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



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
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 If 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._

In treating coronary artery disease, the guiding principle is to rematch the myocardial oxygen supply with demand. Supply can be improved by revascularization, percutaneously, surgically, or potentially by angiogenic therapeutic agents. Myocardial oxygen demand can be effectively reduced by reductions in heart rate, contractility, and afterload. A strong positive association between heart rate and myocardial oxygen consumption is well recognized. Thus lowering heart rate is a logical goal of angina treatment.

A third reason compelling cardiologists to take note of heart rate is the evidence that the reduction in clinical events achieved by rate-lowering agents in coronary artery disease, particularly after infarction, and in heart failure, is proportional to the degree of rate reduction.2,3

So how does and how should the expanded information about heart rate and cardiovascular disease influence cardiologists’ practice today? Clearly, and least controversially, rate-lowering medication is indicated for the control of symptomatic coronary artery disease. The benefit of anti-ischemic therapy is unlikely to be optimal without adequate heart rate lowering. Generally speaking, a resting rate >70 beats per minute (bpm) requires rate-lowering therapy, assuming it is well tolerated. A less used but probably preferable approach is to assess the exercise heart rate, since at least with β-blockers, the rate-limiting effect during exercise is more prominent than rate lowering at rest. In addition, it is of course exercise that tests the antianginal efficacy of such medication.

Adequate heart rate control by a single agent may be impossible and require additional agents. The recent ASSOCIATE study (Antianginal efficacy and Safety of the aSsociation Of the If Current inhibitor IvabrAdine with a beTa-blockEr) showed that additional blockade of the If current with ivabradine was effective in patients with chronic stable angina already receiving β-blockers.4 Although not explicitly tested, the use of ratelowering agents to improve prognosis after myocardial infarction may increase the pressure on cardiologists to achieve adequate rate reduction.2 The evidence is perhaps less compelling in heart failure, which therapeutically is also somewhat more complex, but there are some grounds at least for assessing heart rate response in this group too.

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_

Many studies have described the major prognostic impact of heart rate. For example, the Coronary Artery Surgery Study (CASS) of 24 913 patients with suspected or proven coronary artery disease showed an association between heart rate exceeding 83 beats per minute and increased cardiovascular mortality.2 Similarly, the more recently published INternational VErapamil SR-trandolapril STudy (INVEST) in 22 573 patients with coronary artery disease and hypertension found an association between heart rate exceeding >75 beats per minute and increased cardiovascular events.3

Ivabradine is the first drug to show a specific impact on heart rate thanks to a unique mechanism of action: inhibition of the sinus node If current. It has recently been shown to reduce angina frequency and increase total exercise duration and time to 1-mm ST-segment depression in stable coronary artery disease.4,5 In addition, in stable coronary artery disease and left ventricular systolic dysfunction, it was found to lower the incidence of cardiovascular events in the patient subgroup with heart rates of 70 beats per minute or over.6

Evaluation of the pulse has thus been used for thousands of years in the evaluation of patients. Perhaps denigrated as a clinical parameter in the modern era on the grounds of its sheer accessibility and simplicity, we now have incontrovertible epidemiological evidence that heart rate is an important prognostic factor, in particular when it exceeds 70 beats per minute. Ivabradine modulates heart rate in a specific way that accounts for its compatibility with a wide range of standard anti-ischemic therapies. It is thus becoming established as a useful addition to the pharmaceutical armamentarium, providing positive prognostic impact in patients with stable coronary disease and left ventricular systolic dysfunction. The challenge this question raises for cardiologists in 2009 is therefore: have you incorporated themonitoring and, as appropriate, themodulation of heart rate into your day-to-day management of coronary patients?/em

References

1. Lyons AS, Petrucelli RJ. Medicine: An Illustrated History. New York, NY: Abradale/ Abrams; 1987.
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. 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.
4. Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108:387-396.
5. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and anti-ischemic effect of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
6. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomized, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.

6. B. Gorenek, Turkey


Bulent GORENEK, MD, FESC, FACC
Eskisehir Osmangazi University – Cardiology Department – Eskisehir, TURKEY
(e-mail: bulent@gorenek.com)

Relieving the symptoms of angina and improving quality of life and functional status are the key goals in managing patients with coronary artery disease. But as well as looking after the blood pressure and cholesterol levels of their coronary patients, physicians should also monitor their heart rates. There are many reasons for doing so. First, we know heart rate to be one of the most important determinants of myocardial oxygen demand: a high heart rate induces or exacerbates myocardial ischemia because it increases myocardial oxygen demand at the same time as it decreases myocardial perfusion, in the latter case by shortening the duration of diastole. Second, there is an association between reduced heart rate and the growth of collateral vessels in coronary patients. The third reason is that resting and peak exercise heart rate may be predictive of cardiovascular and coronary mortality. For these reasons, reducing the heart rate is becoming an increasingly recognized therapeutic goal in its own right. In our own department, heart rate reduction has been a therapeutic goal in our routine management of angina for many years.

Subanalysis of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction)1 demonstrated that elevated heart rate is a strong independent risk factor in patients with coronary artery disease and left ventricular dysfunction, even in those receiving best-practice background treatment, including with β-blockers. These results extend those of previous observations to a wide range of coronary events such as admission to hospital for fatal and nonfatal myocardial infarction, as well as coronary revascularization. They suggest that coronary patients with a heart rate above 70 beats per minute, who form the majority of the coronary population in clinical practice, are at excess risk of all cardiovascular events and death. Hence the importance of heart ratemonitoring and, as appropriate, modulation in the management of coronary artery disease.

Although resting heart rate independently predicts coronary events in men, the evidence to date suggests that this relationship is weaker or absent in women. However, according to a recently published study, women with a resting heart rate exceeding 76 beats per minute are 1.6 times more likely to develop cardiovascular events; the association is reported to be stronger in younger postmenopausal women.2 These women have higher levels of body weight, blood pressure, and cholesterol. Women with the highest heart rates were also more likely to develop diabetes, smoke, and suffer from depression. In other words, a higher heart rate is beginning to appear a bona fide risk factor for cardiovascular disease in women.

Heart rate should be assessed as a prognostic marker and as a guide to optimal medical treatment in men and also in women. Now that recent clinical trials have clearly shown both the importance of higher heart rates and the benefits of heart rate reduction, we should use heart rate reduction strategies in our daily practice more than in the past. Patients with stable angina, a low ejection fraction, and an elevated heart rate are the best candidates for combined heart rate reduction strategies. However, we need new data and evidence to generalize this recommendation to all coronary patients. _

References

1. 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.
2. Hsia J, Larson JC, Ockene JK, et al; Women’s Health Initiative Research Group. Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study. BMJ. 2009;338:b219.

7. J. A. Kragten, The Netherlands


Johannes A. KRAGTEN, MD, PhD, FESC, FACC
Department of Cardiology Atrium Medical Centre Heerlen Henri Dunantstraat 5
6419 PC Heerlen – THE NETHERLANDS
(e-mail: j.a.kragten@wcnnet.nl)

In patients with symptomatic coronary artery disease, heart rate has yet to become an established treatment target in daily cardiology practice, unless clinical signs, symptoms, and consequences of supraventricular or ventricular tachycardia are present. Heart rate reduction is rarely considered in asymptomatic patients with sinus rhythm of 80 beats per minute (bpm). Currently we often fail to take slightly elevated heart rate into consideration when evaluating our patients in a clinical setting. Yet we act appropriately when the issue is made explicit, as shown by the responses to two simple scenarios that I present in my lectures. In the first, I invite students to choose which of three cyclists, with resting heart rates of 60, 80, and 100 bpm, respectively, is most likely to win a race to the summit of Mont Ventoux. The cyclist with the lowest resting heart rate is invariably chosen. The second scenario asks which of three patients in the emergency room, with heart rates of 60, 80, and 100 bpm, respectively, requires the most immediate medical care. The patient with the highest heart rate is always chosen.

Studies showing a relationship between heart rate and prognosis are already some three decades old. The strong relationship applies in healthy subjects as well as in patients. More recent data show an association between elevated resting heart rate and increased cardiovascular mortality and overall mortality. Careful statistical analysis has shown the association to be independent of other risk factors and not merely an epiphenomenon caused, for instance, by underlying disease that elevates heart rate.

BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventric- ULar dysfunction) was the first study to establish this relationship prospectively, showing an elevated resting heart rate ≥70 bpm to be an independent risk factor for several major cardiovascular events. The explanation for its mode of action is simple: a slower heart rate requires less energy in systole and allows longer for recovery.

How should these results impact our daily practice? Optimal β-blocker treatment is currently defined by a resting heart rate of 60 bpm. However, β-blockers also have other valuable autonomous effects. Does this make heart rate reduction less important? Selective (or pure) heart rate reduction by ivabradine only reduces the heart rate. It has no effects on myocardial contractility, blood pressure, or the central nervous system. Thus any clinical benefit for the patient is due to heart rate reduction per se.

BEAUTIFUL reported a neutral effect on the primary composite end point. Most end points were heart failure–driven in this patient group with a left ventricular ejection fraction of 0.32. Other major factors uninfluenced by pure heart rate reduction determine prognosis in such patients.When coronary end points are evaluated in patients at risk (resting heart rate ≥70 bpm), ivabradine reduces both myocardial infarction and coronary revascularization. This makes elevated heart rate a key therapeutic target in coronary patients.

The study results did not answer all questions. We should aim for lower heart rate in our patients. This is poorly tolerated using β-blockers alone those advocating such therapy should try it for themselves! In medicine it takes time to establish and win acceptance for a new clinical treatment in daily practice. It took over 15 years to bring angiotensin-converting enzyme inhibition into the routine management of heart failure patients. Hopefully the concept of pure heart rate reduction will take less time as the upcoming study data become available.

8. G. M. C. Rosano and C. Vitale, Italy


Giuseppe M. C. ROSANO, MD, PhD
Cristiana VITALE, MD, PhD
Corresponding author:
Centre for Clinical & Basic Research – IRCCS San Raffaele Roma – Rome, ITALY
(e-mail: giuseppe.rosano@gmail.com)

Although the importance of resting heart rate as an independent predictor of cardiovascular morbidity and mortality is not yet generally perceived, strong evidence supports its role not only in coronary artery disease, but also in patients with cardiovascular risk factors and heart failure, and in the general population. An elevated heart rate does not simply favor the progression of atherosclerosis and development of cardiovascular disease and clinical events; heart rate lowering also correlates with clinical benefit. Pathophysiological studies have shown that elevated resting heart rate is directly and independently related to the extent and progression of atherosclerosis via several mechanisms. High heart rate increases the amplitude and frequency of tensile stress on the arterial wall, prolongs coronary endothelial exposure to systolic low and oscillatory shear stress, favors endothelial dysfunction, and increases pulsatile arterial load on the heart. Not only does it promote atherosclerosis, it also accelerates weakening of the fibrous cap, ultimately increasing the risk of plaque rupture and acute coronary events. Elevated heart rate is common in diabetes, altered glucose metabolism, and metabolic syndrome. Since most patients with cardiovascular risk factors and/or cardiovascular disease have different degrees of altered glucose and insulin metabolism, elevated heart rate is often associated with a shift from glucose to free fatty acid oxidation, which in turn further reduces myocardial energy production. Thus elevated heart rate impacts the cardiovascular system via dual effects on hemodynamics and cardiac metabolism.

The need to control heart rate became evident after the Coronary Artery Surgery Study (CASS) showed that higher heart rate was associated with poorer outcome in both sexes. The International Study of Infarct Survival–1 (ISIS-1) found a significant gain in survival from heart rate reduction in the acute myocardial infarction setting. Thereafter β-blockers became the mainstay of coronary treatment. Since the late 1980s, physicians treating coronary artery disease, in particular those trained in Europe, have viewed a low heart rate as essential (the emphasis has been lower across the Atlantic). Physicians became used to using β-blockers without intrinsic sympathomimetic activity, adjusting the dose to a target heart rate <60 beats per minute (bpm). When newer β-blockers came onto the market, the next generation of physicians tended to regard the low heart rate issue as less important.

The therapeutic transformation recently brought by ivabradine has reinstated heart rate control as a therapeutic target and reminded physicians of the prognostic impact of an elevated rate. BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) confirmed that coronary patients with left ventricular dysfunction and heart rate β70 bpm are at significantly greater risk of cardiovascular death and hospitalization for fatal and nonfatal myocardial infarction, heart failure, and coronary revascularization. It also showed an association with significant benefit on coronary end points resulting from heart rate reduction with ivabradine in patients with rates ≥70 bpm. This is extremely important as no current anti-ischemic agent has ever been shown to reduce coronary end points. More recently, ivabradine has proven highly effective alone or in combination with β-blockers for controlling myocardial ischemia.

The strong evidence that elevated heart rate has a direct and independent role as a prognostic factor in cardiovascular disease highlights the need for rate control in all patients at cardiovascular risk. Heart rate monitoring and modulation should therefore feature more prominently than ever in our management of these patients.

Further reading

1. Reil JC, Böhm M. BEAUTIFUL results—the slower, the better? Lancet. 2008; 372:779-780.
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. 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.
4. Tardif JC. Ivabradine: I(f) inhibition in the management of stable angina pectoris and other cardiovascular diseases. Drugs Today (Barc). 2008;44:171-181.
5. Diaz A, Tardif JC. Heart rate slowing versus other pharmacological antianginal strategies. Adv Cardiol. 2006;43:65-78.
6. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation. 1982;66:562-568.

9. U. Thadani, USA


Udho THADANI, MD, MRCP, FRCPC, FACC, FAHA
Professor Emeritus (Active) of Medicine – University of Oklahoma Health Sciences Center – Cardiovascular Section, 920 SL Young, WP 34120
Oklahoma City, Oklahoma 73104 USA
(e-mail: udho-thadani@ouhsc.edu)

Epidemiological data suggest a strong association between adverse cardiac outcomes, including increased mortality, and elevated heart rate (HR) in coronary artery disease (CAD) patients and those with ischemic cardiomyopathy due to reduced left ventricular (LV) systolic function.1,2 β-Blockers reduce cardiac mortality and morbidity in patients with acute myocardial infarction (MI), unstable angina, and dilated cardiomyopathy. It has been proposed that the HRreducing effect of β-blockers is responsible for improved clinical outcomes in these patients.

Substantial data show that in patients with chronic stable angina, HR-lowering drugs such as β-blockers and the selective If current inhibitor, ivabradine, increase angina-free walking time and reduce angina frequency during daily activities and exercise-induced myocardial ischemia.3,4 Further improvement in exercise duration and reduction of exercise-induced myocardial ischemia was recently reported when ivabradine was added to atenolol.5 However, no trials have studied the effects of these HR-lowering drugs in monotherapy on mortality or MI in patients with chronic stable angina and preserved LV function.6 In a large placebo-controlled study in patients with CAD and LV ejection fraction <40%, the majority of whom were already taking a β-blocker, addition of ivabradine did not reduce the primary composite end point of cardiovascular death or admission for MI or new-onset or worsening heart failure. In a prespecified subgroup with HR ≥70 bpm, addition of ivabradine did not reduce the primary end point, but did reduce the secondary end points of admission to hospital for fatal and nonfatal MI and coronary revascularization.2

In patients with atrial fibrillation (AF), lowering ventricular rate with β-blockers, diltiazem, digoxin, and amiodarone—which slow atrioventricular node conduction—improves symptoms and quality of life.

Based on published data and personal experience over several years, it has been my standard practice to monitor HR and adjust drug dosage to achieve optimal β-blockade in patients with chronic stable angina. My target is to achieve a resting HR of 55-65 beats per minute (bpm), provided the patient is able to tolerate the medication and does not experience increased fatigue, breathlessness, symptomatic hypotension, or other intolerable adverse effects. Since resting HR is influenced by emotional state, physical activity, and many other stimuli, I usually rely on HR in the sitting position obtained over 30-60 seconds, after the patient has rested for 5-10 minutes. HR obtained from an electrocardiogram in the supine position is also useful to exclude high-grade atrioventricular block if the heart rate is <50 bpm. In patients remaining symptomatic despite resting HR of 55-65 bpm, I usually evaluate HR response to exercise to assess the adequacy of β-blockade.My target is a HR of 110-120 bpmduring symptom- limited electrocardiogram-monitored treadmill or bicycle exercise stress test.

In patients with dilated cardiomyopathy, I monitor HR primarily to achieve the target dose of β-blocker shown in trials to reduce cardiac mortality and morbidity, rather than specifically to lower it to <70 bpm. This is done over a prolonged period, with special attention paid to any adverse effects that necessitate dose reduction. In patients with AF with rapid ventricular response, I monitor resting HR as well as HR during daily activities, often with Holter monitoring over a period of 24 hours. My target is <80 bpm at rest and <110 bpm during physical activities.

In conclusion, this approach to monitoring HR has permitted me to optimize pharmacotherapy for patients with chronic stable angina, heart failure, and AF. I am very careful when treating elderly patients not to lower HR below 60-70 bpm, as these patients often take multiple medications, have multiple comorbid conditions, and are prone to postural hypotension symptoms.

References

1. Shaper AG, Wannamethee G, Macfarlane PW, Walker M. Heart rate, ischaemic heart disease, and sudden cardiac death in middle-aged British men. Br Heart J. 1993;70:49-55.
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 randomized controlled trial. Lancet. 2008;372:817-821.
3. Thadani U. Current medical management of chronic stable angina. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S11-S29.
4. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and anti ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicenter, placebo-controlled trial. Circulation. 2003; 107:817-823.
5. Tardif J-C, Ponikowski P, Kahan T; ASSOCIATE study investigators. Eur Heart J. 2009;30:540-548.
6. Thadani U. The pursuit of optimum outcomes in stable angina pectoris. Am J Cardiovasc Drugs. 2003;3(suppl 1):11-20.