Pharmacotherapy for chronic cardiovascular disease in women

Although there is currently a widespread call for the use of evidence-based pharmacotherapy, the lack of solid data from studies often restricts its use in women. Women are still underrepresented in studies on coronary artery disease, heart failure, and rhythm disorders. Because of differences in pharmacokinetics, pharmacodynamics, and physiology, women frequently respond differently to cardiovascular drugs than men. Sex-specific differences include lower body mass index and smaller organ size in women, with larger distribution volumes in men. Women have a higher proportion of body fat, which may increase the distribution volume for lipophilic drugs.¹ Heart size is smaller in women², and resting heart rate is 3 to 5 beats faster than for men.^3,4 Length of the cardiac cycle in men is longer, whereas women have a longer corrected QT (QTc) interval and a shorter sinus node recovery time.^5,6

With regard to pharmacokinetics, there is some evidence of sex-specific differences in the activity of some drug-metabolizing enzymes. Men seem to have higher activities of CYP1A2, CYP2D6, and CYP2E1, whereas women appear to have a higher clearance rate for CYP3A4 substrates.^1,7-10 CYP3A4 contributes to first-pass metabolism of more than 50% of cardiovascular drugs. For CYP2C19 and CYP2D6, data are conflicting.^7,11,12 These differences become clinically relevant for substances with a narrow therapeutic margin, as is the case for most antiarrhythmic drugs.

Women have a 50% to 70% greater risk of having adverse drug reactions. Although the underlying reasons have yet to be elucidated, hormonal and immunological factors, in addition to differences in pharmacokinetics and pharmacodynamics, have been proposed.⁹

Beta-blocking agents

Major clinical outcome studies of beta-blocking agent therapy for secondary prevention after myocardial infarction (MI) have not included num­bers of women sufficient to en­able statistically significant findings.^13,14 A meta-analysis of 5 randomized studies with metoprolol (Lo­pres­sor, Toprol XL) that included a total of 5474 patients, however, showed a reduction in cardiovascular death that was similar in women and men.¹⁵ In heart failure, studies support the assumption that the use of beta-blocking agents tends to be associated with a more favorable prognosis for men than for women.

In the Metoprolol CR/XL Ran­domis­ed Intervention Trial in Con­ges­tive Heart Failure (MERIT-HF)¹⁶ and the Carvedilol Prospective Ran­domized Cumulative Survival (COPERNICUS) study,¹⁷ the mortality reduction for women was not significant. It was only in the post hoc analysis of the Cardiac Insufficiency Bisoprolol Study (CIBIS II)¹⁸ that the prognostic advantage for women was significant. Overall, the data for wom­en seem to be less favorable than for men. Once the findings of these 3 major studies on the use of beta-blocking agents for heart failure were pooled in a meta-analysis (with a total of more than 8900 female patients), results also showed a significant re­duction in mortality for women.¹⁹

Antagonists of the renin-angiotensin system

Angiotensin-converting enzyme (ACE) inhibitors are part of evidence-based therapy for heart failure. Two meta-analyses have shown a trend toward fewer benefits of ACE in­hibitor therapy for women with chronic heart failure than for men.^20,21 The combined analysis of 30 studies on ACE inhibitor therapy for heart failure showed a reduction of 37% in mortality or hospitalization for men, but only 22% for women.²⁰ Another meta-analysis of the use of ACE in­hibitors early after MI showed comparable favorable effects for both sexes with respect to prognosis and hospitalization rate.²² Women with asymp­tomatic left ventricular dysfunction appeared not to benefit from ACE inhibitor therapy.²¹

In the Heart Outcomes Prevention Evaluation (HOPE) study, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), and Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) study, ACE inhibitors were evaluated for the treatment of patients without the presence of left ventricular dysfunction.^23-25 In the HOPE study, ACE inhibitor treatment of high-risk wom­en was associated with a 38% reduction in mortality resulting from coronary events, results similar to those for men.²³ The EUROPA study confirmed the results from the HOPE study for men, but the findings for women were not significant.²⁴ The results of the PEACE study showed no significant differences between ACE inhibitor therapy and placebo for both sexes.²⁵ Taken together, data for women are less favorable than for men. More­over, the most frequent adverse reaction to ACE inhibitor therapy, coughing, arises more frequently in women and is 1.5-fold to 2-fold greater in women than in men.^26,27

The effects of treatment with angio­tensin I receptor antagonists on hypertension,²⁸ on heart failure,^29-31 and after MI^32,33 have been evaluated in major recent studies. There were no sex-specific differences shown in these studies. With the exception of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (in which 54% of the sample was wom­en), however, these studies in­cluded appreciably fewer women.³⁴

With regard to aldosterone antagonists, neither the Randomized Aldactone Evaluation Study (RALES), which evaluated the nonselective blocker spironolactone (Aldactone), nor the Eplerenone Post-Acute Myo­cardial Infarction Heart Failure Ef­ficacy and Survival Study (EPHESUS) showed sex-specific differences in subgroup analyses. The RALES study sample consisted of 27% women, and the EPHESUS study sample consisted of 28% women.^35,36

Calcium channel blocking agents

The major hypertension trials with calcium channel blocking agents have included comparable numbers of women and men. These studies have shown no evidence of sex-specific differences in outcomes.^37-41 The Amlo­dipine Cardiovascular Com­munity Trial (ACCT) showed that therapy with amlodipine (Norvasc) resulted in more pronounced blood pressure reduction in women. This effect depended on whether women were using hormone replacement therapy.⁴²

Digitalis

A post hoc analysis of the Digitalis Investigation Group (DIG) trial in patients with heart failure showed clear sex-specific differences. In contrast to men, women taking digoxin (Lanoxin) experienced a higher mortality rate (33.1%) compared with those taking placebo (28.9%).⁴³ The cause was attributed to a relatively excessive dosage in women. An additional crucial aspect is the use of hormone replacement therapy. In the Heart and Estrogen/Progestin Re­place­ment Study (HERS), women receiving hormone replacement therapy and digitalis experienced an in­creased incidence of coronary events in the first year of the study.⁴⁴

Antiarrhythmic drugs

Sex-specific differences in myocardial repolarization (longer QTc) have long been known.⁵ Women have shown a longer QTc interval than have men. The incidence of the acquired long QT syndrome, induced not only by antiarrhythmic drugs but also by a large number of other medications, is appreciably higher in women.^45-48 Class I and III antiarrhythmics, potentially associated with prolongation of the QT interval, more often lead to torsades de pointes tachycardia in women.^45-47 This has been shown for proca­inamide (Pro­canbid, Pronestyl), quinidine (Quinidex), ibutilide (Corvert), and sotalol (Betapace, Sorine).^46,48-50 Even while taking amiodarone (Cordarone), women apparently de­velop torsades de pointes tachycardia twice as frequently as do men.⁴⁷ Al­though available data favor the conclusion that women more frequently develop antiarrhythmic-in­duced pro­arrhythmias than men, the effect of this finding on prognosis is unclear.

Inhibitors of platelet aggregation

The benefits of aspirin for the secondary prevention of cardiovascular disease are well documented for women and men. Aspirin reduces the incidence of MI, stroke, and cardiovascular death by 25% for both sexes.⁵¹ Similarly, the benefits of aspirin for acute MI are well established for women and men.⁵² In contrast, the significance of aspirin for the primary prevention of MI in women is less clear. In the Hy­per­tension Optimal Treatment (HOT) study, aspirin re­duced fatal and nonfatal MI by 36% for the entire group, but not for women.⁵³ In the Primary Prevention Project (PPP) study, aspirin reduced cardiovascular events by 23% in the total group.⁵⁴ A recent analysis of the Women’s Health Study showed that although aspirin reduced the risk of stroke by 24%, it did not influence the risk of MI or mortality. It was only in the subgroup of older women (> 65 years) that aspirin was effective.⁵⁵

For clopidogrel (Plavix), no significant differences have been observed in plasma levels of the main circulating metabolite between women and men. With the exception of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, in which subgroup analyses showed that the beneficial effects of a “loading dose” of clopidogrel were comparable for women and men, neither the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which showed a prognostic advantage of clopidogrel over aspirin, nor the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) provided evidence of sex-specific differences.^56,57

HMG-CoA inhibitors

HMG-CoA inhibitors (statins) only show slight sex-specific differences in pharmacokinetics. In general, the plasma concentrations of statins are higher for women, and the risk of adverse drug reactions appears greater in women.^58-63 Cerivastatin, which is no longer on the market, was associated with an unacceptably high rate of myopathy and rhabdomyolysis, especially for older, thin women.⁶⁴ Major primary and secondary prevention studies have shown that statins reduce the risks of cardiovascular events equally for women and men.⁶⁵ A meta-analysis, which covered 10 outcome studies with a total of 79,494 subjects, showed a relative risk of severe coronary events of 0.73 for men and 0.77 for women.⁶⁶ Despite the beneficial effects, statins are used less frequently in women for the primary and secondary prevention of cardiovascular diseases.⁶⁷

Conclusions

A general problem of sex-specific analyses is that women are often un­derrepresented in end point studies, and statements are mostly reached via subgroup, post hoc, or meta-analyses. Despite these limitations, relevant sex-specific aspects of long-term cardiovascular therapy can be summarized as follows:

• Beta-blocking agent therapy after MI and for heart failure exhibits similar benefits for women and men. For women, however, the plasma levels are higher, the reduction in blood pressure is more pronounced, and the increase in exercise heart rate is lower.

• The use of ACE inhibitors for the treatment of heart failure tends to be less effective for women in terms of mortality and morbidity reduction. Adverse drug reactions in the form of cough also occur twice as frequently in women.

• Outcome studies have shown no relevant sex-specific differences with regard to mortality and morbidity with the use of calcium channel blocking agents. Reduction in blood pressure, however, is more pronounced in women.

• There is evidence of higher mortality in women taking digitalis for chronic heart failure. The cause is assumed to be excessive dosage.

• With antiarrhythmic therapy, pro­arrhythmias in the form of torsades de pointes tachycardia occur more frequently for women than for men.

• The benefits of aspirin for the secon­dary prevention of cardiovascular diseases are equally well documented for women and men. Aspirin’s benefit for pri­mary prevention in women is less clear.

• For statins, primary and secondary prevention studies have shown comparable beneficial effects for women and men.

To improve data quality for wom­­en, future studies should be large enough to ensure an appropriate in­clusion rate for women, dosage should be adapted to weight, and hormonal aspects, such as concomitant hormone therapy, should be systematically in­corporated into the analysis.