Optimizing secondary prevention treatment in stable coronary artery disease

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.

Medicographia. 2009;31:384-391 (see French abstract on page 391)

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.

Modified from reference 1: Smith SC Jr, Allen J, Blair SN, et al. J Am Coll Cardiol. 2006;47:2130-2139. Copyright © 2006, the American College of Cardiology.

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.

After reference 46: Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R.
Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

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.


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. _


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