Important reading for all of us.
Lessons of the Heart
AMERICAN.COM
By John E. Calfee
Tuesday, April 03, 2007
A surprising new study on heart disease treatments won't just change medicine—it will help shape basic science.
Last week, the American College of Cardiology, whose marketing skills approach those of the pharmaceutical industry, provided a stage for clinical trial results comparing ways to prevent heart attacks. Essentially, the COURAGE study asked whether stents—tiny steel mesh tubes inserted in a partly closed artery feeding the heart—would prevent heart attacks and deaths when they were added to aggressive drug therapy consisting mainly of blood thinners, anti-hypertensives, and the renowned statin class of cholesterol-reducers (Lipitor, Crestor, Zocor, and their competitors). The main medical results of the study were simultaneously posted at the New England Journal of Medicine website along with an editorial comment.
The news headlines focused on the implications for treatment. But the COURAGE results are important for another reason. They offer a new window into a remarkable relationship in which results from large-scale tests of medical technology feed back into basic research in biology and the causes of disease. That long and complex feedback process is probably far more important than the coming changes in stent usage.
This trial provided lots of fascinating results, some of them reaffirming and some simply stunning. Almost everyone expected stents to do better than drugs at relieving symptoms like angina (heart muscle pain caused by a lack of oxygen), but most cardiologists probably didn't expect drugs to do as well as stents over the long run, which they generally did. The real surprise was that when added to aggressive drug therapy, stents added essentially nothing in terms of preventing heart attacks and deaths. "When I saw the results, I was incredulous," said William Boden, lead author of the New England Journal of Medicine article, at the A.C.C. press conference. One reason the stents had no impact was that drugs were so effective. Most of these patients suffered from angina and multi-vessel arterial occlusion; 38 percent had had heart attacks. Yet only 8 percent died in almost five years. That was mainly due to drug therapy, as life-style changes (in smoking, weight, and exercise) were minimal.
Does this mean that most coronary heart disease patients—those who have not just arrived at the E.R. with a heart attack—can forget about stents? That is unlikely. Relief from angina pain is of great value. Moreover, inducing patients to comply with the aggressive drug therapy employed in COURAGE is not easy. Finally, COURAGE used older "bare-metal" stents. Newer "drug-eluting" stents slowly release a drug to prevent restenosis—the accumulation around the stent of the fatty arterial plaque that, one way or another, causes most heart attacks. Drug-eluting stents drastically reduce restenosis rates, but they apparently also sometimes cause blood clots later on, which can lead to heart attacks and strokes. Still, on the whole, drug-eluting stents are better for a lot of patients than the bare-metal stents they tended to replace, and a new generation of drug-eluting stents already available in Europe promise to be even safer.
What does this have to do with basic research? The COURAGE trial adds to the ceaseless flow of hypothesis-rejecting data from long, large-scale, and very expensive trials of medical technology, mainly drugs but also, as in this case, medical devices. To the layman and to some cardiologists, these latest results were astonishing and counter-intuitive. How can the act of clearing and propping open partly blocked coronary arteries fail to reduce heart attacks? The apparent answer, as noted by other cardiologists, is that most heart attacks have little directly to do with the gradual closing off of coronary arteries by the growth of plaque. Heart attacks are usually caused by ruptures of arterial plaque, often in arteries with relatively little blockage. Tiny amounts of escaped plaque form clots that cause problems someplace closer to the heart itself. Opening up a couple of highly occluded arteries may therefore make relatively little difference once an immediate crisis (such as a heart attack) has passed. The keys to preventing future heart attack are reducing arterial plaque generally and, especially, dampening the forces (which almost certainly include inflammation) that cause plaque to rupture. That is where the statins apparently do things that stents cannot do. In fact, earlier, less definitive trials had also failed to find that stents prevented heart attacks or deaths in comparison to drug therapy.
This study adds to the ceaseless flow of hypothesis-rejecting data from long, large-scale, and very expensive trials of medical technology.
How do we know where heart attacks come from? The answer lies in feedback from pharmaceutical clinical trials to basic research. Long before the stent trials began to upset received wisdom, massive trials of heart drugs had first validated previously controversial hypotheses and then upset the next generation of hypotheses. Eventually, these trials pushed basic research in unexpected directions.
In the 1950s through the 1970s, an intense intellectual battle raged over the role of what came to be called low-density lipoprotein cholesterol (LDL-C, or "bad" cholesterol for short). Higher LDL-C levels in the blood were associated with heart attacks, but cholesterol is also necessary to life and is spontaneously synthesized throughout the body. There was no way science could resolve the causation question: does higher LDL-C actually cause heart attacks, and would reducing cholesterol through diet and drugs prevent heart attacks? What was needed was a reliable way to push cholesterol levels down fast enough and far enough to test the "cholesterol hypothesis" in randomized clinical trials. Statins proved to be the necessary tool. In the mid-1990s, statin trials finally proved that reducing serum cholesterol actually prevents heart attacks and, more importantly, reduces mortality from all causes (for a while, it looked like the drugs might reduce heart disease deaths but increase deaths from other causes).
Then we got more powerful tools in the form of increasingly potent statins. That's when all heck broke loose, as it were. There seemed to be no limit to the benefits of LDL reductions. Mortality continued to drop when LDL levels were pushed well below what were then regarded as normal levels. Moreover, the benefits of statins seemed to arrive almost immediately, within weeks or months, which can hardly be explained by changes in slow-growing plaque deposits. You can learn about the clinical implications of this research from your internist. But basic understanding of the biology of heart disease also had to be reformulated to account for the rapidity with which statins started to save lives.
Then ever more adventurous trials showed among other things that baseline LDL-C levels (serum cholesterol readings at the start of the trial) sometimes failed to predict who would benefit from aggressive statin treatment. More hypothesis rejection, more revisions in scientific thinking. It became increasingly clear that it was not progressive narrowing of the arteries that caused heart attacks, and it was not merely the halting of plaque growth that gave statins their marvelous power. Hence the odd aura of affirmation with which some cardiologists greeted the more spectacular COURAGE results. This is hardly the end of the story, however. There are still lots of unsolved riddles, including the role of inflammation. And there are new heart drugs in early and late clinical trials, not just for LDL-C but also for HDL-C, the so-called "good" cholesterol.
So there is a bit more to this week's news about stents and heart attacks than meets the eye or is described in the media. We are witnessing another episode in the remarkable story of feedback from drug and device development to basic science. And we can expect more drug-tools to wreak more havoc in scientific understanding of human biology.
John E. Calfee is a resident scholar at the American Enterprise Institute. He wrote the cover story on medical innovation for the March/April issue of The American. It is on newsstands now, and will be posted online Friday, April 4th.
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