Secondary Prevention of Coronary Artery Disease

Claire Duvernoy

Melvyn Rubenfire

INTRODUCTION

The secondary prevention of coronary artery disease (CAD) can be defined as a long-term management strategy for patients who have sustained an acute coronary syndrome (ACS) or have chronic CAD. Goals of secondary prevention include (a) long-term survival, (b) enhanced quality of life by restoring and maintaining normal activities and psychosocial function, (c) prevention of recurrent coronary events, and (d) reduction of new lesion formation and rate of CAD progression.

Cardiology in the modern era is fortunate to have a large number of well-designed randomized clinical trials that have addressed many of the issues surrounding CAD management, and that can serve to guide rational therapy choices. This chapter is divided into segments covering each of the strategies and major therapeutic drug classes used in secondary prevention, with specific sections on preventive cardiology services, the elderly, women, diabetes, and compliance. A summary of the evidence-based secondary prevention strategies, and their potential benefit, is provided in Table 8.1.

RATIONALE FOR SECONDARY CORONARY PREVENTION

The pathogenesis of atherosclerosis includes injury to the endothelium or arterial wall and the thrombotic and inflammatory responses to that injury. The degree of injury, the development of occlusive plaque, and the characteristics of the plaque are dependent on the interaction between lifestyle factors and genetic predisposition that are collectively the “coronary risk factors” listed in Table 8.2. Each of the major risk factors and several new risk factors have been associated with abnormal endothelial function in the absence of occlusive CAD, and most are risk markers for future coronary events. That the majority of known risk factors associated with acute coronary events and rate of plaque progression are modifiable is the basis for the success of secondary prevention.

The sentinel observations by Davies in the mid-1980s (1) and Libby 10 years later (2) have provided extraordinary clarity regarding the pathobiology of ACS. The concept of “rupture of the vulnerable plaque” and the characteristics of the vulnerable plaque initially observed in gross and microscopic pathologic studies have been supported by innumerable studies of ST-segment elevation and non-ST-segment elevation myocardial infarction (MI) and unstable angina by using coronary angiography, intravascular ultrasound, and intracoronary angioscopy. The preponderance of coronary events are due to an occlusive or mural thrombus superimposed on plaque fissuring or rupture of coronary lesions with less than 75% stenosis (Fig. 8.1). The probability of a clinical event depends on the total plaque burden and the individual response to plaque instability. Each of the evidence-based secondary prevention strategies is designed to reduce thrombosis and enhance thrombolysis, decrease plaque growth, and increase plaque stability.

TABLE 8.1. Evidence-based treatment targets for secondary coronary prevention

INTERVENTION	TARGET	POTENTIAL BENEFIT
Antiplatelet therapy	Aspirin, 160-325 mg/d; can ↓ to 81 mg/d for intolerance, or use clopidogrel, 75 mg, if ASA allergic; clopidogrel, 75 mg, and ASA after acute coronary syndromes, 12 mo after DES placement; carry ASA and chew and swallow in possible acute event	25% reduction in all vascular events with ASA. Additiona 20% reduction with clopidogrel and ASA in acute coronary syndromes
Antithrombotic therapy	Oral anticoagulation with warfarin for 3-6 mo for large anterior Ml or significant LV dysfunction	Reduced mural thrombi and emboli, including strokes
β-Adrenergic blockers	Continue β-adrenergic blocker therapy for at least 1 year and indefinitely with impaired LV function and higher risk subsets; BP <135/80 mm Hg	Reduction of 20% for risk of death, 25% for reinfarction, and 30% for sudden death
RAAS inhibition	Use ACEI indefinitely in CAD, diabetes, and vascular disease and titrate to tolerance; BP <135/80 mm Hg	25%-30% reduction in coronary deaths, recurrent Ml, sudden death, CABG
	ARB has equivalent benefit in ACE-I-intolerant pts
Lipid therapy	AHA Step II diet/exercise; initially target LDL-C to <100 mg/dL with a statin, then non-HDL-C to <130 mg/dL with statin combined with niacin or fibrates if necessary, and attempt to increase HDL-C to >45 mg/dL with niacin or fibrates	>25% reduction in mortality and other end points with statins when LDL-C >100 mg/dL; 22% reduction in death or nonfatal MI with fibrates with HDL-C <35 mg/dL
	LDL-C reduction to <70 mg/dL or high-dose statin therapy is reasonable
Diabetes	Near-normal fasting blood glucose and HbA_1c to <7% with diet and drug therapy; consider metformin and glitazones; BP <130/80 mm Hg	Decrease in microvascular and macrovascular complications
Folate	Folic acid supplementation (400 µg) for patients with homocysteine >10 µM; may require 2-10 mg	No evidence, but cost is minimal
Fish oil	Diet high in cold-water fish (twice per week) or up to 1,000 mg of omega-3 fatty acids	More than 20% reduction in mortality and sudden death
Calcium channel blockers	Consider diltiazem in non-ST-elevation Ml, diltiazem, or verapamil in hypertensives unable to tolerate β-adrenergic blockers or those needing additional antianginal therapy	No survival benefit
Nitrates	Oral nitrate as adjunctive therapy for angina or CHF; all patients carry 0.4 mg sublingual nitrate for angina and possible acute coronary event	No evidence of survival benefit
Novel antianginal agents	Ranolazine currently available as third-line agent for refractory angina	Increases exercise performance, decreases anginal attacks; no evidence of survival benefit
Hormone-replacement therapy	No current recommendations to initiate for coronary prevention	None
Smoking cessation	Emphasize stepped approach; prescribe nicotine replacement, buproprion, and/or varenicline if necessary	25%-50% reduction in coronary mortality within 1 to 2 yr
Rehabilitation and stress management	Refer to cardiac rehabilitation program; exercise ≥20-30 minutes at least 3 d/wk, upper-body strength training, education, stress management	25% reduction in recurrent coronary events
Weight/dietary targets	Target to desirable BMI of 18.5-24.9 kg/m² with decrease in gut fat, AHA step II diet; limit salt to 5-6 g; consider Mediterranean diet; encourage nutrition consultation	Facilitated lipid and BP control, reduced progression of CAD, can reduce mortality up to 25%
ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ASA, aspirin; BMI, body mass index; BP, blood pressure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CVE, cardiovascular event; HbA_1c, hemoglobin A_1c; DES, drug-eluting stent; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; MI, myocardial infarction.

CLINICAL RISK STRATIFICATION

The risk factors associated with coronary disease (Table 8.2) are important predictors of long-term prognosis in established CAD. The major risks include age, smoking, hypertension, diabetes, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The 2-year risk of a major coronary event, stroke, or cardiovascular death in men and women with established CAD can be estimated by using gender-specific tables developed by Califf et al. (3) (Table 8.3 for men, Table 8.4 for women). The average risk of a recurrent event in a 55-year-old man is about 6% annually, but can be reduced to less than 2% with excellent control of modifiable risk factors. Whereas the exact score and probability of event by percentage should be used with caution, the information is of value when considering the cost-benefit of each treatment. Additionally, the awareness of an estimate of overall risk, the risk attributable to each variable, and the knowledge that interventions are available to improve each variable (with the exception of age) can be used to motivate even the most recalcitrant patient in the office setting.

TABLE 8.2. Risk factors and risk markers for coronary and noncoronary atherosclerosis

CLASSIC RISK FACTORS	NOVEL AND CANDIDATERISK-FACTORS/MARKERS
Nonmodifiable	Apo B100
Age	Low apo A-1
Gender	Lipoprotein (a)
Family history of premature CAD	Small LDL particle size
Family history of premature CAD	Insulin
Menopause	Insulin resistance
Low socioeconomic status	Triglycerides
Less educated	Homocysteine
Modifiable	Antioxidant status
Hypertension	Chronic infection
Diabetes	Dental hygiene
Total cholesterol	C-reactive protein
LDL cholesterol	PAI-1
IDL cholesterol	Activated factor VII
Low-HDL cholesterol	Fibrinogen
ECG LVH	White blood cell
count
Smoking
Sedentary lifestyle
Obesity
Personality traits: hostility
Stress, depression,anxiety
CAD, coronary artery disease; ECG, electrocardiogram; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; PAI-1, plasminogen activator inhibitor-1.

EVIDENCE-BASED SECONDARY PREVENTION STRATEGIES

Antiplatelet Agents

The risk of ACS is increased with increasing levels of fibrinogen, platelet count and aggregation, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen antigen, and inversely related to plasminogen activator activity. It is therefore not surprising that a strong, consistent reduction in MI and stroke risk occurs with aspirin intake in CAD. Aspirin, a cyclooxygenase inhibitor, is irreversibly bound to platelets and blocks the formation of platelet thromboxane A₂, a potent stimulus for platelet aggregation. Although aspirin also blocks vascular endothelium prostacyclin synthesis, the latter effect is reversible. The use of low-dose aspirin and its relatively short half-life tip the balance in favor of the vasodilating and antiplatelet properties of prostacyclin.

FIGURE 8.1. Pathophysiology of plaque rupture.

Among several different risk categories of patients, including a history of acute MI or prior MI, stroke or transient ischemic attack (TIA), unstable angina, and chronic coronary disease, an approximate 25% risk reduction was found in “vascular events” (nonfatal MI, nonfatal stroke, or vascular death) in a review of trials comparing antiplatelet therapy with placebo (4). No significant increase in benefit was shown for the combination of aspirin plus dipyridamole, when compared with aspirin alone (4).

Aspirin therapy is one of the most intensively studied and well-accepted strategies for the prevention of recurrent cardiovascular events. The usual recommendation for long-term aspirin therapy has been 160 to 325 mg daily. However, benefit for aspirin therapy occurs in doses as low as 75 mg daily. Fulldose aspirin (325 mg) should be prescribed for ACS patients who have undergone percutaneous coronary intervention with stent placement; this dose should be given for 1 month after placement of a bare metal stent, 3 months for a sirolimus-eluting stent, and 6 months for a paclitaxel-eluting stent (5). For long-term preventive use, low-dose aspirin therapy (81 mg) is as effective as the standard dose (160 mg and 325 mg). Enteric coating and lower doses may reduce the risk of peptic symptoms, gastritis, peptic ulcers, and gastrointestinal (GI) bleeding.

An effective alternative to aspirin is clopidogrel, a thienopyridine derivative that binds to and blocks the platelet adenosine diphosphate (P2Y₁₂) receptor. It is related to ticlopidine, another thienopyridine, which has a serious adverse effect—bone marrow suppression—that has limited its widespread use. Clopidogrel has gained widespread use because of its equivalent efficacy and more favorable side-effect profile. The Clopidogrel Versus Aspirin in Patients At Risk of Ischemic Events (CAPRIE) trial compared clopidogrel with aspirin in more than 19,000 patients with known vascular disease (cerebral, cardiovascular, or peripheral) and found an overall risk reduction of 8.7% favoring clopidogrel in the reduction of the composite outcome of stroke, MI, and vascular death. The major benefit occurred in patients with peripheral arterial disease, whereas patients with prior stroke and those with prior MI had negligible decreases in risk (6). For patients with documented prior MI, prior stroke, or symptomatic peripheral arterial disease who were enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, benefit was shown for clopidogrel added to aspirin, with a statistically significant 1.5% absolute risk reduction in the composite of cardiovascular death, MI, or stroke over a median period of 27.6 months (7).

TABLE 8.3. Risk of recurrent event in patients with existing coronary artery disease: men

AGE(YR)	POINITS	TOTALCHOLESTEROL(mg/dL)	POINTS BY HDL-C (mg/dL)									SBP(mm Hg)	POINTS
AGE(YR)	POINITS	TOTALCHOLESTEROL(mg/dL)	25	30	35	40	45	50	60	70	80	SBP(mm Hg)	POINTS
35	0	160	6	5	4	4	3	2	1	1	0	100	0
40	1	170	6	5	5	4	3	3	2	1	0	110	1
45	1	180	7	6	5	4	4	3	2	1	1	120	1
50	2	190	7	6	5	4	4	3	2	2	1	130	2
55	2	200	7	6	5	5	4	4	3	2	1	140	2
60	3	210	7	6	6	5	4	4	3	2	1	150	3
65	3	220	8	7	6	5	5	4	3	2	2	160	3
70	4	230	8	7	6	5	5	4	3	3	2	170	4
75	4	240	8	7	6	6	5	4	4	3	2	180	4
		250	8	7	6	6	5	5	4	3	2	190	4
		260	8	7	7	6	5	5	4	3	2	200	5
		270	9	8	7	6	6	5	4	3	3	210	5
Other	Pts	280	9	8	7	6	6	5	4	4	3	220	5
Diabetes	1	290	9	8	7	7	6	5	4	4	3	230	6
		300	9	8	7	7	6	6	5	4	3	240	6
												250	6
								AVERAGE 2-YR RISK IN MEN WITH CVD
TOTAL POINTS			2-YR PROBABILITY (%)					AGE (YR)				PROBABILITY (%)
0			2					35-39				<1
2			2					40-44				8
4			3					45-49				10
6			5					50-54				11
8			7					55-59				12
10			10					60-64				12
14			20					70-74				14
16			28
18			37
20			49
22			63
24			77

The 2006 update to the American College of Cardiology/American Heart Association (ACC/AHA) secondary prevention guidelines (8) now calls for 12 months of clopidogrel, 75 mg, in combination with aspirin in the year after an acute coronary syndrome. Certainly, the use of clopidogrel in combination with aspirin is considered mandatory in patients who have undergone percutaneous coronary intervention with stent placement. The recommended time frame is at least 1 month for bare metal stents. Although manufacturers’ guidelines have called for dual antiplatelet therapy for at least 3 months for sirolimus-eluting stents, and at least 6 months for paclitaxel-eluting stents, recently released percutaneous coronary intervention guidelines now call for 12 months of dual antiplatelet therapy for all patients after stent implantation who are at low risk of bleeding (9). After 1 year, the need for dual antiplatelet therapy is not clear, and the decision should be individualized.

TABLE 8.4. Risk of recurrent event in patients with existing coronary artery disease: women

AGE(YR)	POINTS	TOTALCHOLESTEROL(mg/dL)	POINTS BY HDL-C (mg/dL)									SBP(mm Hg)	POINTS
AGE(YR)	POINTS	TOTALCHOLESTEROL(mg/dL)	25	30	35	40	45	50	60	70	80	SBP(mm Hg)	POINTS
35	0	160	4	3	3	2	2	1	1	0	0	100	0
40	1	170	4	3	3	2	2	2	1	1	0	110	0
45	2	180	4	3	3	2	2	2	1	1	0	120	1
50	3	190	4	4	3	3	2	2	1	1	1	130	1
55	4	200	4	4	3	3	2	2	2	1	1	140	2
60	5	210	4	4	3	3	3	2	2	1	1	150	2
65	6	220	5	4	4	3	3	2	2	1	1	160	2
70	7	230	5	4	4	3	3	3	2	2	1	170	3
75	7	240	5	4	4	3	3	3	2	2	1	180	3
		250	5	4	4	4	3	3	2	2	1	190	3
		260	5	5	4	4	3	3	2	2	1	200	3
		270	5	5	4	4	3	3	2	2	2	210	4
Other	Pts	280	5	5	4	4	3	3	3	2	2	220	4
Diabetes	3	290	5	5	4	4	4	3	3	2	2	230	4
Smoking	3	300	6	5	4	4	4	3	3	2	2	240	4
												250	4
							AVERAGE 2-YR RISK IN MEN WITH CVD
TOTAL POINTS			2-YR PROBABILITY (%)					AGE (YR)				PROBABILITY (%)
0			0					35-39				<1
2			1					40-44				<1
4			1					45-49				<1
6			1					50-54				4
8			2					55-59				6
10			4					60-64				8
12			6					65-69				12
14			10					70-74				12
16			15
18			23
20			35
22			51
24			68
26			85
CVD, cerebrovascular disease; HDL-C, high-density lipoprotein cholesterol; SPB, systolic blood pressure.
From Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, 1: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ1994;308:81-106, with permission.

Anticoagulants

Long-term anticoagulation after acute MI is generally limited to a subset of patients at high risk for embolic events. Patients with atrial fibrillation or atrial flutter after MI, whether paroxysmal or chronic, should be treated with warfarin to reduce the risk of embolic events. Patients with identifiable left ventricular (LV) thrombus or LV aneurysm after MI should receive oral anticoagulation for at least 3 to 6 months to prevent systemic embolization; treatment of other patients after MI remains controversial. Studies comparing anticoagulation with placebo have shown significant reductions in total mortality, reinfarction, and cerebrovascular events (10). A recent meta-analysis (10) performed to address the efficacy of combination anticoagulant/antiplatelet therapy found no apparent benefit in the combination of low-intensity oral anticoagulation (target International Normalized Ratio, <1.5) plus aspirin, whereas promise was shown by combination therapy using moderate and high-intensity anticoagulant therapy plus aspirin. Large-scale studies comparing anticoagulant with antiplatelet therapy have not been conclusive. One such study, Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) was terminated prematurely after failing to meet enrollment targets. No significant differences were detected in rates of death, MI, and stroke individually and as a composite end point between the three arms (aspirin, clopidogrel, or open-label warfarin) (11). Thus currently no recommendation exists for long-term anticoagulation in patients after MI in the absence of LV thrombus or atrial fibrillation.

β-Adrenergic Blockers

Strong evidence indicates that treatment with β-blocking agents after MI is beneficial in reducing subsequent mortality, recurrent MI, and sudden death in all subsets. Treatment appears to be most efficacious in patients at highest risk (12), and benefit is similar in men and women. One of the first trials to address the question systematically was B-HAT (Beta-blocker Heart Attack Trial), which compared the nonselective β-blocker propranolol with placebo after an acute MI. Significant risk reductions were seen in total mortality, cardiovascular mortality, and sudden death (13). The majority of benefit was seen in smokers, anterior MI, and those with impaired LV function. In years past, patients with significant LV dysfunction were generally excluded from receiving β-blocker therapy because of concern that these agents would increase symptomatic heart failure. However, recent trials have clearly demonstrated efficacy for several agents, including carvedilol, a nonselective β-blocker with some α-1 blocker effects, and metoprolol, a cardioselective β-blocker, in patients with both ischemic and nonischemic cardiomyopathy.

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