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Prescription of Statins to Women Poses New Clinical Challenges

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In women and men, cardiovascular disease is and will remain the leading avoidable cause of premature death in the United States and is rapidly becoming so worldwide.1 Although many women fear breast cancer more than cardiovascular disease, 1 in 8 will develop and 1 in 25 will die of this disease, whereas more than 1 in 3 will die of coronary heart disease and 1 in 6 will die of stroke.2

In women, the primary prevention of cardiovascular disease should include therapeutic lifestyle changes of proven benefit, such as avoidance and management of obesity3 and physical inactivity.4 In addition, drugs of proven benefit are effective, optimally as adjuncts, but also even in the absence of therapeutic lifestyle changes.1In this Commentary, we provide updates on statins in women in both secondary and primary prevention.

In high-risk secondary prevention, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT) trial randomized 4162 patients who recently survived an acute coronary syndrome to 80 mg of atorvastatin or 40 mg of pravastatin daily. The achieved levels of low-density lipoprotein cholesterol were 95 and 62 mg/dL, respectively. Patients assigned to atorvastatin experienced a significant 16% (95% confidence interval [CI], 0.74-0.95) reduction in the primary prespecified end point of myocardial infarction, documented unstable angina requiring hospitalization, revascularization, stroke, or death. In women, those assigned to atorvastatin had a significant 25% reduction (relative risk [RR], 0.75; CI, 0.57-0.99; P = .04). Men also experienced a significant 14% reduction (RR, 0.86; CI 0.75-0.99; P = .04) with no significant difference by gender (P interaction = .38). With respect to safety, there were no significant differences by gender. The authors concluded that the trial provides evidence that women and men derive similar benefits from intensive statin therapy after acute coronary syndrome. In addition, gender should not be a factor in the prescription of intensive statin therapy for secondary prevention.5

In primary prevention, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial6 randomized 17,802 apparently healthy men and women to 20 mg of rosuvastatin daily or placebo. The achieved levels of low-density lipoprotein cholesterol were 55 and 109 mg/dL, respectively. The trial was terminated early, after 1.9 years of treatment and follow-up, by the independent Data and Safety Monitoring Board because of the emergence of a statistically extreme (P < .001) 44% reduction in the primary prespecified end point of myocardial infarction, stroke, arterial revascularizations, hospitalizations for unstable angina, or death from cardiovascular causes. There was also a significant 20% reduction in total mortality. Women and men experienced significant reductions of 46% and 42%, respectively. Subsequently, in a meta-analysis of statins in primary prevention in women, there was a significant 37% reduction (RR, 0.63; CI, 0.49-0.82; P < .001).7

Several comprehensive meta-analyses, using individual patient data of trials designed a priori to test the hypothesis of whether statins reduce clinical cardiovascular disease events, have been performed by the Cholesterol Lowering Trialist’s Collaboration. They include 174,149 subjects, of whom 46,675 (27%) were women who ranged from high-risk secondary patients to low-risk primary prevention subjects.8, 9, 10 There were 22 trials of statin versus placebo or open control (n = 134,537) and 5 trials of more versus less-intensive statins (n = 39,612). The prespecified end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

In the first meta-analysis of secondary and high-risk primary prevention patients, the reductions were 17% (RR, 0.83; 99% CI, 0.76-0.91) in women and 22% (RR, 0.78; 99% CI, 0.75-0.81) in men. For more versus less statins, the reductions were 19% for women (RR, 0.83; 99% CI, 0.76-0.90) and 23% for men (RR, 0.77; 99% CI, 0.74-0.80).8

In a second meta-analysis,6 the effects were weighted per 1.0 mmol/L (38 mg/dL) reduction in low-density lipoprotein cholesterol. The proportional reductions were similar for women (RR, 0.84; 99% CI, 0.78-0.91) and men (RR, 0.78; 99% CI, 0.75-0.81, adjusted P value for heterogeneity by sex = 0.33).9

In a third meta-analysis of low-risk primary prevention of women and men at less than 10% predicted 10-year risk, there were no significant differences by gender in the proportional reductions (adjusted heterogeneity P = .11). The observed net benefits with statin therapy included significant reductions in total mortality for women (RR, 0.91; 99% CI, 0.84-0.99) and men (RR, 0.90; 99% CI, 0.86-0.95) with, once again, no apparent heterogeneity by gender (P = .43). The investigators concluded that in women and men at an equivalent risk of cardiovascular disease, including those previously considered ineligible because of their relatively low absolute risk, statin therapy provides similar benefits.10

The totality of evidence includes numerous individual trials designed a priori to test the hypothesis of whether statins reduce clinical cardiovascular disease events, as well as several comprehensive meta-analyses using individual patient-level data. In women and men who range in risk from high-risk secondary to low-risk primary prevention, statins confer similar statistically significant and clinically important benefits on cardiovascular disease. The primary prevention trials include women at higher and lower risks, as well as those previously considered to be ineligible for statins. Statins are safe for long-term use in men and women but are contraindicated during pregnancy because of their potential to cause birth defects.1

The currently available evidence poses new clinical challenges for healthcare providers. First, in women and men, the lower the low-density lipoprotein cholesterol level the better, and there is no clear threshold for below which there are no incremental benefits. Interestingly, in the primary prevention trial with rosuvastatin,6 women achieved a level of 50 mg/dL and experienced significantly increased clinical benefit compared with those at 109 mg/dL. Second, although the absolute risks of women are lower than that of men and begin to increase after the menopause, those at equivalent risk experience similar benefits of statins in both secondary and primary prevention. Third, 40% of women aged 40 years and older have metabolic syndrome, a constellation of obesity, dyslipidemia, hypertension, and insulin resistance leading to diabetes mellitus. Their risks are almost as high as those who have survived a prior event, so, despite therapeutic lifestyle changes, they are likely to require statin therapy.1 Thus, in women as well as men, the more widespread and appropriate use of statins, as adjuncts, not alternatives to therapeutic lifestyle changes, will yield net benefits.

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-Madeline Pung, BS, Janet Robishaw, PhD, Marc A. Pfeffer, MD, PhD, Charles H. Hennekens, MD, DrPH

This article originally appeared in the October issue of The American Journal of Medicine.

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