How is my high cholesterol treated if I already have heart disease or have had a stroke?

The 2018 American Heart Association/American College of Cardiology (ACA/AHA) Guideline on the Management of Blood Cholesterol strongly recommends a heart-healthy lifestyle for all individuals to lower the risk of cardiovascular disease.¹ The guideline also strongly recommends lipid-lowering drugs to reduce cholesterol levels for anyone who has preexisting disease of the heart or blood vessels (clinical atherosclerotic cardiovascular disease, or ASCVD). People who already have heart disease have a higher risk of having a future heart attack or stroke than those who do not.^2,3 There is also strong evidence that elevated levels of low-density lipoprotein cholesterol (LDL-C) increases the risk of heart disease and stroke and the risk rises as blood concentrations of cholesterol increase.^4,5

According to current guidelines of the AHA and the ACC, a heart healthy lifestyle includes a diet that is rich in vegetables, fruits, whole grains, legumes, non-tropical vegetable oils, and healthy proteins.^6,7 The guidelines also recommend limiting the intake of sweets, sugar-sweetened beverages, and red meat. Caloric requirements should be determined by the need to avoid weight gain or to lose weight if you are overweight in order to minimize risk for ASCVD.

Lipid-lowering medication, and specifically statins, are recommended for anyone with clinical ASCVD to lower LDL-C.¹ Randomized controlled trials and meta-analyses have demonstrated the beneficial effects of statin therapy on the prevention and treatment of ASCVD.^8,9 More intensive statin therapy has been shown to further reduce the incidence of heart attack and stroke when compared with less intensive regimens of statin therapy.^10,11 Other drugs have also been shown to reduce LDL-C including ezetimibe and PCSK9 inhibitors, and may be recommended in addition to statins, under certain circumstances.^1,11

High-intensity statin therapy is recommended for adults ≤75 years of age with pre-existing ASCVD to lower LDL-C levels by 50% or more from baseline.¹ Examples of high-intensity regimens are atorvastatin ≥40 mg/day and rosuvastatin ≥20 mg/day. Moderate-intensity regimens that reduce LDL-C levels 30% – 49% may be substituted in patients with contra-indications to high-intensity treatment or patients who experience adverse side effects from high-intensity treatment.

For people with clinical ASCVD considered to be at very high risk, a secondary goal is to lower LDL-C levels below 70 mg/dL.¹ These include people who have had multiple major ASCVD events or who have multiple high-risk conditions (diabetes, hypertension, chronic kidney disease, heart failure, smoking, age ≥65 years, prior surgical or percutaneous cardiac intervention, or persistent elevations of LDL-C ≥100 mg/dL). If high intensity statin therapy is inadequate to reach this goal, non-statin therapy, specifically ezetimibe, is recommended. If that regimen is still inadequate, it is reasonable, according to the 2018 guidelines, to consider PCSK9 inhibitor therapy, after clinician-patient discussion of net benefit, safety, and cost.

The addition of non-statin drugs to further lower LDL-C is based on recent evidence of their effectiveness in further lowering risk in patients with clinical ASCVD. Wilson et al. conducted a systematic review of 10 randomized controlled trials that compared risks and benefits from statin therapy alone with regimens that added other lipid-lowering therapies to statin treatment.¹² Sample size in the 10 studies ranged from 3,414 to 30,449 patients with known ASCVD or at high risk of ASCVD.  In their analysis, patients taking ezetimibe achieved a median LDL-C of 54 mg/dL, while patients taking the PCSK9 inhibitors, alirocumab and evolocumab, achieved median LDL-C levels of 48 mg/dL and 30 mg/dL, respectively. These reductions were associated with reductions in major vascular events (a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke). The hazard ratio (HR) for major vascular events in patients taking ezetimibe was 0.90 (95% confidence interval [CI] [0.84 – 0.96]), in patients taking alirocumab was 0.85 (95% CI [0.78 – 0.93), and in patients taking evolocumab was 0.80 (95% CI [0.73 – 0.88]). The rates of adverse effects did not differ significantly between treatment and control groups.^12,13

Cannon et al. conducted a randomized double-blind trial of patients hospitalized with acute coronary syndrome with LDL-C levels between 50 and 125 mg/dL (n= 18,144).¹⁴ They followed patients for a median of six years and compared outcomes (composite of cardiovascular deaths, nonfatal myocardial infarction, unstable angina, coronary revascularization, or nonfatal stroke) between patients taking simvastatin 40 mg and ezetimibe 10 mg with patients taking simvastatin 40 mg and placebo. Median LDL-C levels achieved in the simvastatin-ezetimibe group was 53.7 mg/dL compared to 69.5 mg/dL in the simvastatin-placebo group (p<0.001). The adverse cardiovascular event rate in the six years of follow-up in the simvastatin-ezetimibe was 32.7% compared to 34.7% in the simvastatin-placebo group (HR 0.936, 95% CI [0.89 – 0.99], p=0.016), a small, but statistically significant effect size.

Ezetimibe is the most commonly used non-statin lipid-lowering drug. The decision to recommend ezetimibe as the first add-on to statin therapy was based on its availability as a generic drug, its proven safety, and the low incidence of side effects in studies in large numbers of high-risk patients.^14–16

PCSK9 inhibitors have demonstrated effectiveness as LDL-lowering drugs.^1,17,18 The addition of the PCSK9 inhibitor alirocumab to a maximally tolerated statin regimen was shown to reduce LDL-C levels by 50.6% ± 1.4% compared to 20.7% ± 1.9% for ezetimibe after 24 weeks of therapy (p<0.0001).¹⁷ Sabatine et al. followed 4,465 patients in an open-label randomized trial comparing the PCSK9 inhibitor evolocumab plus standard therapy versus standard therapy alone for a median of 11 months. After three months, the LDL-C level was reduced to 70 mg/dL or less in 73.6% of patients in the evolocumab group, as compared with 3.8% in the standard-therapy group. The rate of cardiovascular events at one year was 2.1% in the standard therapy group compared to 0.95% in the evolocumab group (HR 0.47,95% CI [0.28 – 0.78], p=0.003).¹⁸ Further study of longer duration is needed to evaluate the effect of PCSK9 inhibitors on the rate of cardiovascular events over the long term.  The incidence of serious side effects were not significantly different between the two groups¹⁸ but long-term safety remains to be proven.^19,20 In addition, the high cost of PCSK9 therapy warrants consideration as clinicians discuss its relative value in risk reduction.¹

The 2018 ACA/AHA cholesterol guidelines considered the use of statins and other lipid-lowering drugs in patients with ASCVD who are older than 75 years of age.¹ Because the evidence in this age group is less strong and because of the increased potential in this age group to have co-morbidities and drug-drug interactions, the guidelines consider it reasonable to continue therapy if tolerated. Initiation of high-intensity lipid-lowering treatment in this age group should be considered only after weighing potential for risk reduction, patient frailty, and patient and family preferences.

^References

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