034) and a 7% increase in fatal and nonfatal myocardial infarction (HR, 1.07; 95% CI, 1.00- 1.14; P=0.052).

BEAUTIFUL provides the first prospective assessment of the association between resting heart rate and cardiovascular outcomes in patients with stable CAD. The results lend credence to the results of previous studies in the general population and in normotensive and hypertensive CAD patients.9,17,18 This study is also the first clear demonstration that a relatively high resting heart rate places patients at risk for coronary events, even if they are apparently well treated (including with â-blockade) according to current guidelines. Indeed, the majority of subjects in BEAUTIFUL received concomitant â-blocker therapy—87% of patients in the placebo arm received â- blockers, which is a considerably higher percentage than that observed in population surveys in patients with stable CAD. Thus, the results from the placebo arm of BEAUTIFUL underline the potential value of addressing—and reducing— a resting heart rate of _70 bpm in patients with stable CAD.

Figure 2. Elevated heart rate (≥70 beats per minute; bpm) was a predictor of cardiovascular outcomes in the placebo population of
BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).
Adapted from reference 19: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Ltd.

Role of heart rate in the development of
atherosclerosis and coronary events

The most common coronary manifestations of atherosclerosis are stable angina pectoris and acute coronary syndromes. The role of heart rate in the development of myocardial ischemia in patients with stable angina or those suffering from AMI is well known (Figure 3). Increasing heart rate contributes to an imbalance between myocardial oxygen demand and supply, causing both an increase in myocardial oxygen demand and a decrease in coronary blood supply (the latter primarily via a reduction in the duration of diastole, the period during which most myocardial perfusion occurs). Thus, the risk of finding objective evidence of development of myocardial ischemia is related to baseline resting heart rate, with the risk doubled in patients with a baseline heart rate of _90 bpm compared with a heart rate of 60 bpm.20 Experimental evidence supports the role of heart rate in endothelial dysfunction and atherosclerosis progression. Pressure wave–induced vascular stress, sensed by vascular mechanoreceptors that, in turn, trigger a cascade of signaling molecules, alters endothelial responses. Abnormal mechanical stress is thought to directly induce endothelial injury and to increase endothelial permeability to low density lipoprotein particles and circulating inflammatory mediators.21 An increased heart rate may also be directly involved in plaque rupture, resulting in coronary thrombosis,22 presumably by increasing the time during which plaques undergo mechanical perturbation. Based on these considerations, it is reasonable to infer that heart rate reduction may be a key therapeutic strategy in patients with CAD, both to prevent ischemia and to prevent cardiovascular events.

Figure 3. Role of heart rate in the pathophysiology of coronary
artery disease. CV, cardiovascular.

Criteria for validating heart rate as a risk factor

Several criteria are used to assess the validity of epidemiologic associations in CAD.23,24 Plausibility, based on our current understanding of pathophysiology, provides a basis for concluding that a relation is consistent with the associated disease— CAD in this case. Strength is determined by the relative risk of developing an outcome with the factor versus the risk without. Gradation of effect, analogous to a dose-response curve in pharmacology, is defined by the quantitative impact of a change in the magnitude of the factor or the duration of exposure to the factor versus the outcome of interest. The clearer the gradation of effect, the more likely the factor is indeed a beneficially modifiable risk factor. Consistency is the demonstration of an association between the factor and outcome in a variety of populations, for example, cohorts involving various age groups, both sexes, and different ethnic groups. Perhaps most importantly, if the factor is modifiable with currently available strategies, a diminution of the factor should beneficially modify the outcome. In theory, heart rate reduction should reduce mortality, particularly cardiovascular mortality, in patients with CAD, and most especially, those suffering from AMI. Consistent with this hypothesis, in a review of â-blocker trials on AMI, Kjekshus et al25 observed a relationship between reduction in resting heart rate and a reduction in mortality. Furthermore, a recent meta-regression of randomized clinical trials of â-blockers and calcium channel blockers post-AMI strongly suggested that the beneficial effects of these agents are proportionally related to the reduction in resting heart rate.26 A statistically significant relationship was found between reduction in resting heart rate and decreases in cardiac death, all-cause death, sudden death, and recurrence of nonfatal myocardial infarction. This meta-regression suggests that reduction of resting heart rate could be a major determinant of the clinical benefits seen in these trials. This hypothesis was also tested more recently in randomized controlled trials of â-blockers in heart failure caused by left ventricular systolic dysfunction. There was a close relationship between the all-cause annualized mortality rate and heart rate in these studies, and a strong correlation between change in heart rate and change in left ventricular ejection fraction.27 However, â-blockers not only reduce heart rate, but also have several other cardiovascular effects. The novel specific heart rate–lowering agent, ivabradine, therefore provides an opportunity to assess the effects of lowering heart rate without directly altering other aspects of cardiovascular function. In this context, the BEAUTIFUL results have added substantially to our understanding of the role of heart rate reduction in the prevention of coronary events,19,28 as reviewed above. In patients with stable CAD and left ventricular systolic dysfunction who had an elevated heart rate, _70 bpm, ivabradine reduced the relative risk of hospitalization for fatal and nonfatal AMI by 36% (P=0.001) and reduced coronary revascularization by 30% (P=0.016) (Figure 4, page 353).28

Figure 4. Treatment with ivabradine reduces the risk of coronary outcomes in patients with stable coronary artery disease and left ventricular
systolic dysfunction with a resting heart rate 70 beats per minute. RRR, relative risk reduction.
Adapted from reference 27: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

Treatment with ivabradine was also associated with a 22% reduction in the relative risk of a composite end point of hospitalization for fatal and nonfatal AMI and unstable angina pectoris (P=0.023) compared with placebo. These data suggest that heart rate is a risk factor for CAD, and that its reduction may decrease coronary events in this population. Heart rate has already appeared in European guidelines regarding the prevention of cardiovascular events, and should be seriously considered in future guidance documents relating to patients with CAD.

Conclusion

Resting heart rate has been directly related to all-cause mortality, cardiovascular mortality, and development of clinically evident cardiovascular disease in the general population, hypertensive patients, and patients with CAD. These data emphasize the importance of heart rate as a cardiovascular risk factor, particularly among patients with CAD. As a result, heart rate should be measured routinely in daily clinical practice. The results of BEAUTIFUL suggest that treatment with ivabradine in patients with ischemic heart disease and a heart rate _70 bpm may reduce coronary outcomes. Thus, emerging data support the addition of heart rate to the list of risk factors for CAD, potentially importantly altering management strategies for patients with CAD. _

References

1. Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353:89-92.
2. Greenland P, Knoll MD, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003;290:891-897.
3. Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898-904.
4. Miura K, Daviglus ML, Dyer AR, et al. Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: The Chicago Heart Association detection project in industry. Arch Intern Med. 2001;161:1501-1508.
5. Yusuf S, Sleight P, Pogue J, et al; Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
6. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo- controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
7. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:2217- 2225.
8. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112:736-749.
9. Aboyans V, Criqui MH. Can we improve cardiovascular risk prediction beyond risk equations in the physician’s office? J Clin Epidemiol. 2006;59:547-558.
10. Kannel WB, Kannel CE, Paffenbarger R, et al. Heart rate and cardiovascular mortality in the Framingham study. Am Heart J. 1987;113:1489-1494.
11. Ducimetière P, Richard J, Claude JR, et al. Recherche d’autres facteurs de risque des cardiopathies ischemiques. In: INSERM, ed. Les Cardiopathies Ischémiques: Iincidence et Facteurs de Risque. L’Etude Prospective Parisienne. Paris, France: INSERM; 1981:53-120.
12. Seccareccia F, Pannozzo F, Dima F, et al. Heart rate as a predictor of mortality: the MATISS project. Am J Public Health. 2001;91:1258-1263.
13. Jouven X, Empana JP, Schwarz PJ, et al. Heart rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352:1951-1958.
14. Jouven X, Empana JP, Escolano S, et al. Relation of heart rate at rest and longterm (>20 years) death rate in initially healthy middle-aged men. Am J Cardiol. 2009;103:279-283.
15. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.
16. Zuanetti G, Mantini L, Hernandez-Bernal F, et al. Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study. Eur Heart J. 1998;19(suppl F):F19-F26.
17. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
18. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008;29: 1327-1334.
19. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008; 372:817-821.
20. Andrews TC, Fenton T, Toyosaki N, et al; Angina and Silent Ischemia Study Group (ASIS). Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. Circulation. 1993;88:92-100.
21. Giannoglou GD, Chatzizisis YS, Zamboulis C, et al. Elevated heart rate and atherosclerosis: an overview of the pathogenetic mechanisms. Int J Cardiol. 2008;126:302-312.
22. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482.
23. Chatterjee K, Cheitlin MD, Karliner J, et al, eds. Cardiology. An Illustrated Text Reference, II. Philadelphia, PA: JB Lippincott; 1991.
24. Borer JS. Heart rate: from risk marker to risk factor. Eur Heart J Suppl. 2008; 10(suppl F):F2-F6.
25. Kjekshus J. Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial infarction intervention trials. m J Cardiol. 1986;57:43F-49F.
26. Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
27. Flannery G, Gehrig-Mills R, Billah B, et al. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865-869.
28. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left ventricular dysfunction (Beautiful): a randomized, double- blind, placebo-controlled trial. Lancet. 2008;372:807-816.

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by L . R. Padial , Spain

Luis Rodriguez PADIAL MD, PhD, FESC
Cardiac Unit Hospital Virgen de la Salud – Toledo, SPAIN

Stable coronary artery disease (CAD) is an important worldwide health problem. Patients with stable CAD are at significant risk of developing subsequent cardiovascular complications that bear a high mortality; effective preventive measures against such complications are therefore necessary. Control of cardiovascular risk factors constitutes the main tool for improving prognosis in these patients. Key factors in this respect are cholesterol reduction in virtually all patients, and blood pressure reduction when needed. Furthermore, smoking should be avoided in all patients, and diabetic patients should have tight glucose control maintained. It has also been demonstrated that certain drugs (ie, antiplatelet drugs, β-blockers, angiotensin- converting enzyme inhibitors) can further improve the prognosis in some or all patients with stable CAD. Despite all of this, as demonstrated in BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), many patients with stable CAD remain at high risk due to an elevated heart rate, one of the main determinants of myocardial oxygen demand. In such patients with CAD and left ventricular dysfunction, the use of ivabradine on top of state-of-the-art preventive treatment was able to significantly reduce ischemic complications such as myocardial infarction and revascularization, although without affecting heart failure complications. Since many patients with stable CAD remain at risk despite their current treatment because of a high heart rate (over 70 beats per minute), ivabradine can help to further improve their cardiovascular prognosis.

Coronary artery disease (CAD), usually secondary to atherosclerosis, is a leading cause of death and disability in Western societies. Moreover, due to its sharply increasing prevalence in non-Western countries, it will inevitably be a major health problem worldwide in the years to come. Patients with stable CAD have a high risk of developing subsequent cardiovascular events, such as angina pectoris, myocardial infarction, and stroke. The identification and control of major cardiovascular risk factors (ie, hypertension, dyslipidemia, smoking, obesity, inactivity, and diabetes) are two of the main tasks of caregivers for patients with known CAD, as this can potentially reduce subsequent morbidity and mortality in such patients.^1,2 These tasks are usually included under the term “secondary prevention.” Since not all patients comprising the “secondary prevention” category share the same risk, a group of “very high risk” subjects has been defined among those with established CAD, in which even more aggressive control of risk factors, especially lipid levels, has to be pursued. This “very high risk” group includes patients with CAD and multiple risk factors (especially diabetes), severe or poorly controlled risk factors (especially active smoking status), multiple risk factors of the metabolic syndrome (particularly high-density lipoprotein [HDL] cholesterol <40 mg/dL and non-HDL cholesterol ≥130 mg/dL), and those with acute coronary syndromes.³

Furthermore, although secondary prevention usually applies to patients with established CAD, there are some individuals without known CAD whose risk of subsequent cardiovascular events is similar to that observed in patients with CAD.⁴ Such patients, regarded as having “CAD equivalent,” should be managed as aggressively as patients with established CAD. Those with noncoronary atherosclerotic disease, diabetes, chronic kidney disease (serum creatinine >1.5 mg/dL or estimated creatinine clearance rate <60 mL/min per 1.73 m²), and multiple risk factors that confer a 10-year risk larger than 20%, which comprise most metabolic syndrome patients, are among the groups included in the “CAD equivalent” category.

Comprehensive application of all available secondary prevention measures has a very important impact on CAD populations of all ages. In the USA, between 1980 and 2000, the age-adjusted CAD death rate per 100 000 population in men and women between the ages of 25 and 80 years fell from 543 to 267 in men and from 263 to 134 in women. Although several factors played a role in this mortality decrease, it is estimated that half of the reduction was due to the implementation of preventive measures.⁵ Furthermore, in an older population (average age of 80 years) that survived for at least 30 days after a myocardial infarction, a 3% mortality reduction was observed each year from 1995 to 2004, mostly due to the implementation of secondary preventive measures (statins, antiplatelets, etc).⁶ The same has been observed in CAD patients after revascularization.^7,8 Despite this positive trend observed in the last decades, mortality remains high in this population, and so new treatments are needed to further improve prognosis in this high risk population.

Risk factor modification for secondary prevention of CAD will be reviewed herein (Table, page 386), with a special focus on new information regarding control of heart rate in stable CAD patients.

Control of hypertension

Several trials have demonstrated a decrease in morbidity and mortality with reduction of high blood pressure. In a metaanalysis of patients with mild to moderate hypertension, lowering of blood pressure with antihypertensive therapy decreased the rate of stroke by 40% and the rate of CAD by 16%.⁹ There is suggestive evidence that a blood pressure goal of less than 130/80 mm Hg, rather than the goal in the general population of less than 140/90 mm Hg, can improve outcome in patients with CAD, as in patients with diabetes and proteinuric chronic kidney disease.¹⁰

Lifestyle modifications such as moderate reduction in salt intake, weight reduction in obese patients, avoidance of excess alcohol intake—ie, limiting intake to 1 or 2 drinks a day— and regular aerobic exercise are generally recommended. When it comes to the use of antihypertensive drugs, patients with CAD appear to achieve most benefit from blood pressure reduction, but they can obtain further benefit from β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs).¹¹ Since most patients need treatment with two or more drugs to achieve the required reduction in blood pressure, small doses of diuretics and/or calcium channel blockers are frequently needed on top of the initial antihypertensive treatment.¹²

Lipid modification During the last few decades, many randomized trials have shown a reduction in morbidity and mortality with cholesterol reduction, mostly with statins. More recently, several trials have demonstrated a benefit with reduction of low-density lipoprotein (LDL) cholesterol to low levels such as 60-70 mg/dL in high-risk patients.^13,14 The goals for LDL cholesterol levels are thus less than 100 mg/dL in CAD patients¹ and less than 70 mg/dL in “very high risk” CAD patients as previously described.³

Table. Secondary prevention for patients with coronary and other vascular diseases. BMI, body mass index; CKD, chronic kidney disease.

Both dietary modification and drug therapy should be used to obtain these targets, taking into account that drug therapy should not be delayed when the target is unlikely to be obtained early with lifestyle modification only.¹⁵ Given the enormous evidence of morbidity and mortality reduction with statins, these drugs are first-line therapy for all patients with lipid disorders. Other drugs, such as ezetimibe, can be used on top of statins if the target lipid level is not achieved.³ Statins appear to produce benefits beyond their LDL cholesterol– lowering effect; these appear to be acute and to contribute to the clinical benefits observed with these drugs.

Recent evidence has indicated the value of using high sensitivity C reactive protein to detect patients who could benefit from the use of statins to reduce their LDL cholesterol levels; in particular, in patients without known CAD, so-called primary prevention.¹⁶ This useful information may not only further expand the role of statins in cardiovascular prevention, but it could also potentially widen the number of patients without CAD that should be treated more aggressively. Obviously, more studies are warranted in this area. In patients with high levels of triglycerides (more than 200 mg/dL), the target level for non-HDL cholesterol (total cholesterol minus HDL cholesterol) should be less than 130 mg/dL.⁴ Fibrates are especially useful for lowering triglycerides and increasing HDL cholesterol,¹⁷ and are frequently used in association with statins to further reduce LDL cholesterol levels. Niacin can also be helpful in this context.

Blood glucose control in diabetics

Tight blood glucose control is recommended in all diabetic patients given its benefits in the reduction of microvascular and macrovascular cardiovascular complications, not only in the short term but also in the long term.¹⁸ The target level for glycated hemoglobin (HbA1C) recommended in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for patients with diabetes and CAD is less than 7%, which is the same target level advised for diabetics without CAD.¹ A goal of 6.5% or less is recommended in the European Society of Cardiology guidelines.¹⁹ Certain recent findings from clinical trials have been somewhat contradictory with regard to these recommendations. The lack of a significant reduction in cardiovascular disease events with intensive blood glucose control in the clinical trials Action to Control CardiOvascular Risk in Diabetes (ACCORD),²⁰ Action in Diabetes and VAscular disease: Preterax and DiamicroN MR Controlled Evaluation (ADVANCE),²¹ and the Veter- ans Affairs Diabetes Trial (VADT)²² should not lead clinicians to abandon these general recommendations, and the ACC/ AHA has therefore issued a position and scientific statement on intensive blood glucose control and the prevention of cardiovascular events. This states that lowering HbA1C levels to less than 7% in order to reduce microvascular and neuropathic complications in type 1 and type 2 diabetes remains a class I recommendation. A target of less than 7% is also reasonable for reducing the risk of macrovascular complications, a class IIb recommendation, at least until more evidence becomes available.²³

Lifestyle changes

There are some lifestyle changes that have proven benefits in cardiovascular prevention, and these are outlined below.

_ Smoking cessation
Quitting smoking produces a reduction in cardiovascular morbidity and mortality within a matter of months, and allows achievement of a comparable risk status to nonsmokers in 3 to 5 years. Complete smoking cessation as well as avoidance of environmental tobacco smoke should be recommended in all patients with cardiovascular disease or CAD equivalent.²⁴ Caregivers should ask patients about this habit, and advice should be given on the best strategy to stop smoking if necessary.

_ Diet
The low level of cardiovascular mortality in Mediterranean countries has prompted recommendation regarding the Mediterranean diet, low in calories and meat, and rich in vegetables, fruits, olive oil, legumes, and nuts. Several trials have shown its benefits in patients with myocardial infarction.²⁵ Furthermore, diets rich in omega 3 acids, found in fish, should also be recommended in CAD patients, as this has been associated with a reduction in subsequent cardiovascular events in patients with myocardial infarction. Observational studies in healthy adults and randomized trials in patients with established CAD indicate that modest fish oil consumption reduces the risk of CAD death and sudden cardiac death. This is of particular importance in patients with established CAD or at high risk for CAD.^26,27 Fish consumption to achieve an average ingestion of 250 mg/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) should be advised in all patients at risk of cardiovascular disease. When a fish oil supplement is used, it should contain both EPA and DHA; a 1-g daily supplement containing 200 to 800 mg of EPA and DHA is a reasonable option.¹

_ Physical activity
Regular exercise has been associated with a significant reduction (20%) in cardiovascular mortality and a trend toward a reduction in myocardial infarction in secondary prevention.²⁸ The benefits of regular exercise are varied and are mostly due to weight reduction, lipid lowering, blood pressure reduction, and type 2 diabetes mellitus prevention. Symptom-limited exercise testing should be performed in patients with CAD before they engage in an exercise program, and high-risk patients should attend a medically supervised facility in which their symptoms can be detected and treated.

As a general recommendation, most patients should perform exercise for a minimum of 30 minutes per day—preferably daily, but at least five days per week. Exercise should involve moderately intensive aerobic activity (eg, walking), with a target heart rate of 60%-75% of maximal heart rate. An increase in daily lifestyle activities (gardening, climbing stairways, etc) should also be encouraged.

_ Alcohol consumption
People who consume one or two alcoholic drinks daily have a lower mortality risk than those who drink more alcohol than this or drink no alcohol at all. In one pooled estimate involving five prospective cohort studies, total mortality was reduced by 20% in those who drank small to moderate amounts of alcohol compared with nondrinkers.²⁹ So, moderate ingestion of alcohol is recommended for people who drink alcohol regularly.

_ Weight reduction
Obesity, and especially central or abdominal obesity, is associated with an increased risk of cardiovascular disease. Obesity contributes to hypertension, dyslipidemia, and insulin resistance, which could explain the increment in mortality observed. 30 All patients with cardiovascular disease should undergo measurement of waist circumference and calculation of their body mass index. A body mass index of between 18.5 and 24.9 kg/m2 should be obtained.¹ In patients with an increased waist circumference, the metabolic syndrome should be excluded, and if present, it should be treated. Diet, exercise, and drugs should be used to obtain weight reduction, with an initial target of a 10% reduction in body weight.

Metabolic syndrome

Patients with central or abdominal obesity (ie, a waist circumference over 102 cm in men or over 88 cm in women), hypertension, low HDL cholesterol, elevated triglycerides, and elevated glucose levels have insulin resistance and a high risk of cardiovascular disease. Diagnosis of the metabolic syndrome is made when three or more (out of the five) factors are present. All patients with the metabolic syndrome must be treated aggressively in order to reduce the associated cardiovascular risk.

Other therapies

It has been shown that some drugs have added benefits for patients with cardiovascular disease. Some of these must be recommended to all patients unless there is contraindication (aspirin), whereas others (â-blockers, clopidogrel, etc.) should be recommended only in some subsets of patients.

_ Aspirin
Long-term aspirin therapy can reduce myocardial infarction, stroke, and vascular death in patients with different manifestations of prior cardiovascular disease.³¹ A low dose of aspirin (75-150 mg/day) is recommended, since in an indirect comparison, it was found to attain the same antiplatelet effects as a medium dose (150-325 mg/day) but with a lower risk of gastrointestinal bleeding, although this has not been confirmed by other authors.³² Aspirin can reduce subsequent cardiovascular events by approximately 25%.³¹ Current guidelines recommend indefinite treatment with oral aspirin (75-325 mg/day) in patients with cardiovascular disease.

_ β-Blockers
â-Blockers improve survival in patients with myocardial infarction, especially in those with decreased left ventricular systolic function. Therefore, unless contraindicated, β-blockers must be given to all patients with myocardial infarction and left ventricular systolic dysfunction.¹ In the prethrombolysis era, several trials showed a mortality benefit of 10% to 15% in patients treated with β-blockers such as propranolol, metoprolol, or atenolol.³³ The benefits of â-blockade have also been confirmed in the reperfusion era with up to a 40% reduction in mortality in those with ST-segment–elevation or non–ST-segment–elevation myocardial infarction.³⁴

_ ACE inhibitors and angiotensin receptor blockers
ACE inhibitors have been shown to reduce cardiovascular complications in stable CAD patients. Indeed, based on the evidence obtained from HOPE (ramipril) and EUROPA (perindopril),^35,36 ACE inhibitors have become guideline-recommended treatment for stable CAD patients.³⁷ In addition, ACE inhibitors and ARBs reduce cardiovascular morbidity and mortality in patients with myocardial infarction and left ventricular systolic dysfunction.¹ Several ACE inhibitors (for example, enalapril, captopril, ramipril, perindopril) have demonstrated efficacy in such patients. ACE inhibitors are recommended in all myocardial infarction patients who do not fall into the lower risk category defined as those with a normal left ventricular ejection fraction, well-controlled cardiovascular risk factors, and those having undergone a revascularization procedure. For these lower risk patients, ACE inhibitor therapy is also considered reasonable, however. ARBs are recommended in patients who are intolerant to ACE inhibitors and have clinical or radiological signs of heart failure, a left ventricular ejection fraction ≤40%, or hypertension. In patients with diabetes, ACE inhibitors and ARBs are particularly recommended, as they can diminish the speed of renal function deterioration.

Several subgroup analyses of major cardiovascular trials have suggested that ACE inhibitors and ARBs can reduce the rate of new-onset diabetes by about 25%, although a prospective trial aimed at analyzing this issue (DREAM) failed to confirm the observation.³⁸ There is some evidence that in high risk patients, such as those with previous myocardial infarction, certain ACE inhibitors reduce cardiovascular mortality beyond the reduction associated with blood pressure reduction,35,36 although for ARBs, this is a matter of some controversy following publication of the results of two recent large-scale trials, ONTARGET and TRANSCEND.^39,40 ACE inhibitors should be used first line for the treatment of hypertension in patients with cardiovascular disease; in the case of intolerance to ACE inhibitors, ARBs can also be used first line.

_ Clopidogrel and warfarin
Clopidogrel is an antiplatelet drug that can be helpful in patients intolerant to aspirin or those who are resistant to it. Furthermore, some trials have shown that the addition of clopidogrel to aspirin can be useful in some high-risk patients with cardiovascular disease, especially those with acute coronary syndromes or who are within 1 year of these events. Patients with peripheral vascular disease and stroke can also attain benefit from this drug.41 Patients who undergo coronary stent implantation should be on combination therapy for several months—especially patients with drug eluting stents, for whom a period of at least 12 months is recommended. Warfarin is only recommended in rare cases in which the patient cannot tolerate aspirin or clopidogrel or when there are specific indications (atrial fibrillation, thrombus, or embolic events). The international normalized ratio (INR) in these cases should be 2.5-3.5. When associated with aspirin and clopidogrel, the risk of bleeding is increased.⁴²

_ Influenza vaccination
Influenza vaccination is currently recommended in all patients with CAD, as influenza infection can produce some complications in patients with know cardiovascular disease, and some trials have shown a reduction in cardiovascular events in such patients as a result of influenza vaccination.⁴³

New insights: heart rate control with ivabradine

Since the publication of the last guidelines on secondary prevention in CAD, new data has emerged that bears the potential to further improve secondary cardiovascular prevention. In BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction),⁴⁴ investigators aimed to reduce the heart rate of patients with stable CAD already treated with upto- date secondary prevention drugs and strategies, and to investigate the effects of this heart rate reduction.

Elevated heart rate is a risk factor for total and cardiovascular mortality in a wide range of populations including the general population, hypertensives, and CAD patients. Even recently in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, a heart rate higher than 84 beats per minute (bpm) was found to be linked to a 61% increase in the risk of development of new-onset atrial fibrillation in hypertensive patients.⁴⁵

Figure. Ivabradine reduces the risk of hospitalization for fatal or nonfatal acute myocardial infarction in those with a heart rate ≥70 beats per minute.

Heart rate is one of the major determinants of myocardial oxygen consumption, and as a consequence, heart rate reduction is one of the cornerstones of angina prevention and treatment. In a long-term follow-up study in treated stable CAD patients, Diez et al found that those patients with a higher heart rate had significantly higher mortality. In the placebo armof BEAUTIFUL, cardiovascular outcomes were compared in 2693 patients with a heart rate of ≥70 bpm and in 2745 patients with a heart rate <70 bpm. For every 5-bpm increase, there were significant increases in cardiovascular death (8%), admission to hospital for heart failure (16%), and coronary revascularization (8%). However, evidence for the benefit of heart rate reduction in patients with stable CAD was not available until recently, when the results of BEAUTIFUL were published.

In BEAUTIFUL,46 over 10 000 patients with CAD and left ventricular dysfunction were randomized either to ivabradine or placebo on top of standard treatment, which included β-blockers in almost 90% of cases. Despite the fact that ivabradine was unable to show any significant effect on the composite primary end point of the trial due to its lack of effect on heart failure events—the major determinants of morbidity and mortality in this high-risk population—several important conclusions can be drawn from this trial. First, in the placebo arm, a significant increase in risk was observed in patients whose heart rate remained higher than 70 bpm, which helped establish a clinical target for the treatment of these patients. Second, in the subset of patients with a heart rate β70 bpm who received treatment with ivabradine, a significant reduction in ischemic events was observed (Figure). Thus ivabradine is an anti-ischemic drug able to improve prognosis in this high-risk stable CAD population.

Obviously, this information strengthens the role of ivabradine, although we will have to wait for the next set of new guidelines to see how this is reflected in its placement within the guidelines. For the time being, I think that this new information tells us that patients with CAD and left ventricular dysfunction whose heart rate is above 70 bpm appear to obtain some clinical benefit when their heart rate is decreased with ivabradine on top of β-blockers; they should therefore probably also be treated with ivabradine to reduce ischemic events when the dose of β-blocker cannot be increased further. Given that in BEAUTIFUL the benefits were mainly driven by coronary events and not heart failure complications, it may be reasonable to extrapolate these results to all patients with CAD until further information is gathered.

Conclusion

Despite the fact that numerous measures can be taken to decrease the mortality and morbidity of patients with established CAD or those at high risk of developing it, the major problem currently stems from the lack of application of these measures in a large number of patients. In the Euro Heart Survey, only a minority of patients is currently receiving treatment and achieving the recommended targets.⁴⁷ It is thus necessary to take steps to improve application of these already established measures and to further expand our knowledge of the subject with new scientific information. Otherwise, the global burden of cardiovascular disease will continue to rise. _

References

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2. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J. 2007;28:2375-2414.
3. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
4. National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Circulation. 2002;106:3143-3421.
5. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in US deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
6. Setoguchi S, Glynn RJ, Avorn J, Mittleman MA, Levin R, Winkelmayer WC. Improvements in long-term mortality after myocardial infarction and increased use of cardiovascular drugs after discharge: a 10-year trend analysis. J Am Coll Cardiol. 2008;51:1247-1254.
7. Goyal A, Alexander JH, Hafley GE, et al; PREVENT IV Investigators. Outcomes associated with the use of secondary prevention medications following coronary artery bypass graft surgery. Ann Thor Surg. 2007;83:993-1001.
8. Mehta RH, Bhatt DL, Seteg G, et al. Modifiable risk factors control and its relationship with 1 year outcomes after coronary artery bypass surgery: insights from the REACH registry. Eur Heart J. 2008;29:3052-3060.
9. Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med. 1993;153:578-581.
10. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treat ment of High Blood Pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
11. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115:2761-2788.
12. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28:1462-1536.
13. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350:1495-1504.
14. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352: 1425-1435.
15. Grundy SM, Balady GJ, Criqui MH, et al. When to start cholesterol-lowering therapy in patients with coronary heart disease. A statement for healthcare professionals from the American Heart Association Task Force on Risk Reduction. Circulation. 1997;95:1683-1685.
16. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med. 2008;359:2195-2207.
17. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.
18. Holman RR, Paul SJ, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008; 359:1565-1576.
19. Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular disease: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association of the Study of Diabetes (EASD). Eur Heart J. 2007; 28:88-136.
20. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: 2545-2559.
21. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: 2560-2572.
22. DuckworthW, Abraira C,Mortiz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129-139.
23. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation. 2009;119:351-357.
24. Antman EM, Hand M, Armstrong PW, et al; Canadian Cardiovascular Society; American Academy of Family Physicians; American College of Cardiology; American Heart Association. 2007 focused update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51:977.
25. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-785.
26. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.
27. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84:5-17.
28. Clark AM, Hartling L, Vandermeer B, McAlister FA. Meta-analysis: secondary prevention programs for patients with coronary artery disease. Ann Intern Med. 2005;143:659-672.
29. Iestra JA, Kromhout D, van der Schouw YT, Grobbee DE, Boshuizen HC, van Staveren WA. Effect size estimates of lifestyle and dietary changes on all-cause mortality in coronary artery disease patients: a systematic review. Circulation. 2005;112:924-934.
30. Krauss RM, Winston M, Fletcher BJ, Grundy SM. Obesity: impact on cardiovascular disease. Circulation. 1998;98:1472-1476.
31. Antithrombotic Trialists’ Collaboration. Collaborativemeta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
32. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119:624-638.
33. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.
34. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730-1737.
35. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
36. Fox KM; European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
37. Fox K, Garcia MA, Ardissino D, et al; Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. ESC Committee for Practice Guidelines. Guidelines on the management of stable angina pectoris: executive summary. Eur Heart J. 2006;27:1341-1381.
38. Bosch J, Yusuf S, Gerstein HC, et al; DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-1562.
39. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.
40. TRANSCEND Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensinconverting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372: 1174-1183.
41. CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348: 1329-1339.
42. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167:117-124.
43. Naghavi M, Barlas Z, Siadaty S, et al. Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation. 2000;102:3039-3045.
44. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
45. Okin PM, Wachtell K, Kjeldsen SE, et al. Incidence of atrial fibrillation in relation to changing heart rate over time in hypertensive patients: the LIFE study. Circ Arrhythmia Electrophysiol. 2008;1:337-343.
46. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
47. Daly C, Clemens F, Lopez-Sendon JL, et al. The impact of guideline compliant medical therapy on clinical outcome in patients with stable angina: findings from the Euro Heart Survey of stable angina. Eur Heart J. 2006;27:1298-1304.

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To what extent has monitoring of heart rate reduction in your coronary patients become part of your daily practice?

1. M. Al-Anazi, Saudi Arabia
2. E. Alegria, Spain
3. P. Brugada and L. Capulzini, Belgium
4. A. M. Dart, Australia
5. L. M. M. Gonçalves, Portugal
6. B. Gorenek, Turkey
7. J. A. Kragten, The Netherlands
8. G. M. C. Rosano and C. Vitale, Italy
9. U. Thadani, USA
1. M. Al-Anazi, Saudi Arabia

1. M. Al-Anazi, Saudi Arabia

Menwar AL-ANAZI, MD
Director of Adult Cardiology Prince Sultan Cardiac Center – Riyadh, SAUDI ARABIA
(e-mail: anazimd@yahoo.com)

Cardiovascular practice in theMiddle East has, over the last two decades, made great leaps in terms of both quality and access. Its greatest challenge is diabetic atherosclerosis. Angina accounts for over 40% of outpatient clinic volume and despite expensive polypharmacy many such patients remain symptomatic.

Table. Demographic correlates (%) of heart rate (HR).
Bpm, beats per minute.

Recent epidemiologic studies have confirmed that resting heart rate is an independent predictor of cardiovascular and all-cause mortality in both sexes with and without documented cardiovascular disease. A relatively high heart rate accelerates the progression of coronary atherosclerosis, increases the incidence of myocardial ischemia and ventricular arrhythmia, and impairs left ventricular function. Various studies have documented a continuous increase in risk with heart rates above 60 beats per minute (bpm). Given this evidence of the role played by heart rate, it is not surprising that a number of observational studies should have confirmed the benefits of heart rate reduction. Clinical trial data suggest that heart rate reduction itself is an important mechanism of benefit of heart rate–lowering drugs used after acute myocardial infarction, in chronic heart failure, and in stable angina. An optimal heart rate may be difficult to determine for a given individual, but it seems desirable to maintain resting heart rate substantially below the traditionally defined tachycardia threshold of 90 or 100 bpm. (Table). This applied equally to patients already treated with other heart rate–lowering agents. Linear regression identified various predictors of heart rate uncontrollability, including previous hospitalization for congestive heart failure, systolic and diastolic blood pressure, age, severity of angina, and angiographic coronary artery disease._

Despite the availability of β-blockers and calcium channel blockers, we had always suspected that heart rates in our patients with angina or heart failure were suboptimal. To test this suspicion, in July-August 2007 we performed a multicenter cross-sectional study of resting heart rate, measured by palpation, in an outpatient population with stable coronary artery disease and/or heart failure selected by cluster sampling, and assessed the association between resting heart rate and ongoing therapeutic management strategies for cardiovascular events.

The findings consolidated our previous impression that uncontrolled heart rate is very common in this important outpatient cardiology population

Stable patients with coronary artery disease and/or congestive heart failure receiving guideline-recommended treatment continue to exhibit inadequate control of resting heart rate. This observation offers an undoubted window of opportunity for considering recent advances in heart rate modulation such as I_f inhibitors.

Further reading

1. Palatini P, Benetos A, Julius S. Impact of increased heart rate on clinical outcomes in hypertension: implications of antihypertensive drug therapy. Drugs. 2006;66:133-144.
2. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
3. Eagle KA, Lim MG, Dabbous OH. A validated prediction model for all forms of acute coronary syndrome estimating the risk of 6-month post discharge death in an international registry. JAMA. 2004;291:2727-2733.
4. Levine H. Resting heart rate and life expectancy. J Am Coll Cardiol. 1997;30: 1104-1106.
5. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.

2. E. Alegria, Spain

Eduardo ALEGRIA, MD, DPhil
Department of Cardiology University Clinic of Navarra PO Box 4209
Pamplona 31080 SPAIN
(e-mail: e.alegria.cardiologia@gmail.com)

Heart rate (HR), blood pressure, temperature, and respiratory rate are traditionally considered “vital signs” in the clinical history. High blood pressure was upgraded to “risk factor” status decades ago, and has now been joined by elevated HR as a potential therapeutic target in its own right.¹ Resting HR is a known independent predictor of outcome in cardiovascular patients² and the general population.³ Clinical trial data suggest that HR reduction is the principal mechanism of β-blocker benefit. The pathophysiological explanation is that a fast HR reflects high sympathetic tone and favors coronary atherosclerosis, myocardial ischemia, cardiac hypertrophy, and ventricular arrhythmias.¹ Nevertheless, this has not translated fully into the management of coronary disease. Although most doctors intuitively consider faster HR as an ominous prognostic sign, and take a slow HR to indicate a lesser likelihood of angina and/or a correct β-blocker dosage, few manage HR as a risk factor on a par with cholesterol, blood pressure, etc, checking it regularly, titrating specific treatment, and monitoring long-term response. Yet HR is simplicity itself to measure, from the pulse or electrocardiogram, and is available at every visit._

This simple and powerful prognostic index has not yet entered clinical routine mainly because of the difficulty in defining optimal HR in a given individual. Recent subanalysis of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventric- ULar dysfunction) in patients with stable coronary disease, left ventricular dysfunction, and excellent evidence-based background therapy showed that in its own right, an initial HR ≥70 beats per minute (bpm)—irrespective of cause, treatment, or clinical situation—markedly increases the risk of cardiovascular complications, whether related to myocardial ischemia or heart failure progression.²

BEAUTIFUL showed how the HR risk factor can be effectively prevented with ivabradine,⁴ a drug that specifically lowers HR by inhibiting the f-channel controlling sinus node discharge.⁵ In 5392 patients with initial HR ≥4

The two goals in treating coronary disease are to relieve angina and prevent acute complications. Antianginal drugs and revascularization achieve the first goal; for the second, several evidence-based cardioprotective measures are available: diet and weight control, exercise, antiplatelet therapy, statins, and adrenergic and angiotensin inhibitors. As a proven antianginal6 that protects against the complications of cardiac ischemia in patients with elevated HR, ivabradine helps to achieve both goals.

More specific comments elicited by this Controversial Question include: (i) persistent reluctance about accepting HR as a risk factor and therapeutic target is due to inertia over translating clinical trial results into practice; (ii) elevated HR should be considered a risk factor in its own right and not just an indicator of stress or inadequate β-blocker dosage; (iii) HR should be measured regularly, treated if elevated, and monitored in follow-up visits; and (iv) ivabradine should be upgraded from a second-line antianginal to an evidence-based treatment for preventing ischemic events in coronary patients with basal HR ≥70 bpm.

Personally, I record HR in every inpatient and outpatient, but the BEAUTIFUL results have encouraged me to check this prognostic parameter more strictly still and keep it as low as possible in my coronary patients.

References

1. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830.
2. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
3. Kannel WB, Kannel C, Paffenbarger RS, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494.
4. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
5. DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate. Drugs. 2007;67(suppl 2):15-24.
6. Tardif J-C, Ponikowski P, Kahan T; ASSOCIATE Study Investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.

3. P. Brugada and L. Capulzini, Belgium

Pedro BRUGADA, MD
Lucio CAPULZINI, MD
Corresponding author:
Head, Heart Rhythm Management Centre Cardiovascular Centre
Free University of Brussels (UZ Brussels) VUB – Laabeeklaan 101 – 1090 Brussels, BELGIUM
(e-mail: pedro@brugada.org)

It is no secret that the pulse has held a major role in the history of medicine. With a little effort we can imagine a relationship between the fantastic descriptions of the pulse from the past and the scientific data from recent clinical trials. Ancient Chinese and Indian medicine assigned great emphasis to study of the pulse. Even today, Tibetan doctors consider analysis of the pulse the first and essential step in approaching a disease, with questions to the patient as only a second step. Well into the 18th century many European universities had chairs entitled De pulsibus et urinis, testifying to the fact that clinical evidence derived from “flowing blood” was increasingly associated with disease of the heart and vessels and with apparently unrelated organs as well.

In the last two decades, epidemiological studies with longterm follow-up have addressed the importance of heart rate (HR) in healthy humans. The association between resting HR and all-cause and cardiovascular mortality is observed in hypertension, metabolic syndrome, and coronary artery disease (CAD). Moreover, after adjusting for other atherosclerosis risk factors, an independent association between baseline HR and all-cause and/or cardiovascular mortality applies in both sexes, especially in subjects with previous myocardial infarction and/or heart failure. Yet elevated HR has remained a neglected cardiovascular risk factor. Only now is it being considered an essential noninvasive index of prognostic stratification in postmyocardial infarction and heart failure.

Elevated HR plays a major role in CAD, not only as a trigger of ischemic episodes but also as a significant predictor of cardiovascular morbidity and mortality. HR is a primary determinant of myocardial oxygen demand and may also affect myocardial perfusion. This mechanism is the primary basis for the anti-ischemic and antianginal effects of heart rate–lowering drugs. HR lowering also increases coronary blood flow, hence myocardial oxygen supply, mitigating ischemia by increasing diastolic perfusion time. In theory, the disruption of atherosclerotic plaques is partly due to mechanical perturbation of the plaque by the foreshortening and twisting of large epicardial arteries during systole, which is diminished by HR lowering. In agreement with many epidemiological studies, substantially increased risk is observed at lowish heart rates of 70-80 beats per minute (bpm). Several trials have retrospectively shown that reduced heart rate accounts for the benefits of β-blockers and nondihydropyridine calcium channel blockers in CAD and heart failure. BEAUTIFUL (morBiditymortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) and its subanalyses point in the same direction: HR reduction on ivabradine improved coronary outcome in stable CAD patients with HR ≥70 bpm, even on top of best-practice therapy.

Thus, assuming a linear relationship between resting HR and clinical outcome in CAD, we can argue that “slower is better,” although a specific target rate beyond which further HR reduction should be considered unwarranted has still to be defined.

In summary, the evidence indicates that resting HR is a strong independent predictor of cardiovascular morbidity and mortality in CAD. We cannot therefore afford to ignore HR monitoring in our day-to-day management of such patients. The pulse is one of the simplest parameters to measure, with even a single casual value being a strong predictor of events if based on good number of cardiac cycles. In addition, in ivabradine, a novel selective agent that selectively inhibits the If pacemaker current in the sinoatrial node, we have an agent that makes HR lowering a readily attainable pharmacological target in CAD patients, even when cotreated or with the classical contraindications to β-blockers and/or calcium channel antagonists such as atrioventricular conduction disturbances, bronchial spasm, and severe peripheral arterial disease. _

4. A. M. Dart, Australia

Anthony M. DART, BA, BM, BCh, FRACP, FRCP, DPhil
Director of Cardiovascular Medicine at the Alfred Hospital & Associate Director of Baker IDI Research Institute Cardiovascular Medicine Services (Heart Centre)
The Alfred Hospital, 3rd Floor, Philip Block Commercial Road – Melbourne Victoria 3004, AUSTRALIA
(e-mail: a.dart@alfred.org.au)

Epidemiological studies have long demonstrated an association between resting heart rate and future cardiovascular events.¹ The association does not depend on the presence of overt cardiovascular disease at the time of initial heart rate measurement and is frequently independent of other prognostic factors. It is stronger formen than for women and particularly strong for sudden cardiac death._

Since the response to any drug is individual, monitoring heart rate response to drugs with rate reduction as their major or one of their major effects offers an easy way to assess drug efficacy in an individual. Finally, although the evidence suggests that rate reduction benefits all patients at risk of cardiovascular disease, it is strongest for those with rates ≥70 bpm, as observed in BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).⁵ This requires further evaluation and consideration of issues such as which heart rate to measure (basal, mean 24-hour, peak exercise, recovery exercise), whether the evidence is equally applicable to women, and the fact that existing information relates to sinus rhythm. The availability of drugs such as ivabradine that lower heart rate as their principal pharmacodynamic effect offers the exciting potential of definitive answers to many outstanding questions regarding the role of rate reduction in cardiological practice.⁶

References

1. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494.
2. Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post–myocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
3. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
4. Tardiff JC, Ponikowski P, Kahan T. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
5. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
6. Hall AS, Palmer S. The heart rate hypothesis: ready to be tested. Heart. 2008; 94:561-565.

5. L. M. M. Gonçalves, Portugal

Lino M. M. GONÇALVES, MD
Cardiology Department – Coimbra University Hospital – Coimbra, Avenue Bissaya Barreto – 3000-075 Lisbon PORTUGAL
(e-mail: goncalv@ci.uc.pt)

Since the beginning of time, man has viewed the characteristics of the pulse as pointers to health, disease, and death. Ancient Chinese doctors were responsible for the first written reference to the pulse as a diagnostic tool in around 500 BC. Indeed it was the single most important tool at their disposal. Patients would extend their arm through a bedside curtain for the physician to determine the symptoms, diagnosis, prognosis, and proper treatment by intensive palpation of the pulse. Literally hundreds of possible characteristics were obtainable, since the pulse had three distinct divisions, each associated with a specific organ, and each division had a separate quality, of which there were dozens of varieties. Examination even took into consideration the hour, day, and season of the year. It was thus hardly surprising that the Muo-Ching textbook should have devoted its 10 volumes exclusively to details of the pulse.¹_