Although many risk factors for CHD are not modifiable, it is now clear that interventions, such as smoking cessation, treatment of dyslipidemia, and lowering of BP can both prevent coronary disease and delay its progression and complications after it is manifest.
Lowering LDL levels delays the progression of atherosclerosis and in some cases may produce regression. Even in the absence of regression, fewer new lesions develop, endothelial function may be restored, and coronary event rates are markedly reduced in patients with clinical evidence of vascular disease.
A series of clinical trials has demonstrated the efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in preventing death, coronary events, and strokes. Beneficial results have been found in patients who have already experienced coronary events (secondary prevention), those at particularly high risk for events (patients with diabetes and patients with peripheral artery disease), those with elevated cholesterol without multiple risk factors, and those without vascular disease or diabetes with elevated high-sensitivity C-reactive protein (hsCRP) with normal LDL levels. The benefits of statin therapy at moderate and high doses (Table 10–7) are recommended by the cholesterol treatment guidelines. The IMPROVE-IT study showed that ezetimibe, 10 mg daily, combined with simvastatin was modestly better than simvastatin alone in reducing the risk of MI and ischemic stroke, but not mortality, in stabilized patients following an acute coronary syndrome. This was associated with a reduction of LDL to 53.7 mg/dL compared to 69.7 mg/dL. With this data, ezetimibe can be used in combination with statin therapy in patients who are not at target cholesterol level for secondary prevention or cannot tolerate high-dose statin therapy.
Benefits occurred regardless of age, race, baseline cholesterol levels, or the presence of hypertension. It is clear that for patients with vascular disease, statins provide benefit for those with normal cholesterol levels, and that more aggressive statin use is associated with greater benefits. All patients at significant risk for vascular events should receive a statin regardless of their cholesterol levels, and many recommend that with those who have prior cardiovascular events should have their LDL lowered below 70 mg/dL. The Heart Protection Study demonstrated that simvastatin 40 mg/day reduces vascular events by more than 20% in patients with prior MI, stroke, peripheral vascular disease, or diabetes with total cholesterol levels as low as 135 mg/dL. The treatment benefit in this trial, and in an overview of major placebo-controlled randomized trials, was similar regardless of baseline LDL cholesterol, with equal benefit above or below 100 mg/dL. The PROVE-IT trial showed that vascular events were reduced with more aggressive lipid lowering (atorvastatin 80 mg/day compared to pravastatin 40 mg/day following an acute coronary syndrome), providing more evidence of “lower is better” for patients with vascular disease. The TNT (Treating to New Targets) trial likewise found greater benefit with more aggressive LDL lowering (atorvastatin 80 mg versus 10 mg) in a population of patients with CHD and LDL cholesterol less than 130 mg/dL. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial provided only modest support for very aggressive lipid lowering, showing a nonstatistically significant reduction in major coronary events with 80 mg/day of atorvastatin compared with 20 mg/day of simvastatin in patients with prior MI. Although true regression of plaque is uncommon even with intensive lipid therapy (as in the REVERSAL and ASTEROID trials), progression can be prevented at least in the short run in many patients. The JUPITER trial showed that for men age 50 years or older and women age 60 years or older, with LDL less than 130 mg/dL and without cardiovascular disease or diabetes, and with hsCRP 2 mg/L or higher, rosuvastatin 20 mg/day reduced cardiovascular events by 44%.
Statins have not been shown to provide clinical benefit in patients who have heart failure with reduced LVEF or with end-stage renal disease, based on large randomized clinical trials. Patients with chronic heart failure may derive little benefit since they frequently die of progression of heart failure.
Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce LDL cholesterol levels significantly beyond levels associated with traditional statin therapy. These therapies have been studied in randomized trials of patients with maximally tolerated statin therapy (and for patients with statin intolerance) and have lowered LDL with signals of improved cardiovascular outcomes. The FOURIER trial showed that the PCSK9 inhibitor evolocumab, on top of statin, reduced the composite of atherothrombotic outcomes by 20% but did not reduce mortality. The ODYSSEY Outcomes trial demonstrated alirocumab reduced cardiovascular events in patients with acute coronary syndromes. Alirocumab and evolocumab have been approved by the FDA for patients on maximally tolerated statin therapy with familial hypercholesterolemia and atherosclerotic vascular disease, or both, and who require additional lowering of LDL. These medications cost approximately $6000 per year in the United States. Alirocumab has also been approved by the FDA for secondary prevention of cardiovascular events. Inclisiran (a small interfering RNA that goes to the liver and prevents the production of PCSK9) has been studied as a twice yearly injection showing reduction in LDL. Outcomes trials are ongoing, and the therapy is not FDA approved as of early 2020.
While fish oil supplements have not been shown to provide benefit for reducing risk, icosapent ethyl, a concentrated eicosapentaenoic acid at a high dose, was shown to be beneficial in the REDUCE-IT trial. Patients with established cardiovascular disease or with diabetes and other risk factors, with fasting triglyceride level of 135–499 mg/dL, who were on statins were randomized to 2 g of icosapent ethyl twice daily or placebo. There was a 26% relative risk reduction in cardiovascular death, MI, and stroke, as well as a 20% relative risk reduction in cardiovascular death. Late in 2019, icosapent ethyl was approved by the FDA as an adjunct to maximally tolerated statin therapy to reduce the risk of MI, stroke, coronary revascularization, or unstable angina requiring hospitalization in patients with triglycerides 150 mg/dL or more) and either established cardiovascular disease or diabetes mellitus and two or more additional risk factors.
Treatment to raise HDL levels has failed to show benefit. The AIM High trial found no benefit from the addition of niacin in patients with vascular disease and a serum LDL near 70 mg/dL who were receiving statin therapy. The HPS2-THRIVE trial found no benefit but rather substantial harm of extended-release niacin (2 g) plus laropiprant (an antiflushing agent) for preventing vascular events in a population of over 25,000 patients with vascular disease who were taking simvastatin. There was significant toxicity from niacin with increased diabetes, infection, gastrointestinal and musculoskeletal symptoms, and bleeding. A trial in postinfarction patients has demonstrated that gemfibrozil (600 mg twice daily), which increases HDL, in patients with relatively low LDL levels prolongs reinfarction-free survival, although the larger FIELD trial failed to show prevention of nonfatal MI or CHD death with fenofibrate for patients with type 2 diabetes mellitus. The ACCORD trial likewise showed no benefit of statin with fenofibrate versus statin alone in a population of patients with type II diabetes at high risk for cardiovascular events. Three trials of cholesteryl ester transfer protein (CETP) inhibitors, which raise HDL levels with variable amounts of reduction in LDL levels, were stopped because of no benefit or harm. These trials emphasize that an impact on surrogate outcomes, like lipid levels, may not translate into benefits on clinical outcomes.
While antioxidant therapy has theoretical appeal, many large, well-controlled studies have failed to demonstrate a benefit with vitamin E therapy. In fact, the Heart Protection Study and the Heart Outcomes Prevention Evaluation (HOPE) trial found that vitamin E may even be harmful by increasing the likelihood of heart failure and other trials have suggested that vitamin E may hinder the effectiveness of statin therapy. The Physician’s Health Study showed no benefit of a multivitamin in preventing cardiovascular disease in men averaging 64 years of age over 11 years of follow-up.
Elevated plasma homocysteine levels are associated with an increased risk of vascular events. Although homocysteine levels can be reduced with dietary supplements of folic acid (1 mg/day) in combination with vitamin B6 and vitamin B12, two randomized clinical trials have shown that they are of little or no value in preventing vascular events.
For primary prevention, aspirin has little overall benefit, including for patients with established diabetes, and is no longer recommended for most patients. Antiplatelet therapy is a very effective measure for secondary prevention and patients with established vascular disease should be treated with aspirin. The exact dose of aspirin in chronic CAD (81 mg vs 325 mg) is being evaluated in a large ongoing pragmatic trial (ADAPTABLE). While clopidogrel was found to be effective at preventing vascular events for 9–12 months after acute coronary syndromes, and there are some benefits in prolonging dual antiplatelet therapy after coronary stenting, clopidogrel was not found to be effective at preventing vascular events in combination with aspirin with longer-term treatment in the CHARISMA trial. This trial included patients with clinically evident stable atherothrombosis or with multiple risk factors; all were treated with aspirin and observed for a median of 28 months.
In the COMPASS trial, rivaroxaban, a direct factor Xa inhibitor, at a dose of 2.5 mg twice daily in addition to 100 mg of aspirin, was shown to reduce cardiovascular death, MI, and stroke by a relative risk reduction of 24% compared to 100 mg aspirin monotherapy in stable patients with CAD and peripheral artery disease. Bleeding was modestly increased. All cause mortality was also reduced by 18%. This regimen is approved by the FDA and is used for long-term management of patients with CAD and peripheral artery disease.
The effect of hormone replacement therapy in postmenopausal women has been clarified, and it is clear that neither combined estrogen–progesterone nor estrogen alone therapy is protective. In fact, both cause harm, although hormone replacement therapy for short-term management of menopausal symptoms appears to be relatively safe. Transdermal estrogen may have lower risk of thromboembolic disease than oral hormone replacement therapy. Control of BP has been shown to prevent infarctions. Individuals who exercise for at least 30 minutes a week are at lower risk for subsequent coronary events, and 30 minutes of exercise five times a week reduces by half the risk of developing diabetes among people at risk.
The HOPE and the EUROPA trials demonstrated that angiotensin-converting enzyme (ACE) inhibitors (ramipril 10 mg/day and perindopril 8 mg/day, respectively) reduced fatal and nonfatal vascular events (cardiovascular deaths, nonfatal MIs, and nonfatal strokes) by 20–25% in patients at high risk, including patients with diabetes with additional risk factors or patients with clinical coronary, cerebral, or peripheral arterial atherosclerotic disease. The PEACE trial did not show benefit of the ACE inhibitor trandolapril in a lower-risk population of patients with CHD, most of whom had been treated aggressively with medical and revascularization therapies. An overview of these trials has demonstrated that while low-risk patients may not derive substantial benefits from ACE inhibitors, most patients with vascular disease, even in the absence of heart failure or LV dysfunction, should be treated with an ACE inhibitor.
ARBs may have similar effects as ACE inhibitors in preventing vascular events, as shown in the 25,620 patient ONTARGET trial that randomized patients to ramipril, telmisartan, or both. Outcomes were similar with ramipril and telmisartan, and there was no added benefit (and increased risk of kidney dysfunction and hypotension) with using both. However, the use of telmisartan in patients intolerant to ACE inhibitors did not show a significant benefit in reducing cardiovascular death, MI, stroke, or heart failure hospitalization in the TRANSCEND trial.
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