Do You Really Need Maximum-Dose Lipitor®?August 2007
By Jay S. Cohen, MD
In an effort to boost profits, Pfizer is convincing doctors to prescribe the strongest, riskiest, and most expensive dose of Lipitor® to more and more patients—despite concerns about its safety and efficacy.
In recent years, the use of “statin” cholesterol-lowering drugs has elicited tremendous controversy. Doctors who believe in natural approaches to disease prevention have suggested that statin drugs are poison that should be avoided altogether. Pharmaceutical company-influenced cardiologists, on the other hand, have stated that virtually everyone over age 40 should be on a statin drug.
Life Extension advocates a common-sense approach to maximize benefit and minimize risk (and cost) by selecting a statin drug dose that fits your individual needs. We believe that no one should take a statin drug unless warranted by both clinical history (such as being at high risk for heart attack) and a blood test documenting unacceptable cholesterol-LDL levels.
In this article, one of the world’s foremost experts on statin drugs, Jay S. Cohen, MD, reveals how today’s sordid system works against the medical and economic interests of patients—and what you can do to avoid being victimized.
If your doctor recommends the maximum, 80-mg dose of Lipitor® for you at your next visit, do not be surprised. Better yet, be prepared for it, because Pfizer has launched an intensive marketing campaign to convince doctors to prescribe maximum-dose Lipitor® to everyone at risk of a heart attack or stroke. Many doctors are following Pfizer’s lead, yet Pfizer’s own studies raise serious concerns about the safety of maximum-dose (also called “intensive-dose”) Lipitor®. Here is the story of maximum-dose Lipitor ®—including its marketing, the recent studies, and what you should know and do.
The Maximum-Dose Lipitor® Campaign Begins
Lipitor® (atorvastatin) is the best known of a popular group of cholesterol-lowering drugs called statins. The statin class of drugs includes Lipitor® (atorvastatin), Zocor® (simvastatin), Pravachol® (prava-statin), and others (see Table 1). Lipitor® is the best-selling prescription drug in the United States and worldwide. In 2005, Pfizer sold $8.4 billion worth of Lipitor® in the US and $12.2 billion worldwide; still, the company is angling to sell even more. The main thrust of Pfizer’s current marketing campaign is to persuade doctors to prescribe more maximum-dose Lipitor®.
The campaign began in earnest in 2005, after a study of maximum-dose Lipitor® for reducing heart attacks was published in the New England Journal of Medicine.1 The study, known as the Treating New Targets (TNT) study, was funded by Pfizer, and it received glowing coverage from newspapers and news programs that described maximum-dose Lipitor® as if it was a medical breakthrough. Unfortunately, it was not. Yet the coverage made a strong impression, and so began the campaign to persuade doctors to medicate ever more patients with the most powerful, expensive dose of Lipitor® available.
As doctors prescribe more maximum-dose Lipitor® than ever, serious questions remain about maximum-dose Lipitor®. Is it effective? Is it worth the high cost? Is it safe? Statins are important drugs. Some people require strong statin treatment. Yet the great majority of people with elevated cholesterol do not need high doses of strong statins. The risk of side effects is greater with stronger doses than with milder ones. There is no scientific basis for using more medication than needed for any medical condition, and this applies particularly to the use of statin drugs. Treatment should be individualized. Safety should be emphasized. Overmedication should be avoided. Side effects should be prevented. These are fundamental principles of medical science. The indiscriminate, widespread, “shotgun” use of maximum-dose Lipitor® violates all of them.
How Effective Is Maximum-Dose Lipitor®? The TNT Heart Study
In the 2005 TNT study, 10,001 people with stable heart disease received either maximum-dose 80-mg Lipitor® or a standard dose of 10-mg Lipitor® daily.1 Maximum-dose Lipitor® reduced levels of harmful low density lipoprotein (LDL) to an average of 77 mg/dL. This represented a substantial reduction in LDL. In comparison, standard-dose Lipitor® reduced LDL to an average level of 101 mg/dL, which was also a good result.1
Over the five years of the study, 434 people (8.7%) in the 80-mg group experienced another cardiovascular incident (such as a heart attack or stroke) versus 548 people (10.9%) in the 10-mg group. This was an improvement of 2.2%, which meant 104 fewer cardiovascular incidents with maximum-dose Lipitor® compared with standard-dose Lipitor®. Twenty-nine fewer deaths from cardiovascular causes (126 versus 155) occurred with maximum-dose Lipitor®. These were also good results. However, this improvement in deaths was completely offset when 31 more people taking maximum-dose Lipitor® died from other causes. Overall, maximum-dose Lipitor® did not reduce the number of deaths in comparison with low-dose Lipitor®. In fact, the total number of deaths slightly increased in those taking maximum-dose Lipitor®. This startling fact means that maximum-dose Lipitor® increased the risk of death due to non-cardiovascular causes! This included 10 more deaths from cancer in the maximum-dose Lipitor® group versus the 10-mg group.1
Was there a reason that people taking maximum-dose Lipitor® died more often from other causes? The study did not address this critical question. Yet Dr. Bertram Pitt, the expert who wrote the editorial accompanying the maximum-dose Lipitor® study in the New England Journal of Medicine pointed out the obvious: “Although the risk of coronary heart disease events was reduced by treatment with 80 mg of atorvastatin per day, the overall risk of death was not… it is a matter of concern.”2
After reviewing the results of the study, Dr. Pitt advised caution: “We need further reassurance as to the safety of this approach.”2 Dr. Pitt suggested that if doctors want to achieve very low LDL levels with their patients, they should do so with methods other than maximum-dose statins.
The TNT was an important study because it was the first to test the hypothesis that a LDL of 70 mg/dL is better than a LDL of 100 mg/dL in people with heart disease. Although the results were not reassuring, Pfizer found enough in this study to launch its campaign to convince doctors to prescribe maximum-dose Lipitor to more patients. To boost the campaign, another study of maximum-dose Lipitor® was published a year later.
How Effective Is Maximum-Dose Lipitor®? The Stroke Study
In August 2006, the New England Journal of Medicine published a large study of maximum-dose Lipitor® for people with a recent stroke. Despite results that were barely better than placebo, the authors of this Pfizer-funded study concluded that all people who suffer a stroke should receive maximum-dose Lipitor®.3 Why would the authors suggest such an extreme, unproven, expensive approach? Perhaps it was because every one of the eleven authors was either a Pfizer employee or a Pfizer consultant.
After all, medicating large numbers of stroke patients with maximum-dose Lipitor® would boost sales by billions of dollars. Each year, approximately 15 million people worldwide suffer a stroke. About 5 million of these strokes occur in people in affluent countries, including 700,000 strokes in the US. Overall, about 5.4 million Americans and 55 million people worldwide have had a stroke.4,5 If it could be shown that maximum-dose Lipitor® could reduce the risk of another stroke in people who had already sustained one, the marketing opportunity was huge.
In the study of maximum-dose Lipitor® for stroke, all of the 4,731 subjects had experienced a recent stroke. Of these, 2,365 people received maximum-dose Lipitor® and 2,366 received placebo. Of those receiving maximum-dose Lipitor®, 11.2% had another stroke. Of those receiving placebo, 13.1% had another stroke. Thus, maximum-dose Lipitor® reduced the frequency of a second stroke by 1.9%, a modest improvement over placebo. This result did not support the widespread use of maximum-dose Lipitor® for all stroke patients.3 Instead, it suggested the need for further studies to confirm that the improvement was due to maximum-dose Lipitor® rather than chance.
The stroke study revealed other problems with maximum-dose Lipitor®. One of them was a serious increase in hemorrhagic strokes, which are characterized by bleeding in the brain. Fifty-five people taking maximum-dose Lipitor® sustained a second hemorrhagic stroke, whereas only thirty-three people taking placebo sustained a second hemorrhagic stroke. In effect, the incidence of second hemorrhagic strokes increased 67% with maximum-dose Lipitor® compared with placebo.3 This raises the question of whether maximum-dose Lipitor® was responsible for the increase in hemorrhagic strokes, and it is a warning to doctors to be cautious and selective in prescribing maximum-dose Lipitor® to stroke patients.
Another worrisome finding was that maximum-dose Lipitor® did not reduce the number of deaths overall. The drug reduced the number of fatal strokes, but this benefit was offset by an increased number of deaths from other causes. Two-hundred-sixteen of the 2,365 (9.1%) people taking maximum-dose Lipitor® died. Two-hundred-eleven of 2,366 (8.9%) people taking placebo died. Overall, the total number of deaths was higher with maximum-dose Lipitor®.3 In other words, the risk of death among these subjects was slightly greater with the Lipitor® than with placebo.
This finding was similar to that of the 2005 TNT heart study. Both studies showed that maximum-dose Lipitor® increased deaths from other causes. This was a very disturbing finding. It was so troubling that when the 2005 study had been published, Dr. Pitt warned against the use of maximum-dose Lipitor®. Unfortunately, with the publication of the 2006 stroke study, similar words of caution were not seen. Instead, the author of the accompanying editorial, who was also a consultant to Pfizer, called for the widespread use of Lipitor® in stroke patients.6
My view is that Dr. Pitt’s warning still stands. Until medical science can explain why so many people in these studies died from other causes while receiving maximum-dose Lipitor®, the safety of this medication should not be assumed.
Liver Injuries—A Strong Warning Sign
Side effects from statin drugs can be serious. Side effects include muscle pain, muscle degeneration, joint pain, memory impairment, depression, gastrointestinal discomfort, kidney injury, kidney failure, and liver injury.7,8 These and other side effects may be mild or severe. According to Dr. William Davis, a cardiologist, “The drug companies will tell you that the likelihood of side effects from statins is low. Nevertheless, many who prescribe these drugs—and their patients who take them—may tell you otherwise. Like many of my colleagues, I have hundreds of patients who, when they take a statin agent, develop annoying, sometimes incapacitating muscle aches and weakness that abruptly stop when they discontinue use of the drug, and return when drug use is resumed. The association appears clear.”9
The risk of liver injury with statin drugs is also dose-related. Liver injuries with statins can be dangerous. Cases of liver failure and death with statin drugs have been reported to the FDA. In the TNT heart study, only nine subjects developed significant liver injury (liver enzymes more than three times normal on two consecutive measurements) with low-dose Lipitor®, yet such findings occurred in 60 people receiving maximum-dose Lipitor®. In the stroke study, 51 people developed liver injury with maximum-dose Lipitor®, while only 11 developed liver injury with placebo.1 These are worrisome findings.
Severe liver injury has led to the withdrawal of several drugs—after scores of people died from liver failure. When the drug Rezulin® (troglitazone) was introduced in 1997, we were told that the drug caused modest liver enzyme elevations in a small percentage of patients. Soon, cases of liver failure and death with Rezulin® were reported to the FDA. In 1999, we learned that the manufacturer had withheld vital information from doctors and patients about the drug’s liver toxicity. Subjects receiving Rezulin® during studies had developed dangerous elevations of liver enzymes.10,11 By the time Rezulin® was pulled from the market in 2000, nearly 100 people had died.
Is maximum-dose Lipitor the new Rezulin®? It could be, but it is difficult to tell. In the heart and stroke studies, the authors withheld information about the degree of liver injuries occurring in people taking maximum-dose Lipitor®. We do not know whether the liver injuries were mild or severe.
In order to obtain this vital information, I published a letter expressing concern about the high number of liver injuries occurring with maximum-dose Lipitor® in the stroke study. I requested information on the actual liver enzyme elevations that occurred in individuals receiving the drug.12 Unfortunately, this information was still not released.
This has raised my level of suspicion. Why would the authors refuse a simple request for information about the elevations in liver enzymes that occurred in their study? One would think they would be eager to show that maximum-dose Lipitor® is safe. Why the secrecy? If the authors are reluctant to reveal the data, why? What does it show? Interestingly, this is very similar to what occurred with Rezulin®. The key information was kept from the public for years until the FDA stepped in—two years too late for some unfortunate people.
Did the FDA learn the lesson with Rezulin®? Will it now investigate the safety of maximum-dose Lipitor® before people are harmed? Not likely. Recent investigations reveal that the FDA’s ability to identify risks and ensure drug safety is severely compromised. The FDA pours far more money and manpower into rushing new drugs to the marketplace than into assuring the safety of our medications. So should we expect the FDA to investigate when an intensely marketed, highly potent, maximum-dose drug causes significant increases in liver injuries in two major studies? In a healthy system, yes. In the current system, no.
Until a thorough investigation is done, we must assume that maximum-dose Lipitor® may have the potential to cause serious, life-threatening liver injuries. Doctors should prescribe maximum-dose Lipitor® with appropriate care, checking patients’ liver enzyme levels regularly.
Profits Over Safety?
When you have been a doctor for a while, you begin to see how things work in the medical-pharmaceutical system. For instance, it is patently obvious that when a drug company undertakes large, expensive studies for already-approved drugs, it has an agenda. With maximum-dose Lipitor®, Pfizer’s agenda seems clear: push the drug for as many heart and stroke patients as possible. Expand the market. Increase sales. Ignore the safety concerns. Dismiss the higher risk of serious side effects. Downplay the questionable benefits and high costs. Emphasize the positive, disregard the negative. Ply doctors with samples so they can get patients started—and then stuck—on the product. Remember, ultimately, it’s not about science; it’s about sales.
If this sounds cynical, consider what Pfizer itself reported about Lipitor® sales, according to Bloomberg News:
“Pfizer said Wednesday that it had increased second‑quarter revenue from its Lipitor® cholesterol pill by persuading doctors to prescribe more expensive doses of the drug, the best‑selling prescription medicine. Pfizer, the world’s biggest drug maker, said it sent thousands of sales people to doctors’ offices to tout studies showing that higher doses cut the risks of heart attack, stroke and death better than do other cholesterol drugs... The number of patients taking the highest doses of Lipitor® in June rose by more than 10% compared with May, analysts said.”13
This was the agenda all along: publish large studies, obtain favorable news coverage, and then send in the sales reps. The strategy seems to be working. While sales of many drugs have been dropping, sales of maximum-dose Lipitor® are up. In 2005, Lipitor® generated 40% of Pfizer’s profits, and the 2006 numbers will probably be higher.
Why push maximum-dose Lipitor® instead of a lower dose? Because the 80-mg pill is more expensive than lower doses. A 80-mg pill of Lipitor costs about $3.93 per day, 34% more than the 10-mg pill, which costs $2.61 per day. The $1.32 extra per pill of maximum-dose Lipitor® adds up,13 especially when one considers that the active ingredient (atorvastatin) costs relatively nothing. A year’s supply of 10-mg Lipitor® costs about $954. A year’s supply of maximum-dose, 80-mg Lipitor® costs more than $1,400. Now multiply this by a few million patients, and it adds up to billions.
The Underlying Strategy
For years, while Lipitor® has been the best-selling drug in the world, Zocor®’s sales were close behind. Now that Zocor® is available as a lower-cost generic, Lipitor®’s top standing is at risk. So, an unspoken goal of the maximum-dose Lipitor® studies and the marketing campaign has been to convince doctors that Lipitor® possesses some magical power to reduce heart attacks and strokes that other statins lack. If doctors can be convinced of this, they will continue to prescribe expensive, brand-name, maximum-dose Lipitor® instead of other statin drugs that are now far less costly.
Three statin drugs are now available as generics—Mevacor® (lovastatin), Pravachol® (pravastatin), Zocor® (simvastatin)—but Zocor® is the first major threat to Lipitor’s dominance. Zocor® is nearly as potent as Lipitor®, and doctors have confidence in Zocor® as a high-potency statin. Now that generic Zocor® is available, individuals and health insurance organizations will often choose it over high-cost Lipitor®.
For example, the state employees’ health insurance commission in Massachusetts isn’t buying the “more Lipitor®” campaign. Instead, the commission is promoting the generic therapies. Regarding maximum-dose Lipitor®, Bob Carey, a spokesman for the commission, said, “the vast majority of people don’t need that megadose.”14
When you think about it, the maximum-dose Lipitor® campaign is prompting doctors to break several basic principles of optimal treatment. The Pfizer campaign suggests that doctors should prescribe maximum-dose Lipitor®, with its greater risks and costs, to all heart disease and stroke patients. Yet medical science and the FDA advise that statin treatment should be individualized. Statin drugs and doses should be selected based on the individual needs of different people.
If doctors begin prescribing maximum-dose Lipitor® to all cardiovascular patients, many will become overmedicated, side effects will ensue, and people will leave treatment. As it is, many people already find statins difficult to take. Already more than two-thirds of the millions of people placed on statin drugs eventually discontinue treatment. This situation will worsen if doctors follow Pfizer’s advice to ignore cholesterol levels; ignore patients’ age, size, and state of health; and prescribe maximum-dose Lipitor® indiscriminately to all heart and stroke patients.