Meanwhile the five-year ALLIANCE study, funded by Pfizer, was conducted on heart patients being treated by primary-care doctors rather than in a more rarefied academic setting. "What made this study different was that it was a real-world trial," says Donald Hunninghake, the principal investigator and a professor of medicine and pharmacology at the University of Minnesota. That made the results especially impressive to physicians. The intent was to get LDL levels to 80 or below. There was an overall reduction in heart problems of 17 percent in aggressively treated Lipitor patients compared with a second group of patients whose physicians were free to use the statin of their choice. The risk for nonfatal heart attacks was reduced by 47 percent.
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No one knows why dialing up the dosage and using Lipitor had the protective effect shown in these studies. Nissen has long argued, however, that the answer goes beyond the idea of lowering LDL levels. "The PROVE-IT people have been pitching the idea that it's the LDL, stupid. Well, it's not," he says. He thinks that inflammation in the walls of the coronary arteries is behind many heart events and that Lipitor has a stronger anti-inflammatory effect than Pravachol does. For evidence, he notes that in the PROVE-IT patients Lipitor was much more effective than Pravachol at lowering the level of C-reactive protein, which seems to be an indicator of inflammation. "This is not just about cholesterol lowering," he insists.
Most cardiologists asked to comment on these studies agreed: The important message is that most people at risk for heart disease aren't being treated aggressively enough. Cannon estimates that patients are getting about half the dose they require, partly because many doctors have traditionally been cautious with statins. They tend to start at a low dose and gradually move to a higher dose one step at a time. "It doesn't work," says Cannon, who now advocates starting high, using doses shown in trials to be effective.
New cholesterol guidelines will inevitably be issued within two or three years. Hunninghake thinks the LDL target could be as low as 70, rather than today's standard of 100. For people with a history or serious risk of heart disease, he says, "there's no doubt that the lower you get the LDL, the better you're going to be."
Magic number? What is that magic LDL level, and is it possible that it might be risky to dip below it? "Part of the reason for doing big trials is to find out whether pushing LDL way down, say below 50, might be dangerous," says John LaRosa, who is involved in the design and execution of another Lipitor trial as well as serving as president of SUNY Downstate Medical Center in Brooklyn, N.Y. "A decade ago, there was a lot of fussing about lowering cholesterol too far--that it caused stroke and traumatic death." The evidence was limited, he says, but the issue will surely resurface. He observes that the LDL level in umbilical cord blood is about 35, "so maybe that's the natural level." In many trials, investigators are alerted when a patient's LDL falls below a certain point, often 25. It's more a heads-up than an alarm, however. "I don't think we've established any basis for believing there's an LDL too low to treat to," says Nissen. "I've had patients with LDLs of 20, and they had no problem."
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