Statins, Cholesterol, Women and Primary Prevention: Evidence-Based Medicine or Wishful Thinking?

Theodore Eisenberg; Martin T. Wells

Disclosures

Future Cardiol. 2009;5(1):1-4. 

A basic tenet of modern cardiology is that elevated cholesterol increases the risk of myocardial infarction (MI). Significantly lowering cholesterol should, therefore, reduce MI risk. Statins reduce cholesterol and, in some contexts, adverse heart outcomes, but meta-analyses of primary prevention clinical statin trials have found no statistically significant cardioprotective effect for women.[1,2,3,4] These meta-analyses reasonably reflect the individual primary prevention trials. Of these studies, none showed statistically significant cardioprotection for women and some yielded hazard ratios exceeding one.[5,6,7,8,9] The meta-analyses are consistent with the absence of effect for women in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), atorvastatin's (Lipitor®) primary prevention clinical trial, and are also consistent with the unpublished Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women (CASHMERE) atorvastatin clinical trial,[27] which demonstrated no improvement in carotid intima-media thickening (IMT) in a study limited to postmenopausal women. The cholesterol-heart attack link and the achievement of lowered cholesterol without protective effect is an important scientific puzzle.

Several responses exist in regards to the absence of evidence of primary prevention benefit for women despite lowered cholesterol. First, the negative CASHMERE results have been dismissed by some owing to the IMT end point used.[28] Second, primary prevention benefits for women have been claimed based on extrapolation from men, as stated by the National Cholesterol Education Program (NCEP).[10] Third, the absence of primary prevention benefits for women might be ignored in light of evidence of women benefiting in some secondary prevention clinical trials. These responses are not fully satisfactory solutions to the puzzle.

Dismissal of CASHMERE based on the IMT end point is questionable given the primary prevention studies that do not use a proxy end point. It is also inconsistent with the approval and marketing of statins based on clinical trials demonstrating the effects using an IMT end point. IMT cannot credibly be suspect only when it yields a negative result. Carotid IMT progression meets accepted definitions of a surrogate marker for cardiovascular disease and atherosclerotic progression end points in statin trials.[11] Several statin studies have yielded positive IMT results. For example, Kuopio Atherosclerosis Prevention Study (KAPS), a primary prevention study of the effect of pravastatin on arterial thickening in men with elevated cholesterol, yielded a beneficial result.[12] Asymptomatic Carotid Artery Progression Study (ACAPS), a lovastatin study, demonstrated an improvement in IMT for both men and women in a population that included asymptomatic women.[13] The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) trial assessed the effects of pravastatin on moderately hypercholesterolemic patients and found beneficial IMT results.[14] Dismissal is also inconsistent with recommendations of children being placed on statins based on IMT studies.[15]

The NCEP position that the "rationale for therapy is based on extrapolation of benefit from men of similar risk"[10] is not fully consistent with the finding that statistically significant heterogeneity exists across primary prevention results for men and women.[1] It is not just that there is no direct evidence of benefit for women, the heterogeneity suggests that extrapolation from men to women is statistically inappropriate. For atorvastatin, the hypothesis is also inconsistent with the negative results in CASHMERE.

That leaves extrapolation from secondary prevention women's results to support primary prevention statin use, yet the risk profiles for women in the two groups obviously differ. Such extrapolation might be considered if the primary and secondary prevention results for women are sufficiently homogeneous. This has not been demonstrated, and even if it were the puzzle of the absence of effect in primary prevention trials would remain.

Concern about the absence of evidence of benefit for many women increases given the known adverse effects of statins and their widespread use, possibly resulting in billions of wasted healthcare dollars. However, for some groups of reasonably healthy women, the concern may run deeper than the absence of benefit and wasted money. Some primary prevention clinical results raise the possibility of not only the absence of cardioprotection, but also of increased cardiovascular risk for some women.

The key primary prevention atorvastatin trial ASCOT demonstrated a 10% (not significant) increased risk of heart problems for women compared with placebo. The point estimate of increased risk in ASCOT for nondiabetic women exceeds 10% since a separate analysis of diabetics in ASCOT yielded a risk ratio of 0.9 for women.[16] Since approximately 25% of the subjects in ASCOT had diabetes, the mildly protective effect for female diabetics suggests that the rest of the ASCOT female subjects were at increased risk of heart problems by more than 10%. This increased risk might be even higher since 14% of ASCOT subjects had other cardiovascular disease (some of whom might also have had diabetes) and might, therefore, be regarded as secondary prevention subjects for whom atorvastatin presumably decreased the risk. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) pravastatin trial[9] showed a substantially increased risk of coronary heart disease plus cerebral infarction for women aged less than 60 years old (IR: 1.98; exact p = 0.096), and statistically significant heterogeneity between women aged less than 60 years and women aged greater than or equal to 60 years. The MEGA trial's open-label methodology suggests caution in putting great weight on its results but, together with ASCOT, counsels against unthinking prescription of statins for reasonably healthy women on the basis of hypothesized cardioprotection.

Without robust evidence of benefits of primary prevention statin use in women with elevated cholesterol, and some evidence of cardiac risk for some statins or subgroups of women, the cardiology tenet may need to be rethought and increased credence given to those who have questioned it.[17] In particular, how can some statins simultaneously lower cholesterol, not reduce heart risk and even be mildly associated with increased risk for some subgroups of women? Of course the absence of evidence of beneficial effect does not establish the absence of benefit. But the scientific burden of proof of benefit traditionally is on the proponent of the treatment.

Perhaps the anti-inflammatory effect of statins reduces adverse heart outcomes, as suggested by the Justification for the Use of Statins in Primary Prevention: Intervention Trial Evaluating Rosuvastatin (JUPITER)[18] trial results that demonstrate that lowering high-sensitivity C-reactive protein (CRP) levels in men and women with high CRP, but without elevated cholesterol, is associated with improved heart outcomes. CRP's sex-based differences might explain the pattern of statin results.[19,20] Evidence suggests that CRP is a better predictor than elevated cholesterol of cardiovascular events in women.[21] Under this hypothesis, the cholesterol-lowering tenet has been an obstacle to understanding the pattern of statin results, as least for women. Skepticism concerning the evidence supporting cholesterol as a risk factor for women can be traced to discussion of the Framingham results.[22] JUPITER's relation to results from primary prevention studies of women is ambiguous because the confidence interval for women in JUPITER overlaps minimally, if at all, with the cumulative confidence interval for women in an existing primary prevention meta-analysis.[1]

Evidence-based concerns regarding primary prevention statin use also raise questions about the US FDA-based system regulating drug approval and advertising. It is troubling that the system permits approval of prescribing and marketing to women without requiring a large enough primary prevention study to resolve the uncertainty concerning the direction of atorvastatin's effect for women with elevated cholesterol. Some women may be having heart attacks because of statins and the FDA has not used its authority to shed light on that question, either by withholding approval or by conditioning continued approval on conduct of the needed study. With sales of atorvastatin alone exceeding $US 1 billion per month, the cost of conducting the necessary tests is not a reasonable excuse for failure to conduct the tests.

With respect to advertising, Pfizer (USA) markets atorvastatin as preventing heart attacks. The advertising does not disclose that the drug was associated with increased risk to women, not decreased risk, and the physician who only reads the main ASCOT article's abstract does not learn of the possibly increased risk to women. Physicians who use the 'health professionals' portion of Pfizer's website are not told of the CASHMERE results or of the women-specific ASCOT results.

The failure to effectively report the CASHMERE results to health professionals raises another legal question. Under state tort law, the 'learned intermediary' doctrine sometimes insulates manufacturers from liability based on the presumed knowledge and expertise of an expert intermediary - in this case a doctor. If doctors lack full information regarding a drug's efficacy or safety, the assumption underlying the learned intermediary doctrine - the expert's knowledge - is not warranted and the doctrine is of questionable applicability.

Medical journals may also have a role to play in encouraging effective disclosure of negative clinical trials. The problem of publication bias seems well established.[23] Many journals already have rules precluding publication of clinical trial results in place unless the trials are preregistered.[24,25] The rules have been demonstrated to improve reporting of clinical trials.[26] Journals might consider a company-based rather than a study-based principle. Pharmaceutical companies that fail to publish, publicize or effectively communicate negative results might be barred from publication in leading journals any studies they fund.

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