Statins are the best-selling drugs in the world, with more than 25 million people, including 13 million Americans, spending $27.8 billion on the cholesterol drugs in 2006, according to IMS Health. About half of that was for Pfizer’s Lipitor, which last year had $18.4 billion in sales in the United States alone.
But recent events have invigorated a long-running controversy about value of the blockbuster drug, questioning whether it is overprescribed and inappropriately advertised. The drugs are manufactured by several large pharmacy companies in addition to Pfizer, the leaders being Merck’s Mevacor and Zocor, AstraZeneca’s Crestor, and Bristol-Myers Squibb’s Pravachol.
“There is no question that for people who know they have coronary disease, statins have a significant beneficial impact,” says Howard Brody, MD, professor of family medicine at the University of Texas Medical Branch at Galveston. “But now it is being prescribed for a much broader range of patients, bringing into question the cost of treatment versus benefit.”
Statin proponents are vocal in support of the use of the drug as a prophylaxis. “The efficacy and effectiveness of statins has been established by decades of research,” says David Nash, MD, chairman of the Department of Health Policy at Jefferson Medical College of Thomas Jefferson University in Philadelphia. “Controversy over use of the drug is somewhat perplexing in that there is plenty of evidence that the science is solid.”
Nash is certainly correct in that the effectiveness of statins in reducing cholesterol is well established. The government’s National Cholesterol Education Program (NCEP) guidelines say that as many as 40 million Americans should be taking statins to fight heart disease, especially patients with diabetes or a family history of heart disease.
But recent research questions the so-called “lipid hypothesis” of the causality of cardiovascular diseases (CVD). Dyslipidemia is defined as elevated blood cholesterol, elevated concentrations of low-density lipoprotein cholesterol (LDL-C), or abnormal proportions of LDL-C and high-density lipoprotein cholesterol (HDL-C). For decades, dyslipidemia has been identified as a causal factor in atherosclerosis and other CVDs.
In the past 50 years, dozens of studies have led most medical scientists and clinicians to accept the lipid hypothesis, and the primary focus of CVD health care guidelines has been to lower LDL- C. A small, vocal group of clinicians says, however, that there has been significant bias in the studies and that the hypothesis has never been truly substantiated. They say that it is also well-established that other medical conditions can contribute to causing CVD.
It is the supposed overuse of statins to lower LDL-C that is generating much of the current cholesterol controversy, however. In January two manufacturers, Merck and Schering-Plough, reported results of a trial of the effectiveness of the combination of two cholesterol drugs — Merck’s statin Zocor (simvastatin) and Schering-Plough’s Zetia (ezetimibe, an antihyperlipidemic drug but not a statin), marketed as single-dose Vytorin. The combination drug was found to lower cholesterol better than the statin alone, but this demonstrated no enhanced heath benefit. In other words, combining the drugs did not reduce heart attacks or strokes better than statins alone.
The results were a financial blow to the companies, which had seen sales of Vytorin grow astronomically, from 0.1 percent of prescriptions in 2002 to 15.2 percent in 2006. A panel convened by the American Academy of Cardiology stated that because of the trial’s results, “the aggressively marketed drug combination should be used only as a last resort in treating patients to decrease their levels of low-density lipoprotein cholesterol (LDL-C),” according to a report in the May 21, 2008, issue of JAMA. That trial, titled ENHANCE, has led to a congressional investigation examining whether the results of the trial, which began four years ago, had been suppressed by the companies.
Soon after the announcement of the trial’s results, BusinessWeek published a controversial look at whether all statins are overprescribed. “Do Cholesterol Drugs Do Any Good” in the January 28 edition stated that “except among high-risk heart patients, the benefits of statins such as Lipitor are overstated.”
The article bases its conclusion — that statins are overprescribed — on a statistical methodology named “number needed to treat (NNT).” Here’s an example, as laid out in the BusinessWeek article: In a newspaper advertisement, Pfizer states that “Lipitor reduces the risk of heart attack by 36 percent. However, an asterisk is attached to that figure, leading to a statement in smaller type that reads ‘That means in a large clinical study, 3 percent of patients taking a sugar pill or placebo had a heart attack compared to 2 percent of patients taking Lipitor.’
“The numbers in that sentence mean that for every 100 people in the trial, which lasted 31⁄3 years, three people on placebos and two people on Lipitor had heart attacks,” continues BusinessWeek. “[That’s] one fewer heart attack per 100 people. So to spare one person a heart attack, 100 people had to take Lipitor for more than three years. The other 99 got no measurable benefit. Or to put it in terms of a little-known but useful statistic, the number needed to treat for one person to benefit is 100. Compare that with, say, today’s standard antibiotic therapy to eradicate ulcer-causing H. pylori stomach bacteria. The NNT is 1.1. Give the drugs to 11 people, and 10 will be cured.”
The most common methodology for describing randomized controlled trials is in terms of relative risk reductions (RRRs), the proportional reduction in rates of bad outcomes between experimental and control participants in a trial. It is calculated by dividing the absolute risk reduction by the control event rate. Absolute risk reduction (ARR) is the decrease in risk of a given activity or treatment in relation to a control activity or treatment. Many epidemiologists believe that RRR can be more useful than the absolute risk reduction in determining an appropriate treatment plan because it accounts not only for the effectiveness of a proposed treatment, but also for the relative likelihood of an incident (positive or negative) occurring in the absence of treatment. NNT, on the other hand, may best convey an idea of an intervention’s possible cost-effectiveness, researchers say.
But because a drug’s NNT is high, that does not mean it should not be widely prescribed, say some epidemiologists. Brian Strom, MD, is a professor of public health and preventive medicine in the biostatistics and epidemiology department at the University of Pennsylvania School of Medicine and an expert in the use of NNT. “NNT is a way to make clear the relative value of a drug,” says Strom. “It does not address whether a drug works for the reason it was intended and whether it is reasonably safe, both of which are the responsibility of the FDA based on clinical tests.”
Strom says that using NNT to establish the efficacy and effectiveness of statins and other drugs is “mixing apples and oranges.”
“NNT is useful in determining the cost benefit of a drug. If an NNT is high, but a drug is not expensive and is considered relatively safe, then it is still valuable,” he says. “Statins have proven themselves to be very safe and remarkably effective.”
That’s true, says Brody. “But the issue is statins as a prophylaxis,” he says, “and there is increasing statistical evidence that its widespread use is simply not warranted.”