 |
|
A Practical and Evidence-Based Approach to Cardiovascular Disease Risk Reduction
Ty J. Gluckman, MD;
Bryan Baranowski, MD;
M. Dominique Ashen, PhD, CRNP;
Charles A. Henrikson, MD;
Marc McAllister, BA;
Joel B. Braunstein, MD, MBA;
Roger S. Blumenthal, MD
Arch Intern Med. 2004;164:1490-1500.
ABSTRACT
Implementation of the numerous lifestyle and medical management options for secondary prevention of cardiovascular disease remains a daunting goal for primary care physicians and cardiologists alike. Despite the existence of expert consensus guidelines on cardiovascular prevention by the American College of Cardiology and the American Heart Association, therapies known to improve patient care and decrease morbidity and mortality remain underutilized. This review attempts to simplify cardiovascular risk reduction by summarizing key clinical trials in an "ABC" format. We believe that if health care providers and patients use such a format, important lifestyle and pharmacologic options will more likely be addressed.
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States.1 In 2000, acute myocardial infarction (MI) was diagnosed in 1.1 million Americans and approximately 850 000 patients underwent coronary revascularization.1 In spite of this, studies have documented that medical therapies for secondary cardiovascular (CV) prevention are underutilized and that a wide variation in practice patterns exists for management of patients with coronary artery disease (CAD).2-5 In addition, the average hospital stay for an acute coronary syndrome has been shortened, limiting the opportunity to counsel patients about risk-reducing strategies such as improved diet, increased exercise, and smoking cessation.6 Thus, while advances in risk factor modification and a better understanding of the atherosclerotic process have led to a decline in CVD mortality, implementation of risk-reducing practices for both inpatients and outpatients remains suboptimal.7
The treatment gap in secondary prevention of CVD has become a major challenge in health care. Recognizing that clinical trials remain the cornerstone for defining target treatment goals, our review article uses an "ABC" format8-9 to summarize the key studies that guide an evidence-based approach to secondary prevention of CVD (Table 1). This approach is useful not only in the development of inpatient critical pathways, but also in the outpatient management of individuals with vascular disease and/or type 2 diabetes mellitus (DM). A simplified version of this approach is also helpful in allowing patients to better understand their risk factors.
|
|
|
|
ABCs of Cardiovascular Disease Risk Management
|
|
|
ANTIPLATELET AGENTS
Aspirin
Aspirin irreversibly inhibits the cyclooxygenase enzyme involved in the production of thromboxane, a factor that promotes platelet aggregation. All patients with a history of CVD and/or DM should take 75 to 325 mg of aspirin daily.10-11 Major adverse effects include dose-dependent bleeding, gastrointestinal symptoms (in 2%-10% of individuals), tinnitus and hearing loss (in 0.3% with higher doses), and sensitivity reactions including bronchospasm, urticaria, and angioedema (in 0.3%).12
Evidence: Two large-scale meta-analyses by the Antiplatelet Trialists Collaboration have demonstrated the importance of aspirin therapy in secondary prevention of CVD. The first meta-analysis reviewed 25 trials and demonstrated that aspirin reduced vascular mortality by 15% (SD ± 4%) and CVD events by 30% (SD ± 4%).13A follow-up meta-analysis of about 70 000 patients with CVD found that 75 to 325 mg of aspirin daily resulted in an approximately 33% relative reduction (RR) in CVD events (P<.0001).14
Clopidogrel Bisulfate
Clopidogrel inhibits platelet activation by blocking the binding of adenosine diphosphate to its receptor on the platelet surface. Clopidogrel should be used in place of aspirin in patients who are intolerant of or resistant to the effects of aspirin.15 Clopidogrel (75 mg/d) should also be taken in addition to aspirin (75-325 mg/d) for at least 8 to 12 months by patients with an acute coronary syndrome,16 especially after undergoing percutaneous coronary intervention (PCI).17-18 Major adverse effects include rash (in 4.2% of patients) and gastrointestinal bleeding (in 2.0%).19 The long-term use of clopidogrel is currently limited largely by its cost.20
Evidence: The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study randomized 19 185 patients with a history of a MI, stroke, or symptomatic peripheral arterial disease to receive either aspirin (325 mg/d) or clopidogrel (75 mg/d) for up to 3 years.21 There was an 8.7% RR in CVD events in the clopidogrel group compared with the group receiving aspirin (5.3% vs 5.8%; P = .04). There was no significant difference in adverse effects between patients taking aspirin or clopidogrel.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized 12 562 patients presenting with an acute coronary syndrome to immediate and long-term therapy with aspirin (75-325 mg/d) or aspirin plus clopidogrel (300 mg/d initially, followed by 75 mg/d).16 The clopidogrel group demonstrated a 20% RR in the composite end point of CVD events at 12 months (9.3% vs 11.4%; P<.001). This benefit was seen within a few hours of randomization and persisted throughout the trial. The clopidogrel group experienced a higher incidence of major bleeding (3.7% vs 2.7%; P = .001), but there was no difference in life-threatening bleeding events (2.2% vs 1.8%; P = .13). Post hoc analysis found a lower risk of bleeding but similar efficacy when a lower dose of aspirin (75-81 mg/d) was used in combination with clopidogrel.22
The Percutaneous Coronary Intervention–Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) trial17 and the Clopidogrel for the Reduction of Events During Observation (CREDO) trial18 evaluated combination antiplatelet therapy of aspirin and clopidogrel with PCI. These studies enrolled 4774 patients who were scheduled to undergo PCI. Randomization to aspirin (75-325 mg/d) or aspirin plus clopidogrel (300 mg/d initially, followed by 75 mg/d) occurred prior to PCI and was continued for 8 to 12 months. Most patients, however, received open-label clopidogrel for up to 4 weeks following PCI. Patients receiving combination antiplatelet therapy had a 28% RR in end points that included all-cause mortality, CV death, MI, and/or stroke (P = .02). There were no significant differences in major bleeding between the 2 groups. Thus, patients who present with an acute coronary syndrome and undergo PCI should be given strong consideration for combination antiplatelet therapy for 1 year.
ANTICOAGULATION
Warfarin Sodium
Warfarin exerts its anticoagulant effect primarily by antagonizing the vitamin K–dependent carboxylation of several procoagulant proteins (factors II, VII, IX, and X and proteins C and S). Anticoagulation with warfarin is indicated in patients with atrial fibrillation and/or a left ventricular thrombus, as well as in those unable to take aspirin following an MI.23 Warfarin should also be considered primary therapy in some patients following an acute MI.24 Major adverse effects include dose-dependent bleeding and the potential for drug-drug interaction, especially among medications metabolized by the hepatic cytochrome CYP2C9 and CYP3A4 isoenzymes.25
Whether low-dose aspirin should routinely be added to warfarin remains controversial. Recent analyses suggest a trend toward improved outcomes when combination therapy is used in patients with known CVD.24, 26 However, patients receiving long-term warfarin treatment have a small increased risk of major bleeding compared with patients treated with aspirin alone.24, 26
Evidence: A meta-analysis of 31 trials compared warfarin therapy with or without aspirin with aspirin or placebo alone.26 When compared with placebo, warfarin at moderate (international normalized ratio [INR], 2-3) and high (INR, 2.8-4.8) doses was associated with a 52% and 42% RR in MI, respectively (P<.001). However, patients treated with moderate- or high-dose warfarin and those treated with aspirin had no difference in MI incidence (5.0% vs 5.3%; P = .10). Finally, patients treated with moderate- or high-dose warfarin plus aspirin rather than aspirin alone showed a trend toward a reduction in MI incidence (4.2% vs 7.5%; P = .32). This trend did not reach statistical significance, possibly because of the relatively small numbers of patients included. There was a statistically significant increased risk of major bleeding in patients receiving moderate- or high-dose warfarin.
The Warfarin, Aspirin or Both After MI (WARIS II) study attempted to determine whether treatments with warfarin or warfarin plus aspirin were superior to aspirin therapy alone.24 This open-label trial randomized 3630 hospitalized patients with an acute MI to receive daily warfarin (INR, 2.8-4.2), aspirin (160 mg/d), or warfarin (INR, 2.0-2.5) plus aspirin (75 mg/d) for 4 years. Patients receiving aspirin plus warfarin or warfarin alone had a 29% (P = .001) and 19% (P = .03) RR in CVD events, respectively, compared with those receiving aspirin alone. There was no statistical difference between the 2 groups receiving warfarin; however, patients in these groups were at an increased risk for major, nonfatal bleeding compared with those receiving aspirin alone (0.62/y vs 0.17%/y; P<.001).
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Angiotensin-converting enzyme inhibitors (ACEIs) interfere with the conversion of angiotensin I to angiotensin II. This treatment blocks the renin-angiotensin system and inhibits the breakdown of bradykinin. Angiotensin-converting enzyme inhibitors are indicated in patients with CVD in association with heart failure (HF),27 left ventricular systolic dysfunction (LVSD),27 and/or a recent MI,28 and they are also indicated in patients with CVD and/or DM irrespective of left ventricular systolic function29 as long as the systolic blood pressure(BP) is greater than 120 mm Hg (current American College of Cardiology/American Heart Association [ACC/AHA] class IIa indication8). Major adverse effects include renal insufficiency (in up to 50% of patients with bilateral renal artery stenosis),30 cough (in up to 20% of all patients),31 hyperkalemia (in up to 10%),32 and angioedema (in 0.1%-0.2%).31
Evidence: Three major studies have assessed ACE inhibition in patients with CVD along with clinical HF and/or LVSD (with an ejection fraction  35% or 40%, depending on the study): the Acute Infarction Ramipril Efficacy (AIRE) study,33 the Trandolapril Cardiac Evaluation (TRACE) study,34 and the Survival and Ventricular Enlargement (SAVE) study.35 Each trial randomized patients diagnosed with HF or LVSD to ACE inhibition or placebo within 2 to 16 days of an acute MI. A total of 6843 patients were followed up for a mean of 42 to 59 months. Patients randomized to an ACEI had a 17% to 28% RR in the primary end point of all-cause mortality (P = .019 to P = .001, depending on the study).36
The Fourth International Study of Infarct Survival (ISIS-4),37 the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto Miocardico (GISSI-3) study,38 and the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study39 assessed ACE inhibition immediately following an MI. Each trial randomized patients to an ACEI or placebo within 24 hours of an MI. A total of 78 600 patients were followed up for 6 to 12 months. Patients randomized to an ACEI had a 5% to 29% RR in the primary end point of death (P = .03 to P = .011).40
In the Heart Outcomes Prevention Evaluation (HOPE) study, 9297 patients were randomized to ramipril (10 mg/d) or placebo to assess the occurrence of vascular events in high-risk patients without LVSD.41 High-risk patients were defined as having a history of vascular disease or DM plus 1 additional CV risk factor. Ramipril reduced the risk of CV death, MI, and stroke by 22% over 5 years (14.0% vs 17.8%; P<.001).
ANGIOTENSIN RECEPTOR BLOCKERS
Angiotensin receptor blockers (ARBs) inhibit the effects of angiotensin II at the receptor level and are indicated in patients with diabetic nephropathy,42 hypertension,43 or HF.44 Angiotensin receptor blockers, however, have not been shown to provide greater CVD protection than ACEIs in patients with HF, and therefore should only be used as primary therapy in patients who are intolerant of ACEIs.44 Combination therapy with an ARB and an ACEI in patients with HF appears to provide greater benefit through more complete renin-angiotensin system blockade.45 Major adverse effects are similar to those seen with ACEIs, except for the effects related to bradykinins (eg, cough).46
Evidence: The renoprotective effects of ARBs in patients with nephropathy and DM were evaluated in the Reduction of Endpoints in NIDDM (type 2 non–insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) study47 and the Irbesartan Diabetic Nephropathy Trial.48 These studies randomized 3228 patients to either losartan (up to 100 mg/d), or irbesartan (up to 300 mg/d) vs placebo for 2.6 to 3.4 years. There was a 16% to 20% RR in the composite end point of a doubling of the baseline serum creatinine concentration, end-stage renal disease, or death (P = .02). Among secondary CVD end points, there were no significant differences in fatal or nonfatal events; however, there was a 23% to 29% RR in first hospitalizations for HF (P = .005).
In the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) trial, 9193 patients with essential hypertension (systolic BP >160 mm Hg) and left ventricular hypertrophy detected by electrocardiogram were randomized to losartan (up to 100 mg/d) or atenolol (up to 100 mg/d) over 4 years.49 Treatment with losartan resulted in a 25% RR in both stroke and the development of DM (P = .001), but no statistically significant reduction in MI (P = .50). Among patients with isolated systolic hypertension, however, treatment with losartan resulted in a 46% RR in CV mortality (8.7% vs 16.9%; P = .01).50
The effect of ARBs on cardiovascular outcomes was assessed in a large meta-analysis that evaluated 12 469 patients from 17 randomized, double-blind, placebo-controlled trials.51 There was no significant reduction in all-cause mortality among patients treated with an ARB (RR, 1.09; 95% confidence interval [CI], 0.92-1.29) or an ARB plus an ACEI (RR, 1.04; 95% CI, 0.91-1.20). Patients treated with an ARB plus an ACEI, however, had an RR of 26% in rates of hospitalization for HF compared with patients treated with an ACEI alone (95% CI, 0.60-0.84). Of note, within a more recent trial not included in the meta-analysis, the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) program, there was a 15% RR in the incidence of CV death or hospitalization for HF among patients receiving an ARB plus an ACEI compared with those treated with an ACEI alone (P = .011)45
BP CONTROL
The Seventh Joint National Committee (JNC 7) on prevention, detection, evaluation, and treatment of high BP recommends that patients with DM and/or chronic kidney disease be treated to achieve a BP lower than 130/80 mm Hg.52 The prior JNC 6 guidelines recommended that in diabetic patients with more than 1 g/dL of proteinuria, a BP lower than 125/75 mm Hg should be the target.53 Although the JNC 7 guidelines do not define a goal BP for patients with HF and/or CVD, fastidious control is recommended.52 Finally, the treatment of patients without CVD or DM should be initiated if their systolic BP is 140 mm Hg or higher or their diastolic BP is 90 mm Hg or higher.52
The optimal agent for lowering BP in patients with CVD has yet to be clearly defined. While several medications, including ACEIs,  -blockers, and thiazide diuretics remain first-line agents, ARBs, aldosterone antagonists, and long-acting calcium channel blockers should also be strongly considered, especially for patients with HF and/or stable angina pectoris.52 Most hypertensive patients will require at least 2 antihypertensive medications to achieve their target BP.54
Evidence: A large meta-analysis, the Individual Data Analysis of Antihypertensive intervention trials (INDANA), evaluated more than 40 000 hypertensive patients randomized to treatment with thiazide diuretics, -blockers, or placebo.55 Among patients randomized to a study drug, there were significant reductions in the incidence of stroke and major coronary events (P<.001).
In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 33 357 patients who were 55 years or older and had at least 1 coronary heart disease risk factor were randomized to chlorthalidone (up to 25 mg/d), amlodipine (up to 10 mg/d), or lisinopril (up to 40 mg/d) for a mean of 5 years.56 There was no observed difference in the primary combined outcome of fatal coronary heart disease or nonfatal MI between patients taking any of the 3 antihypertensive drugs (95% CI, 0.90-1.08). Because of their lower cost, thiazide diuretics were considered the preferred first-line antihypertensive agents.
The data reviewed in the ACEI, ARB, -blocker, and aldosterone antagonist sections of this review provide strong support for the use of these medications in hypertensive patients with a history of CVD, HF, and/or DM.
 -BLOCKERS
-Blockers competitively inhibit the effects of catecholamines on -adrenergic receptors. They impart antiarrhythmic, antianginal, and sympatholytic effects by reducing myocardial ionotropic and chronotropic stimulation. -Blockers should be used in the secondary prevention of CVD in patients with an MI,57 HF/LVSD,27 and/or hypertension.58 Major adverse effects include potential short-term exacerbations of HF symptoms,59 fatigue (1.8%),60 and sexual dysfunction (0.5%).60
Evidence: Two major studies, the Norwegian Multicenter Study Group trial61 and the Beta-blocker Heart Attack Trial (BHAT),62 were among the first to assess -blockade following an MI. A total of 5766 patients were randomized to treatment with timolol (up to 20 mg/d) or propanolol (up to 240 mg/d) vs placebo within 5 to 28 days following an acute MI. Among patients taking a -blocker, there was a 26% to 39% RR in death (P = .005 to P = .0005).
The Cardiovascular Cooperative Project, a retrospective review of 201 752 unselected Medicare patients diagnosed with an acute MI,63 tracked differences in mortality among those taking -blockers after discharge. Overall, mortality was decreased by 40% over 2 years in all patients receiving -blockers and by 32% to 40% among the subset of patients previously excluded from some studies because of coexisting chronic obstructive pulmonary disease, DM, and/or severe LVSD.
A large meta-analysis of 54 234 patients from 82 randomized trials attempted to further determine whether CV outcomes differed according to -blockade duration after an MI.57 Long-term (6-48 months)—but not short-term (<6 weeks)—-blockade was associated with a significant reduction in mortality (odds ratio, 0.77; 95% CI, 0.69-0.85).
The effect of -blockade in ischemic LVSD was prospectively evaluated in the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial,64 which randomized 1959 patients with known LVSD (ejection fraction 40%) following a MI to carvedilol (up to 25 mg twice daily) or placebo for a mean of 1.3 years. Patients receiving carvedilol had a significant reduction in all-cause mortality (hazard ratio, 0.77; P = .03) and nonfatal MI (hazard ratio, 0.59; P = .01).
The INDANA meta-analysis55 (reviewed above in the "BP Control" section) supports the use of a -blocker as a first-line antihypertensive agent among patients with CVD.
CHOLESTEROL MANAGEMENT
The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III) recommends a target low-density lipoprotein cholesterol (LDL-C) level less than 100 mg/dL (2.6 mmol/L) in patients with CVD, DM, or, based on the Framingham Risk Score, a 10-year risk of death by MI or coronary heart disease higher than 20%.65 The guidelines classify normal triglyceride (TG) levels as less than 150 mg/dL (3.8 mmol/L) and normal high-density lipoprotein cholesterol (HDL-C) levels as 40 mg/dL (1.0 mmol/L) or greater. In women, HDL-C values less than 50 mg/dL (1.3 mmol/L) are 1 criterion for the metabolic syndrome.
Recent data from the Heart Protection Study (HPS),66 however, challenge the cut point set forth by ATP III and suggest that further LDL-C reduction in patients with a LDL-C of 90 to 100 mg/dL (2.3 to 2.6 mmol/L) results in reduced CV events in subjects with known DM or CVD. Trials are being carried out to better determine the desired threshold for LDL-C in secondary prevention. At any rate, lifestyle changes, including diet and exercise, and pharmacotherapy should be implemented to bring LDL-C levels below 100 mg/dL (2.6 mmol/L).
HMG-CoA Reductase Inhibitors (Statins)
Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme involved in the rate-limiting step of cholesterol synthesis. They are the most powerful class of drugs for lowering LDL-C, but also help to raise HDL-C and lower TG. Statins should be considered the first-line lipid lowering medication for most patients with CVD and/or DM. Major adverse effects include myalgias (1%-6%), significant dose-dependent elevations of serum aminotransferases (0.1%-3.0%), myopathy (0.7%), and fatal rhabdomyolysis (<.00002%).67
Evidence: Four major studies have assessed the role of statins in the secondary prevention of CVD. These include the Scandinavian Simvastatin Survival Study (4S),68 the Cholesterol Recurrent Events (CARE) trial,69 the Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) trial,70 and the Heart Protection Study (HPS).66
The 4S Study assessed 4444 patients with angina or a history of a MI and elevations in total cholesterol and LDL-C (mean of 261 mg/dL and 188 mg/dL, respectively). Patients were randomized to receive dietary modification plus simvastatin (up to 40 mg/d) or placebo with a goal total cholesterol less than 200 mg/dL (5.2 mmol/dL). Over 5.4 years, patients receiving simvastatin had a 30% RR in mortality (8.2% vs 11.5%; P = .0003).
The benefit of lowering mildly elevated cholesterol levels was assessed in the CARE trial, in which 4159 patients with a mean LDL-C of 139 mg/dL and a history of MI were randomized to receive pravastatin (40 mg/d) or placebo. The pravastatin group experienced a 24% RR (10.2% vs 13.2%; P = .003) in the primary end point of a fatal coronary event or nonfatal MI over 5 years. The LIPID study group randomized 9014 patients with a history of MI or unstable angina and an elevated total cholesterol level (155-271 mg/dL) to pravastatin (40 mg/d) or placebo over 6.1 years. There was a 22% RR in total mortality (11.0% vs 14.1%; P<.001) in the pravastatin arm.
The HPS study randomized 20 536 patients with CVD and/or DM to simvastatin (40 mg/d) or placebo over 5 years. All-cause mortality was significantly reduced (12.9% vs 14.7%; P = .0003) and there was an RR of 25% to 30% in major CVD events independent of the LDL-C level.
Fibrates
Fibrates activate peroxisome proliferator–activated receptors to stimulate lipoprotein lipase, resulting in lower TG and higher HDL-C levels.65 They are appropriate first-line agents in patients with isolated hypertriglyceridemia. Combination therapy with a statin can be considered in high-risk patients with elevated LDL-C and either low HDL-C or high TG levels. The major adverse effect is myopathy, which is potentiated by coadministration with statins.71
Evidence: Currently, there are no studies that have independently evaluated the effect of solely lowering TG since fibrates also raise HDL-C. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) randomized 2531 men with CAD to gemfibrozil (1200 mg/d) or placebo over 5 years and found a 22% RR in the primary outcome of nonfatal MI or coronary heart disease death in the patients treated with gemfibrozil (17.3% vs 21.7%; P = .006).72
Nicotinic Acid
Nicotinic acid (niacin) raises HDL-C and inhibits hepatic production of very low-density lipoprotein cholesterol and LDL-C. It can be used in combination therapy with statins in the treatment of hyperlipidemia in patients with normal or low levels of HDL-C.65 Major adverse effects include flushing (in up to 80% of individuals with the crystalline preparation),73 pruritus (in 20%),73 paresthesias (in 20%),73 nausea (in 20%),73 hepatotoxicity, hyperglycemia from insulin resistance,74 hyperuricemia, hypotension,75 and elevation of serum homocysteine levels.76
Evidence: The HDL-Atherosclerosis Treatment Study (HATS) evaluated the effect of niacin in combination with a statin.77 This study randomized 160 patients to simvastatin and niacin or to placebo to evaluate the occurrence of a first CV event and assess the effects on coronary artery stenoses angiographically. The mean ± SD simvastatin and niacin doses were 13 ± 6 mg and 2.4 ± 2.0 g daily, respectively, and resulted in a 42% RR in LDL-C and a 26% relative rise in HDL-C. Treatment with simvastatin and niacin resulted in slight regression rather than progression of angiographic stenoses (P<.001) and a 60% RR in the CV event rate (P = .02).
CIGARETTE SMOKING CESSATION
|
