Confused by competing claims for the newest of the cholesterol-lowering drugs? You're not alone. Bristol-Myers Squibb Co.'s pravastatin, sold as Pravachol, and Merck & Co.'s simvastatin, or Zocor, offer a revolutionary approach to combating heart disease, the nation's No.1 killer. They are locked in a fierce battle over a market estimated at $6.5 billion.
In ads appearing almost everywhere, Bristol-Myers crows that Pravachol is proven to reduce the likelihood of a heart attack in people with high cholesterol but no sign of heart disease. Merck, in its ubiquitous ads, is able to say only that Zocor has been shown to prevent death in those with high cholesterol who already have had heart attacks--a much smaller pool of potential patients. What's not clear from the campaigns is that the drugs, both from a family of medicines called statins, are so similar as to be interchangeable.
TRAILBLAZING. The tale of how these drugs were developed--and why the drugmakers cannot make the same claims--stretches over 17 years. It demonstrates the hurdles industry researchers and academics face in developing trailblazing medicines--especially the difficulties of putting thousands of patients through prolonged studies. The statin story also highlights how key decisions about research--made years before products are sold--can lead to vastly different marketing routes for similar drugs. A bad choice can leave openings that smart marketers can cleverly--if questionably--tap as they battle for turf.
Bristol can make its audacious claim that Pravachol alone has been proven to help prevent first heart attacks only because of a rare misstep by rival Merck. In the late 1980s, Squibb, later taken over by Bristol, was several years behind Merck in pursuing the cholesterol-reduction market. Squibb's drug, licensed from Sankyo Co. in Japan, would be third into the market behind the Merck statins Mevacor and Zocor, virtually guaranteeing only modest sales. But Squibb and Bristol took a risk and wisely backed a $35 million, five-year study on 6,595 men in Scotland, aiming to prove Pravachol could prevent first heart attacks in men with high cholesterol. This so-called primary-prevention study would give Bristol a decisive edge--if it worked. "It was a real long shot," says Dr. Mark E. McGovern, Bristol's executive director of cardiovascular clinical research.
Merck, for its part, had turned down a similar primary-prevention study that almost certainly would have let it make the same case for Zocor. Insiders say the company was feeling pinched financially. It couldn't agree on a study design with British researchers proposing such a trial and was preoccupied with another landmark effort, a then new Scandinavian study that was aimed at proving Zocor's worth in people who had already had heart attacks. The result: With Merck able to claim effectiveness only for the smaller market of patients who've already had heart problems--the secondary-prevention market--Pravachol has grabbed 21.3% of a market once almost entirely owned by Merck, and it is rising fast. "It was a mistake, both commercially and in terms of medical research," says Professor Richard Peto, a highly regarded Oxford University statistician. He is now working on an ambitious 20,000-patient study of Zocor that could equalize the claims for Pravachol and Zocor by 2000.
Of course, no one knew Pravachol would prove to be such a potent heart-attack beater in 1987, when Squibb went looking for researchers to test the drug. Professor James Shepherd, a researcher for the Royal Infirmary in Glasgow, offered to lead a team that would recruit and follow 6,500 Scotsmen who had high cholesterol and at least one other threat to cardiovascular health, such as a smoking habit. The Scots made ideal subjects because their diets--marked by such delicacies as haggis, the fat-rich innards of a sheep or calf boiled in the animal's stomach--are high in cholesterol-laden fried foods and dairy products and low in vegetables. What's more, widespread skepticism among British physicians about the utility of drugs that lower cholesterol eliminated the ethical problem of putting half the test subjects on a placebo.
FEARS. At that point, such skeptics had reason to doubt the value of lowering cholesterol. Scientists had linked the fatty molecule found in blood to heart disease for decades, but cholesterol-cutting drugs had mostly proved problematic. Studies in the 1970s and early '80s had suggested that while such drugs as Atromid-S, Lopid, and Questran cut cholesterol and curbed heart attacks, other problems could arise, including cancer and an odd rise in violent deaths and suicide. The "cholesterol controversy" raged acutely in Britain, where early studies were the most damning. "The question was: `Does reducing cholesterol cause harm?"' recalls Dr. Basil M. Rifkind, a Scottish investigator who now is a senior adviser at the U.S. National Heart, Lung & Blood Institute.
Indeed, before Merck got approval from the Food & Drug Administration to sell the first statin, Mevacor, in 1987, the drug had a rocky ride. In 1980, the company canceled its clinical trials on Mevacor amid baseless reports that a related compound from Japan caused cancer in dogs. It wasn't until 1984 that researchers teamed up under the aegis of the National Institutes of Health decided that lowering cholesterol was valuable. They set up the National Cholesterol Education Project in 1985 with the goal of reducing elevated blood cholesterol levels nationwide. But when Mevacor was finally approved, it was endorsed narrowly for cholesterol reduction, not combating heart disease. While Americans mostly agreed this was a way to attack heart disease, European scientists remained cool to the idea. "It was considered to be dangerous by some doctors," recalls Shepherd.
But as a respected medical leader, Shepherd persuaded enough Scottish doctors to test Pravachol on high-cholesterol patients. He built up enthusiasm for the trial among Glaswegians, partly by persuading them of the prestige value of hosting a world-class trial. Frequent medical exams were a powerful incentive. And to keep up the spirits of participants--and keep them taking daily medications and coming in for regular visits--he used more mundane incentives. "We gave them key rings, bumper stickers," Shepherd says, and advice on dieting.
The researchers even capitalized on local sociology. The study staff made sure to involve both the men in the test--who were the focus because cholesterol-related heart disease was viewed mainly as a male problem--and their wives. This boosted drug-taking and improved diets. "In Scotland, men are not the boss," observes Shepherd. "The wife controls the household."
Still, the effort at times was a tough slog. Participants did not know if they were on the drug or a placebo. Either way, it wouldn't make them feel better: High cholesterol is a silent threat. And since the results were blinded both to researchers and participants, no one knew whose cholesterol was being cut.
Making participants take their pills each night was a challenge, and some 30% of the men dropped out over the five years. "I didn't take it every day," admits Tommy Dingwall, a Glasgow City Council member who still stuck out the full five years. "I was never below 70% [though]. It just became a habit." Dingwall admits he has since lapsed and no longer takes his medicine.
Failure sometimes loomed. One of the darkest moments, Shepherd recalls, came early, in April, 1989, when another Glasgow scientist's 12-year study of 15,000 Scots suggested a link between low cholesterol and higher cancer rates. The study, reported in the British Medical Journal, was downplayed as less convincing than the link between high cholesterol and heart disease. But such headlines as "Cutting cholesterol can increase cancer risk" rattled subjects--400 dropped out. All told, the trial suffered a first-year loss of about 13%.
LIFESAVERS. The Scots, however, soon enough got some encouragement--and competition. About the same time as Shepherd was testing Pravachol, a Merck-funded study for secondary prevention--preventing a second heart attack--was under way in Scandinavia. The Scandinavian Simvastatin Survival Study, known as 4S, was Merck's bid to prove that cholesterol-lowering could save lives. Proving a reduction in mortality was a more aggressive goal than reducing heart attacks and, Merck researchers thought, would produce a more potent marketing claim.
Conducted on 4,444 men and women with coronary disease, the study ran into fewer obstacles than Shepherd's. Dr. Terje R. Pedersen, head of cardiology at the Aker Hospital at the University of Oslo and the study's leader, managed to keep the dropout rate to just 11%, for instance. His subjects had suffered heart attacks or had heart disease already and so were motivated to follow their doctors' advice. The Scottish study linking low cholesterol and cancer shook few. In Scandinavia, says Pedersen, "patients are very confident in their doctors."
Still, there were bumps in the road in 4S, too. In mid-1992, the British Medical Journal ran a letter from a group at Oxford University arguing that the ongoing trials were not big enough to prove that statins save lives. The researchers, whose proposal for a 20,000-person study Merck had canceled, suggested there might not be enough deaths in these smaller studies to draw firm conclusions. The Oxford letter discouraged some 4S investigators and spawned a brief rise in patient dropouts, but the organizers managed to persuade physicians that 4S was big enough to prove claims about Zocor. For his part, Pedersen took his case directly to the Oxford researchers. "I told them this was a rotten thing to do," he recalls.
As it turned out, the critics were wrong on the Merck-sponsored study and right on the Bristol work. In the Scandinavian study, where patients entered with heart disease, 438--or almost 10%--of the participants died. Of these, 182 had been taking Zocor, versus 256 on the placebo--a statistically significant difference that backed Merck's claim that the drug could actually save lives. By contrast, with the healthier population in the Glasgow study, 141 participants, or just 2.1%, died. Among them, 106 patients taking Pravachol died, versus 135 on placebo--a statistical difference that was too small to prove the drug could save lives. But Bristol got a strong heart-attack prevention claim, and future studies will likely provide proof that Pravachol is also lifesaving.
Because it began earlier, Merck's 4S study went public first. The November, 1994, report all but ended the cholesterol controversy. Pedersen reported at the American Heart Assn. annual meeting and in Britain's Lancet that Zocor cut the risk of death by 30% overall, and risk of coronary death by 42%. So Merck the following July won the right from the FDA to say that Zocor was the first and only cholesterol reducer to save lives and prevent heart attacks in people with heart disease who also had high cholesterol. The drug's sales soared.
A year later, Bristol played its trump card. At the next American Heart Assn. meeting, in November, 1995, Shepherd reported his results, published in the New England Journal of Medicine. He found that Pravachol reduced the risk of a fatal or nonfatal heart attack by 31%, and this was in men with high cholesterol but no history of heart attack. So Bristol last July won FDA clearance for its strident claims about helping prevent first heart attacks.
For all the differences in marketing claims, however, Zocor and Pravachol are treated as pretty much the same by practitioners. Zocor lowers cholesterol further, but so long as patients get the desired reduction, Pravachol can be substituted. "It's a matter of physicians' choice and patients' choice," says Dr. James I. Cleeman, coordinator of the National Cholesterol Education Program. Adds the National Heart, Lung & Blood Institute's Rifkind: "They're all of a muchness."
Future studies should stress the similarities. Merck has agreed to partly underwrite the 20,000-person Oxford study. In three years, it should show Zocor's power against first heart attacks. Bristol by next year should get results from a 9,014-person Australian study that will likely prove Pravachol helps prevent second heart attacks.
FEWER STROKES. With the market appeal of the statins established, researchers keep finding more good news about them. Just last week, the New England Journal of Medicine reported that Merck's Mevacor reduced the progression of atherosclerosis in people who had undergone bypass surgery. And last October, a study in the same journal showed that Pravachol helps patients with coronary disease who have just average cholesterol levels. It also reduces the incidence of stroke.
Over time, the marketers could be hard-pressed to differentiate the drugs. But no matter what problems they have, people whose lives are prolonged have plenty of reason to be happy. As the drugmakers and rival scientists wage the war of the statins, it is patients who ultimately win the spoils.