Statins for Women – Statistical Acrobatics

Statins for Women - Statistical Acrobatics

When to prescribe statin therapy for people without established cardiovascular disease is a hotly debated issue among medical doctors. Recent clinical guidelines have recommended extending the use of these drugs to reduce the burden of cardiovascular disease.

Recommendations on statin use are to a large extent based on meta-analyses on data from randomized controlled trials, either comparing statins to placebo or more intensive statin therapy to less intensive statin therapy. However, results from such meta-analyses are often difficult to implement into clinical practice.

For many reasons, detecting a statistically significant treatment effect in a large population may not always be very meaningful to individual patient care. Patients selected for participation in clinical trials often poorly reflect the general population seeking health care. Furthermore, meta-analyses of clinical trials often underestimate the risk of adverse effects.

Therefore, despite a huge amount of data, many issues regarding statin treatment remain unresolved. For example, it has been pointed out that statins may be less effective for women than men although some believe this is due to under-representation of women in statin trials.

Clinicians need all the help and information they can get. Therefore, I was hoping for guidance from a paper from the Cholesterol Treatment Trialists’ (CTT) Collaboration published in The Lancet this week, comparing the effects of statin therapy in women and men.

The researchers performed a meta-analysis on 27 trials of statin therapy. As in previous studies from the same group, the efficacy of treatment is weighted by the difference in LDL cholesterol after one year between the statin vs. control arm for that particular trial. Whether this is the best or the most appropriate approach is a matter of debate but will not be discussed further here.

The study found that the proportional reduction in major cardiovascular events per 1.0 mmol/L reduction in LDL cholesterol was the same for men and women (risk ratio for women 0.84, 99% CI 0.78-0.91; risk ratio for men 0.78, 99%CI 0.75-0.81). These results were achieved by using statistical methods to correct for “important non-sex differences between women and men”.

The authors of the paper conclude that in men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major cardiovascular events.

Irrespective of sex, statins reduce cardiovascular events and all-cause mortality. Benefits greatly exceed known hazards, even among individuals at low absolute cardiovascular risk. In view of the substantial burden of cardiovascular disease in both developed and developing countries, and the widespread availability of generic statins, these results suggest they are an effective means to prevent such disease among women as well as men.

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“Ma’am. It’s Time to Take Your Statin!”

How will these new data help the clinician understand the potential efficacy of statins for healthy women at elevated risk of cardiovascular disease?

Statins and Outcome in People Without Cardiovascular Disease

The outcomes that were recorded by the investigators were major vascular events, major coronary events (defined as non-fatal heart attack or coronary death), coronary revascularization (angioplasty or bypass grafting), stroke, site-specific cancers and cause-specific mortality.

Individuals with no known cardiovascular disease were addressed separately. It is important to acknowledge that these were not necessarily healthy people, some had renal disease or diabetes, both of which are associated with increased risk of cardiovascular disease.

Among men, the annual risk of major vascular events was 1.5% on statins or more-intensive statin therapy, but 2.1% among those on placebo or less intensive statin therapy. The corresponding numbers for women were 1.3 and 1.4%.

The risk ratio per 1 mmol/L reduction in LDL cholesterol was 0.72 (0.66-0.80) for men and 0.85 (0.72-1.00) for women, statistically in favor of statin therapy. However, for the sake of the clinical perspective, it is worth looking more closely at the numbers.

The calculated absolute risk reduction in a year is 0.6% for men and 0.1% for women. Consequently, 167 men and 1.000 women will have to be treated for a year to prevent one major vascular event.

I won’t go into details regarding the risk of adverse effects but suffice to say that a meta-analysis has shown that treating 255 patients with statins for four years led to one extra case of diabetes.

Mortality

Mortality was addressed for the whole group. There was no separate analysis for those without known cardiovascular disease.

Overall, statin therapy produced a 12% relative reduction in vascular mortality (risk ratio 0.88, 95% CI 0.84-0.91) per 1.0 mmol/LDL cholesterol reduction. However, the risk reduction was not significant when looking at the women separately (risk ratio 0.92 (0.82-1.03)).

However, all-cause mortality was significantly reduced for both women (risk ratio 0.91, 99% CI 0.84-0.99) and men (risk ratio 0.90, 99% CI 0.86-0.95).

The annual death rate for men was 2.4% in the statin/high-intensity statin group and 2.6% in the placebo/low-intensity statin group. The corresponding numbers for women were 2.0 and 2.2%.

Thus, the absolute risk reduction for both men and women was 0.2% which means that 500 individuals will have to be treated for a year to prevent one death. Again, this analysis represents the whole study population, with and without known cardiovascular disease.

Statins for Women – Statistical Acrobatics

The evidence for the benefits of statin therapy in men and women with established cardiovascular disease is well established.

The recent meta-analysis from the CTT Collaboration addresses the question whether the efficacy of statins differs between women and men. Although they seem to believe otherwise, the CTT investigators fail to prove that the effect of statins in women without known vascular disease is clinically meaningful.

Furthermore, despite the statistical acrobatics, their results still suggest that statins are less effective for women than men in primary prevention. Of course, this may be due to women, in general, having lower risk than men. The use of statistical methods for the purpose of proving otherwise is of limited practical value.

The CTT investigators claim that statins are an effective means to prevent cardiovascular disease in women as well as men. However, they acknowledge that their meta-analysis had limited ability to detect adverse effects in general and no ability to detect such effects beyond five years of therapy.

With regards to primary prevention, the high number needed to treat to prevent an event highlights the fact that the great majority of those treated with statins will not benefit. This is particularly true for women.

So from the clinician’s perspective, the CTT investigators have failed to provide any useful arguments to convince women without known cardiovascular disease to take statin drugs.

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