From the Recent Literature: Further Insights on Major Themes

The medical literature keeps piling up in ways that reinforce the fundamental messages I have been ragging on about in this blog. For a couple of examples, join me as I visit the November, 2010 issue of "Primary Care Medical Abstracts" put out by my good friends Drs. Richard Bukata and Jerry Hoffman. This, for those who came in late, is a series of audio recordings of comments on 30 representative journal articles each month of interest to primary care docs. I had to go three deep into their list of 30 abstracts to come up with two prize examples.

The first study, from Denmark, looked at bleeding complications in about 40,000 patients who had been placed on an anti-clot drug following a heart attack. It has been generally agreed that in this very-high-risk group, such treatment is beneficial. But the number of complications the Danes discovered is sobering. They counted it as a serious complication if the bleeding was so bad that you either died, or had to be admitted to the hospital. (As Rick noted, a nick while shaving did not qualify.) Here are the risks (per person-year) of having such a major bleed depending on the drug you were taking:

• Aspirin: 1 out of 40
• Coumadin/warfarin or similar: 1 out of 23
• Clopidogrel (Plavix): 1 out of 22
• Aspirin plus Plavix: 1 out of 27
• Plavix plus Coumadin: 1 out of 8

In the previous post I reminded you of the statitics that suggest that appoximately 111,000 Americans die every year as a result of prescription medicines properly taken. You might well wonder how properly prescribed drugs could be so harmful. Well, here's one example. It is generally agreed that these drugs are needed in the setting of recent heart attack. Yet when you figure out how many people are likely to have serious bleeding, given the odds quoted above, you start to add up to large numbers of folks.

Next study: A team based at Cambridge, UK did a meta-analysis of 11 studies of statin drugs used to lower cholesterol in patients who are at high risk for coronary artery disease, but so far have not had a heart attack or other vascular event (primary prevention studies). We have noted in previous posts that statins definitely seem useful in secondary prevention (once you've had a heart attack or vascular event); that they appear to be questionably useful, if at all, in primary prevention generally; and as you get into higher and higher risk populations, you start to get more potential benefit in primary prevention, even if the number needed to treat remains high.

These investigators decided to look at an important study endpoint, all-cause mortality. Many statin trials produce paradoxical results. They show decreased mortality from heart disease, but no reduction in all-cause mortality, meaning more patients must die of something other than heart disease to make up the difference. These investigators decided to use all-cause mortality as their endpoint, reasoning that if you die, you are probably not a happy camper, regardless of exactly what you die of.

They found that there was no statistically significant likelihood that statins decreased all cause mortality across the 11 trials, though there was a trend in that direction. Conclusion: either statins do not reduce your overall risk of dying, or else the evidence for such an outcome is quite modest--even if you start out at quite high risk for a heart attack. If you decide that the right answer is "modest evidence" rather than "none," their data translate into a number needed to treat of 1428 for 1 year. That is, 1428 people would have to take statins for a year in order for one of them not to keel over dead. Rick and Jerry add that the total subject population in these 11 trials was 65,000. If you cannot find a statistically signifiant benefit from statins from studying that many people, it is quite unlikely that statins have any benefit to write home about, again as a primary prevention drug specifically.

Also driving home another point I've made before, in the 65,000 folks in these studies, their LDL ("bad") cholesterol dropped from 138 to 94, which by most estimates is a substantial drop. Despite this there were no, or only a very small number, fewer deaths. So it seems increasingly likely that whatever good statins might do for some people in some circumstances, it is probably not a result of their cholesterol lowering properties but for some other reason.

Take home message: Once again we see that the modern medical mantra, that everyone with high cholesterol should be tested and placed on a statin for prevention, is based on company marketing much more than science--even though all the supposedly "evidence-based" guidelines say that this is what you should do.

Sorensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 374:1967-74, December 12, 2009.

Ray KK, Seshashi SR, Ergou S, et al. Statins and all-cause mortality in high risk primary prevention. Archives of Internal Medicine 170:1024-31, June 28, 2010.