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Safe Drug Use: An Interview

Posted by medconsumers on November 1, 2008

Prescription Drug Use: New Podcast Dispels Many Myths

One of the many information sources used in preparing our articles is Therapeutics Initiative, which publishes a free online newsletter. This project was established in 1994 by the Department of Pharmacology and Therapeutics in cooperation with the Department of Family Practice at the University of British Columbia, Vancouver. According to this Web site, its purpose is “to provide physicians and pharmacists with up to date, evidence-based, practical information on rational drug therapy. The Initiative is an independent organization, which is at arms length from government, pharmaceutical industry and other vested interest groups.”

Last Spring, two professors affiliated with this program began podcasting on the Therapeutics Initiative Web site (www.ti.ubc.ca). One of them, James McCormack, Pharm.D, who is with UBC’s Faculty of Pharmaceutical Sciences, is interviewed by Maryann Napoli, Center for Medical Consumers.

MN: Your podcasts are unique. There is no show that I know of in the mainstream U.S. media that draws upon the evidence the way you do to dispel myths about drug treatment. You are addressing primary care physicians, but there is much to be learned by anyone who takes drugs.

JM: Thank you. My co-host, Dr. Mike Allan, who is a great family doc at the University of Alberta, Edmonton, and I have been doing these podcasts primarily because they are fun to do and hopefully the information is useful to the listeners.

MN: I’m going to touch on different subjects to give my readers an idea of the range of topics you address in your shows. I’ll start with dose. Whether you’re talking about drugs for high blood pressure or antibiotics for sinusitis or strep throat, you make the point that drug doses are often set arbitrarily and the high-end doses are usually too high for most people. Is there general advice you can give here?

JM: If the condition [for which you will be taking the drug] will kill you tomorrow, take a big dose just in case. If the condition is not life-threatening or urgent, then there is absolutely no reason to start with the dose that is typically recommended. Typically, those are the doses that have been shown to work in most people.

MN: Because there’s a range of responses.

JM: Yes. It has been established that the initially recommended doses, especially for new drugs are, on average, too high for many people. When you look at the dose-response curve from trials, you see that many people respond to lower doses, but there is absolutely no way you can predict in advance who will respond to what dose. If there’s no hurry, and given that many conditions get better on their own, start with a small dose. Typically, ¼ of the recommended dose is where to start.

MN: Now for the duration of drug treatment. In one show, you said something that sounded like heresy because the public is told to complete the 10- or 14-day antibiotics regimen or something horrible will happen. Yet you said that for respiratory infections like sinusitis, bronchitis, and even community-acquired pneumonia [as opposed to hospital-acquired pneumonia], people can stop taking their antibiotics when they feel better and have no fever for three days. Typically that would be a 5-day course for many people, but you also said it depends on how quickly they respond.

JM: Three-day courses of antibiotics have been shown in studies to be effective for bladder infections and there is even a study of 3-day treatment for pneumonia. For almost all upper respiratory tract infections the most you need is five days. The key is if you are not improving after 2-3 days, you need to be reassessed by the prescribing physician. Interestingly, there was no evidence to support that 10- to 14-day recommendation in the first place. However, there are a few infections that require taking antibiotics for a longer time—bone infections, prostate infections, cardiac infections, but for most non-life-threatening infections, shorter [until you have felt better for 3 days] is usually just as good.

MN: You often joke that “we [health care practitioners] don’t know what we’re doing.” You said it recently in one of your shows about upper respiratory illnesses. Why is it that doctors don’t know the correct dose or type of antibiotic to use for these common conditions?

JM: It ‘s not so much we don’t know what we are doing, but we don’t always have studies that look at the answers to the important day-to-day clinical questions. I want to know what is the best drug and how long must it be taken. Many of the antibiotics in use today came on the market way before we did lots of trials. Unfortunately, the research done by drug companies often doesn’t answer the questions we need to know the answers to. We do what we were taught and don’t question whether it’s the best way to do something. How can I predict whether you would need 10 or 5 days of an antibiotic?

MN: People on anti-hypertension drugs might be surprised to learn from your show that drugs reduce the risk of heart attack, cardiac death, stroke by only 1-2% over five years. You said that there is uncertainty about whether this is due to the mechanism of the drugs or the lowered blood pressure.

JM: We don’t know exactly, but we’re pretty convinced that some of the effect is from blood pressure lowering. But there are a number of studies that show drugs that equally lower blood pressure do not produce equal reductions in the rates of heart disease. For instance, atenolol* is a highly prescribed drug that lowers blood pressure. However in clinical trials lasting 5 years, the people taking atenolol had the same number of heart attacks or strokes as those taking a placebo. That tells you something else is going on. Either blood pressure reduction is not the major reason for that 1-2% benefit from anti-hypertensive drugs, or any potential benefit from atenolol’s blood pressure lowering effect was offset by the inherent toxicity of atenolol. Even though we don’t know exactly what is going on, we do know that patients who take atenolol for 5 years are not reducing their chance of heart disease, which is the only reason to take drugs for high blood pressure.

MN: Given your general advice about starting with a low drug dose and the lack of certainty that anti-hypertensives work by lowering blood pressure or some other mechanism, why is dose a guide here?

JM: Because the major reason to start with a low dose is to reduce side effects and the second is to reduce cost. You’re right, it’s a catch-22 situation here. The drugs are given to lower blood pressure. We know very well that lower doses typically produce most of the blood-pressure lowering effects and increasing doses rarely adds much more benefit. We also know from studies that even if you did nothing, many patients’ blood pressure would go down over time.

MN: Blood pressure goes down without drugs?

JM: We know from any anti-hypertensive trials about 50% of the people on placebo will have normal blood pressure within a year. So take low doses, see the doctor periodically to have blood pressure measured and every year or so, in conjunction with your physician, start slowly cutting back on your medications to see if you still need them. Don’t lose sleep over your blood pressure. It’s inappropriate to scare people by telling them it is a silent killer. Blood pressure of, say, 160/100 increases your risk of cardiovascular disease by 2-3 % over 5 years compared to someone who has a blood pressure of say 140/85. That’s what you need to know.

MN: Why give anti-hypertensive drugs if untreated blood pressure goes down in so many people?

JM: The 1-2% reduction in cardiovascular disease over five years we mentioned earlier. Hopefully, there will be more over a lifetime. Many people see this as an important difference [over a placebo—that is, no treatment]. However, and most importantly, if these drugs cause any side effects you are on the wrong drug.

MN: I liked something you said about osteoporosis: “If you’re not prepared to take one of the bone drugs like Fosamax or raloxifene, then don’t have a bone density test. That makes so much sense, but I doubt many women have had this explained.

JM: It’s in the Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation; 2000. “Utilizing any procedure to measure bone density is not indicated unless the results will influence the patient’s treatment decision,” which is in agreement with the U.S. Preventive Service Task Force recommendations for postmenopausal women.

MN: In describing studies, you often show how small the benefit of drug treatment can be, demonstrating that most people with self-limiting conditions get better in time without treatment. For example, you cite a Cochrane Review of the best trials involving the use of steroid intra-nasal spray for sinusitis, which made 73% feel better, compared with 66% of those on placebo.

JM: People don’t know the questions they should ask about drugs. Most important is: What will happen if I do nothing? What’s my ballpark chance of death, heart attack, stroke, fracture, symptoms etc) over, say, the next 5-10 years if I don’t take drugs. Then get the doctor to give a rough idea of how much the drugs will reduce that chance. Then get a ballpark estimate about your chance of having severe side effects.

Based on that information, you decide whether or not to take the drug and whatever decision you make, your doctor should support that decision.

*Atenolol has been sold under brand names like Tenoretic, Tenormin and Apo-Atenolol for nearly 35 years. A 2004 analysis of four randomized trials, published in the British journal Lancet, challenged atenolol’s safety and efficacy.

Maryann Napoli, Center for Medical Consumers ©

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Avoid Drug-Related Injury

Posted by medconsumers on May 1, 2008

One Way to Avoid a Drug-Related Injury

It can take years to learn the full range of serious adverse reactions to prescription drugs. That point was driven home last month when, in one issue of the journal Archives of Internal Medicine, several studies revealed new-found harms. The popular diabetes drugs, Actos and Avandia, increase the chance of having a fracture. Fosamax and other drugs in the class known as bisphosphonates, widely prescribed for osteoporosis since 1995 to prevent fractures, can cause an irregular heartbeat called atrial fibrillation. And postmenopausal hormone drugs, once aggressively urged for all women over 50 to prevent heart attacks and strokes actually cause strokes in some women, regardless of the type of hormone regimen or when it was started.

You get the picture: the drugs taken to prevent one major health problem can often cause another. The editorial that accompanied these new studies offered the excellent suggestion that doctors should quantify the benefits and risks so their patients can fully understand what they are getting into once they are told to go on long-term drug therapy. If, say, a bone drug helps only one in 100 women avoid a hip fracture and the same drug causes a potentially fatal atrial fibrillation in one in 100, then it’s a wash.

Jerry Avorn, MD, and William H. Shrank, MD, Harvard Medical School, offered a more immediate suggestion for avoiding drug-related injuries that targets people over the age of 65 years, the group with a high prevalence of adverse drug reactions. In a recent issue of the British Medical Journal, Avorn and Shrank wrote, “When an elderly person experiences an adverse drug reaction, it may be mistakenly attributed by the patient or doctor to a new disease or (even worse) the aging process itself. Examples include the parkinsonian side effects of many antipsychotic drugs and the fatigue, confusion, or depression-like symptoms that can result from excessive use of heavily marketed psychoactive drugs.”

Avorn and Shrank go on to describe what they called an opportunity for “total cure” by stopping the offending drug or lowering its dose. “In our own practices we have often seen patients on a seemingly inexorable trajectory towards institutional care whose functional capacity was restored by thoughtful reassessment of their drug regimens. This has led to the useful if overstated recommendation that any new symptoms in an older patient should be considered a possible drug side effect until proved otherwise.”

Maryann Napoli, Center for Medical Consumers ©
May 2008

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Failed Vytorin Study Raises Questions About Cholesterol

Posted by medconsumers on February 1, 2008

A firestorm of bad publicity erupted over cholesterol drugs last month when an expensive combination drug proved to be no better than an older drug alone. This finding was suppressed for 20 months by Merck and Schering-Plough, the two companies that make Vytorin, which is a one-pill combination of Zetia and Zocor. Their two-year trial failed to prove that Vytorin is better than Zocor alone for slowing plaque accumulation; instead atherosclerosis worsened in those taking Vytorin.

But the study results were not revealed until the two drug companies were pressured into doing so by an article in The New York Times and a Congressional inquiry. Worldwide, about one million prescriptions for Vytorin and Zetia are written each week, and they generated about $5 billion in sales last year. Zocor can be purchased under its generic name simvastatin for less than $6 for a month’s supply; whereas an equivalent amount of Vytorin costs about $100. It was obviously in the two companies’ interest to withhold the negative results for as long as they could get away with it.

When Vytorin came on the market two years ago, it was impossible not to be cynical about its purpose. Merck’s patent for Zocor was running out, and its blockbuster status would soon be diminished with generic competition. The company joined forces with Schering-Plough, maker of Zetia, and sought FDA approval for Vytorin. Their FDA-required trials showed a 17% greater reduction in LDL, the so-called bad cholesterol, than Zocor alone.

Making this 17% reduction in LDL look like an amazing achievement was not much of a stretch. Merck and the makers of other statin drugs like Lipitor and Pravachol had already paved the way. Their respective marketing machines had long ago misled most of us (doctors included) into thinking that cholesterol reductions equal heart attack reductions. One consistently overlooked fact about statins: They are far better at lowering cholesterol than preventing heart attacks or strokes. And those small reductions in heart attacks and strokes shown in clinical trials are largely confined to high-risk middle-aged men and those with heart disease or diabetes. Vytorin, on the other hand, has not been proven to reduce heart attacks or strokes in anyone.

LDL Reduction Irrelevant

Though doctors tend to focus their statin-taking patients on the size of their LDL reductions, heart disease researchers have long ago noted that this is likely irrelevant. Statin trials often show that the size of the cholesterol reductions are not consistent with reductions in heart attacks. Such observations led researchers to suspect that the ability of statins to reduce heart attacks and strokes has less to do with cholesterol reduction and more to do with other biological effects like plaque stability and anti-inflammatory effects. Another important but overlooked observation: “Elevated LDL identify less than one half of individuals who will die from coronary heart disease” (Rosenson et al. Antithrombotic Properties of Statins, JAMA, May 27, 1998).

The fall-out from the Vytorin debacle continues to reverberate. At this writing, Merck and Schering-Plough are running full-page ads daily in the Times and Wall Street Journal, warning people not to be confused by a single study and to continue taking Vytorin. The advice was backed by the American Heart Association, which appeared to be an independent source until The Times reported that the AHA receives nearly $2 million a year from Merck/Schering-Plough Pharmaceuticals.

One of the unintended consequences of two drug companies withholding their negative trial results is that it led some in the media, notably Alex Berenson, an investigative reporter for the Times, to look back at another important failed cholesterol drug trial and question the very foundation of heart disease prevention. In his heretically titled article “Cholesterol as a Danger Has Skeptics,” Berenson cites Pfizer’s trial of its much-anticipated drug torcetrapib that raised HDL, the good cholesterol, and lowered LDL. The trial had to be stopped in 2006 because the drug caused heart attacks and strokes. (Sound familiar? Postmenopausal hormones were widely prescribed because they were so good at improving cholesterol levels but they also increased the risk of heart attack, stroke and blood clots.) “Torcetrapib’s failure shows that lowering cholesterol does not prove a drug will benefit patients,” said a skeptical Walter Reed cardiologist quoted in Berenson’s article.

Many researchers, physicians and scientists around the world have long questioned the import of high cholesterol for anyone other than middle-aged men. In fact there is an International Network of Cholesterol Skeptics (disclosure: we belong), but the skeptics have been marginalized over the years. Now some mainstream media like Business Week and the cardiology Web site, TheHeart.org are willing to give them voice.

Could the house of cards be falling? Would the house of cards be allowed to fall when a worldwide $40 billion-a-year industry is at stake?

For More Information

The International Network of Cholesterol Skeptics www.thincs.org

Business Week magazine (www.businessweek.com) click into past issues, January 17, 2008 Lipitor cover story: “Do Cholesterol Drugs do any Good?”

TheHeart.org from Web MD www.theheart.org, see video blog of Eric J. Topol, MD, who questions the import of LDL reduction in “Temple of the LDL Cholesterol.”

Maryann Napoli, Center for Medical Consumers ©
February 2008

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Heart News 2007

Posted by medconsumers on December 31, 2007

The heart-related news has lately been a roller coaster of good, bad, and maybe not so bad. One popular prescription cholesterol-lowering statin drug might soon be sold over the counter. Defibrillators of the kind implanted years ago in Vice President Dick Cheney were in the news last month when studies showed they are more likely to be given to white men. But this needn’t be seen as yet-another example of women and minorities deprived of appropriate heart care. A new study showed that men with implanted defibrillators had a higher death rate than women with exactly the same heart condition who were not given implanted defibrillators.

And remember those drug-coated stents that scared heart patients over a year ago when it was announced that they increased the risk of potentially fatal blood clots long after they were inserted to prop open a constricted artery? Well, drug-coated stents made headlines again last month suggesting that they may not be so dangerous after all.

What do we make of all this?

For starters, an over-the-counter cholesterol-lowering drug might be a good idea for certain people. Not simply as a money-saver, but as a means of getting good-quality written drug information to the user. With a few exceptions, prescription drugs do not automatically come with FDA-approved printed information, though it comes tucked into the packaging of virtually all drugs sold over the counter.

We might be grasping at straws here, but mandated consumer drug information produced with FDA oversight is far better than the current situation. Then warnings like this about Lipitor—“tell your doctor if you have more than two drinks a day”—might actually reach the people who take the drug.

The prescription drug under consideration for over-the-counter status is Mevacor. That it is a statin drug and therefore a member of the top-selling drug class worldwide—$35 billion in annual sales—makes the switch all the more interesting. (Other statins are Lipitor, Crestor, Lescol, Pravachol, and Zocor.) Merck, the company that makes Mevacor, has recently applied to the FDA for permission to sell the drug over the counter. And an advisory committee of experts will decide the issue this month. (In 2005, an FDA Advisory Committee rejected a similar application for Mevacor.)

Two statin drugs Pravachol and Zocor are already available generically, which means that their patents have run out and now any company can produce these drugs under their generic names at a far lower cost than any brand-name statin. For example, Zocor, prescribed generically as simvastatin, costs from 75 cents to $1 a day at most retail drug stores and 10 cents a day, if purchased at a discount pharmacy like Costco’s. Lipitor, on the other hand, can cost $2.50 to $4 a day. From the FDA point of view, generic versions are equivalent to branded drugs because they must go through a process of proving that to the agency.

Many drug plans are encouraging members who take an expensive statin to switch to one of the generic versions with financial incentives like lower co-payments. And if Mevacor gets FDA approval for over-the-counter sale, statin users will have yet another low-cost alternative with the added feature of eliminating some doctor visit charges.

All this is cutting into the huge profits long enjoyed by Pfizer, the company that makes Lipitor, which is the most prescribed drug in the world. Naturally, the company wants to make as much money as possible before Lipitor loses its patent in March 2010. Consequently, Pfizer has escalated its long-running ad campaign featuring Dr. Robert Jarvik, inventor of the Jarvik artificial heart, who has been hugely successful in convincing many doctors and consumers that Lipitor is superior to other statins.

Currently, some of the Jarvik/Lipitor ads, say, “There’s a common misconception that all cholesterol-lowering medications are the same.” And more specifically, “In clinical studies LIPITOR lowered bad cholesterol significantly more than generic Zocor and Pravachol.”

Both points refer to a 2004 clinical trial that found people with heart disease showed a reduced degree of atherosclerosis progression if they were on high-dose Lipitor (80 mg) for 18 months, compared with those on a moderate dose of Pravachol (40 mg). There was also a greater reduction in LDL, or “bad” cholesterol, shown in the heart patients who took the high-dose Lipitor.

Three things to keep in mind about this trial, known by its acronym REVERSAL: Its participants all had heart disease (the overwhelming majority of U.S. statin-takers do not); REVERSAL was not designed to see whether Lipitor or Pravachol prevented heart attacks or strokes. And lastly, it compared a high-dose of Lipitor with a moderate-dose of Pravachol, leaving open the possibility that Pravachol at 80 mg might be just as good. Still, REVERSAL provides the basis for the Pfizer claim that Lipitor is not only better than other statins but it should also be prescribed in high doses for people with heart disease.

As for the most crucial goals of statin therapy: all statins, with the exception of Crestor, have been shown in clinical trials that predate REVERSAL to reduce the risk of heart attack and stroke in people who already have heart disease.

Healthy But High Risk

As for people without heart disease, the proven benefit of statins is largely confined to high-risk men between 30 and 69 years. The magnitude of this benefit, however, is not impressive—1.5% fewer of those taking a statin will suffer a non-fatal heart attack. But one analysis of all statin primary prevention trials showed that this 1.5% benefit was canceled out by an equivalent risk of experiencing a serious reaction to the statin.

The promotional activities of statin manufacturers have successfully focused most doctors and the general public on the excellent cholesterol-lowering effects of these drugs. But no head-to-head comparison study of all six statins has answered the most important-to-consumers questions: Which drug is best at preventing a heart attack or stroke? How large is the benefit?

There is a Jarvik/Lipitor print ad that answers the how-large-is-the-benefit question for high-risk people without heart disease. “In patients with multiple risk factors for heart disease, Lipitor reduces risk of heart attack by 36%* if you have risk factors such as family history, high blood pressure, age, low HDL (‘good’ cholesterol) or smoking.” In smaller print, the same ad has this explanation of “reduces risk” under the asterisk: “That means in a large clinical study, 3% of patients taking a sugar pill or placebo had a heart attack compared to 2% of patients taking Lipitor.” This ad is a rarity because it explains the 36% reduced risk. Take Lipitor for years and your risk of having a heart attack drops from 3% to 2%.

Lately, Pfizer has been trying to stem the exodus to generic statins by touting a new study that purportedly shows more heart attacks or strokes in people who switched from Lipitor to simvastatin, compared with those who stayed on Lipitor. There’s little reason to take this study too seriously.

First of all, Pfizer funded the study, and drug company-funded studies are notorious for coming up with conclusions that favor their products. Second, it was presented on a poster at a recent European cardiology conference, and has yet to be published or fully peer reviewed. (The New York Times, however, recently reported that this study has been accepted by the British Journal of Cardiology and will soon be published.) Lastly, the study is based on an analysis of medical records of British heart patients who did or did not switch from Lipitor to the generic version of Zocor (simvastatin). The study’s design is not regarded as high quality; in fact the authors describe its limitations this way: “This is an observational database study, and as such has recognizable limitations; therefore the findings should be regarded as hypothesis-generating.”

NB: There’s a consensus among cardiologists that statins are generally safe and are extensively studied. Perhaps they are, but three of the five major primary prevention randomized trials have not released all of their statistics on serious adverse reactions, according to James Wright, MD, and John Abramson, MD, who co-authored a commentary early this year in The Lancet, entitled “Are Lipid-Lowering Guidelines Evidence-Based?” The full story about the safety of statin drugs is unknown.

NEWS ABOUT DEFIBRILLATORS

An unexpected finding showed up when a team of Duke University researchers tracked elderly people with heart failure who did and did not have defibrillators implanted to prevent sudden death. Those who had a defibrillator implanted lived no longer than those who did not. That was the contrary-to-expectations finding 180 days after implantation.

But when these heart patients were followed longer, the results were worse for the men. Their mortality rate in the year after implantation was higher than that of women without defibrillators, though all had similar heart problems. To take into account the fact that women live longer than men, Leslie H. Curtis, PhD, and colleagues at Duke University School of Medicine, confined their study to men and women under the age of 75 years.

Their new findings come at a time when implantable defibrillators are, once again, in the news for having serious defects that have caused a few deaths. These devices monitor the patient’s heart rhythm and deliver an electric shock once dangerously erratic rhythms are detected.

The Duke researchers analyzed a national 5% sample of the Medicare claims filed for more than 35,000 people from 1991 through 2005. All had been diagnosed with heart attack and either heart failure or cardiomyopathy. Men were three times more likely than women to have the device implanted. Of those with heart disease but no prior cardiac arrest or tachycardia (rapid heartbeat), defibrillators were implanted in 32 per 1,000 men and about 9 per 1,000 women.

The gap between man and women didn’t close for the most seriously ill patients—those with prior cardiac arrest or tachycardia. For this group, the implanted defibrillator rate was 102 per 1,000 men and 38 per 1,000 women.

A related study, published in the same October 3 issue of the Journal of the American Medical Association, found that black men and women were also less likely to have a defibrillator implanted than white men.

“The bad news may not be for women and minorities, but for white men who are undergoing a procedure that for primary prevention does not extend their lives,” wrote Rita F. Redberg, MD, in an editorial that accompanied the two studies.

NEWS ABOUT DRUG-COATED STENTS

The bad news about this topic originally came from the World Congress of Cardiology in September 2006. Presented at this international conference were clinical trials that found a slightly increased risk of death and a higher rate of potentially fatal blood clots in people who had drug-coated stents implanted during a coronary-artery-opening procedure called angioplasty. The trials compared them with other heart patients whose constricted coronary arteries were propped open with stents not coated with a drug.

The higher risks among those given drug-coated stents did not show up until four years of follow-up. These complications were confirmed in two separate analyses of the combined results of company-sponsored trials by Boston Scientific, maker of the Taxus stent, or Johnson & Johnson, maker of the Cypher stent. The medicine coating these stents is intended to keep the constricted arteries from closing up again.

Last month the national media reported good news about drug-coated stents from the annual meeting of the American Heart Association in Orlando, Florida. Two-year follow-up results from a new, yet-to-be-published clinical trial showed that drug-coated stents are no more risky than bare-metal stents. Some media reports left the impression that the issue of stent safety had been resolved with this trial. “Heart Stent Gets a Reprieve From Doctors” was the over-the-top New York Times headline.

Keep in mind that the new trial announced at the heart meeting lasted only two years and the blood clots in the above-mentioned company-sponsored trials did not show up until four years. More details will be available when the new trial is published in Circulation, the journal of the American Heart Association, according to a “Late-Breaking News Release” from the heart meeting.

The meeting organizers managed to focus the media on stents rather than the more critical issue—overuse of artery-opening procedures. Many of the one million or so Americans who undergo angioplasty each year (with or without stents) can be treated just as successfully with drug therapy. It is generally the same multiple drug therapy advised for everyone who undergoes angioplasty. This was proven in a government-sponsored study called the Occluded Artery Trial, or OAT, published last year in The New England Journal of Medicine. A follow-up analysis of the OAT results was presented at the American Heart Association meeting. Yet no mainstream media reported the new OAT analysis, according to Health News Review, a medical media watchdog group led by journalist Gary Schwitzer.

All 2,166 OAT participants had a totally blocked major coronary artery and were 3 to 38 days away from suffering a heart attack. All were randomly assigned to receive an artery-opening procedure plus drug therapy or drug therapy alone. The multiple-drug therapy included daily aspirin, beta-blockers, ACE inhibitors and cholesterol-lowering drugs.

After four years, the OAT participants in the angioplasty/drugs group had the same rate of survival, second heart attack, and heart failure as the group given drug therapy alone. When the 469 American OAT participants were singled out (this was an international trial), the angioplasty-treated heart patients generated costs that were $10,000 higher than the drug-treated people. After three years, the cost difference had dropped to $7,000.

In an editorial that accompanied the OAT findings last year in The New England Journal of Medicine, L. David Hillis, MD, and Richard A. Lange, MD, wrote, “The open-artery hypothesis, although not previously validated in a prospective, randomized study, has nonetheless been embraced by many practicing physicians.” Translation: Heart surgeons have been opening constricted coronary arteries for years on the unproven premise that this will save lives and reduce the risk of a future heart attack. The OAT results failed to validate that hypothesis.

Opening a blocked artery during or right after a heart attack has been proven beneficial, but the OAT results showed no benefit to the common practice of performing angioplasty well after the patient had been stabilized—3 to 38 days after suffering a heart attack.

Maryann Napoli, Center for Medical Consumers ©
2007

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Avandia Debacle: Strong Medicine Needed to Cure FDA’s Ills

Posted by medconsumers on June 1, 2007

Scarcely two weeks after the Senate overwhelmingly passed legislation touted as a major fix of FDA’s failing effort to assure drug safety, The New England Journal of Medicine published an analysis linking the diabetes drug Avandia to a 40% increase in the risk of heart attack. This finding is especially troubling because people with diabetes are already at high risk of cardiovascular problems. A million diabetics are estimated to be current Avandia users in the U.S.

The review of safety data from dozens of trials was conducted by Cleveland Clinic cardiologist Steven Nissen, MD, and biostatistician Kathy Wolski, MPH. In 2005, another Nissen-led study concluded that an about-to-be-approved diabetes drug, Pargluva, had a high risk of cardiovascular problems, a finding that convinced the FDA not to grant approval. Avandia and Pargluva are both members of a class of diabetes drugs known as PPAR. Another drug in the class, Rezulin, was withdrawn in 2000 because of its liver toxicity; while a fourth, Actos, remains a best-seller.

Subsequent revelations have raised even more questions about the FDA’s ability to assure drug safety. According to The New York Times, John B. Buse, MD, Chief of Endocrinology at the University of North Carolina and President-elect of the American Diabetes Association, wrote to the FDA seven years ago warning of Avandia-associated heart problems. And almost a year ago, Glaxo, maker of Avandia, informed the FDA that its own internal analysis suggested cardiac risks associated with the drug.

But the FDA has said that the evidence of safety problems is inconclusive and that there is no cause for regulatory action. Not so with the FDA’s European counterpart. The European Medicines Agency, which apparently has a lower threshold for action, put out strong warnings about cardiovascular risk back in September 2006. And the director of the FDA division responsible for post-market safety recently told members of Congress that his staff’s recommendation of a black box warning for the drug’s label was overruled by senior management.

So, will the recently passed Senate bill fix the FDA’s poor record in assuring drug safety? In an editorial commenting on the Avandia review, drug safety experts Bruce M. Psaty, MD, and Curt D. Furberg, MD, concluded, “While the Senate bill has many strengths…none of its provisions would necessarily have identified the cardiovascular risks of rofecoxib [Vioxx] or rosiglitazone [Avandia] in a timely fashion.” I agree and suggest that any hope for meaningful changes at FDA now rests with several proposed bills being discussed in the House of Representatives. And, I believe, the Avandia experience identifies the most critical reforms that must be part of any legislation if it’s to make a difference.

First, there must be complete transparency of all trial data and FDA access to insurance industry (including Medicare) databases so the agency can determine how drugs are being used and what outcomes they are generating. The public’s health can only benefit from having good minds like those of Nissen and Wolski analyzing data and reaching their own conclusions. Second, unlike FDA’s handling of Avandia, the public should always be immediately alerted to any signals of toxicity.

Most important, Congress must mandate creation of an independent FDA drug safety office, one that is all about public protection. A dedicated safety office would likely have been watching more vigilantly for signs of problems with PPAR diabetes drugs given their poor safety record.

Arthur A. Levin, MPH, Center for Medical Consumers ©
June 2007

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Only One in 2000 Women Benefit from Mammography

Posted by medconsumers on December 1, 2006

Over the 31 years of publishing our newsletter, we have reported frequently about the lack of honesty in the mammography-screening information directed at women. Whether it comes from the American Cancer Society or a family physician, the information tends to be heavy on the lifesaving benefits and light on potential harms.

Here’s something a woman is unlikely to hear: “For every 2000 women* who go for mammography screening throughout a ten-year period, one woman will have her life prolonged. BUT ten additional healthy women, who would not have received a breast cancer diagnosis had they avoided mammography screening, will be treated unnecessarily for a breast cancer that would never have become life-threatening. And more than 200 women will experience significant psychological distress for many months because of false-alarm findings on a mammogram.”  click here for the source of this quote

This important information, so crucial to a woman’s informed decision-making, comes from a recent update of a 2001 Cochrane Review of the world’s major mammography screening clinical trials with a combined total of a half a million women. In all seven trials, which form the basis of the U.S. screening recommendations, women were randomly assigned to receive screening mammograms or not. These trials, conducted in North America and Europe, were published many years ago, but researchers continue to argue over their interpretation and conclusions.

* These statistics apply to women, aged 50-69 years. Odds of lifesaving benefit are even smaller for women in their forties.

Original Review in 2001
The 2001 Cochrane Review of these trials was co-authored by Peter Gotzsche, MD, of the Nordic Cochrane Centre in Copenhagen, as is the 2006 update published recently in the Cochrane Library. The original review triggered a prolonged debate in the American media in 2001-2002 after The Lancet published a summary of its results. The lifesaving benefit of mammography screening was shown to be far more modest than previously thought and the harms had been greatly underestimated.

The Cochrane Review also found that the mammography-screened women in the trials had more mastectomies, more lumpectomies, and many more cases of ductal carcinoma in situ (DCIS) than the women who were not screened. Although most cases of DCIS, a tiny non-invasive cancer within the milk duct, do not progress, they were—and in some parts of the country, still are—always treated with breast removal. Now radiation therapy is the more common treatment for DCIS.

In the two trials judged to be of the highest quality by the Cochrane reviewers, there were 30% more cancers in the mammography-screened groups than in the unscreened groups and 31% more mastectomies and lumpectomies. Yet surprisingly, in both of these trials, conducted in Canada and Malmo, Sweden, respectively, mammography screening did not reduce the rate of breast cancer deaths. The other five trials, judged to be of inferior quality by the Cochrane reviewers, did show a modest reduction in breast cancer deaths.

Old Trials, New Data
You might wonder why we are still learning new information from these seven trials, which were conducted between the 1960s and 1980s. The answer lies in the Cochrane reviewers’ thorough assessment of the enormous amount of data that was originally withheld and, in some cases, continues to be generated by these trials. The data, it should be noted, were requested by the Cochrane reviewers.

The long-term data provided by the Canadian trial are a case in point. Mammography’s ability to detect many more cases of DCIS has long been known. Not until this trial published 11- to 16-year follow-up results for women in their forties did it become evident that mammograms also detect non-palpable invasive breast cancers that do not progress. This means that some breast cancers can begin to invade the surrounding tissue, but go no further.

This was demonstrated by the Canadian trial results: There were 43 more invasive breast cancers and 42 more cases of DCIS in the women who underwent mammography screening, compared to those who did not. Yet 16 years later, the breast cancer death rate of both groups was exactly the same. (It is likely that there were just as many breast cancers of both types in the women not given mammograms, but these women benefited from being unaware of them.) Currently, doctors are not able to determine which cases of DCIS and invasive cancer will not progress to become life-threatening. All are treated as if they will be lethal.

Bottom Line: Mammography screening was introduced 35 years ago to reduce the rate of breast cancer deaths by finding and treating breast cancer before it can be felt by a woman or her doctor. even trials have produced contradictory results about the reduction in deaths. And some of these trials found that mammography can detect non-palpable breast cancers—both invasive and noninvasive—that do not progress. All are treated as if they will. For the first time, the benefit and harms have been quantified for women who want to make an informed decision. Based on the combined results of these trials, the Cochrane reviewers produced the one in 2000 women will have her life-prolonged estimate stated at the beginning of this article.

“Women, clinicians and policy makers should consider the trade-offs carefully when they decide whether or not to attend or support screening programs,” concludes the updated Cochrane Review, which was originally commissioned and funded in 1999 by the Danish Institute for Health Technology Assessment and the (Danish) National Board of Health.

 

Maryann Napoli, Center for Medical Consumers ©
December 2006

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Report Side-Effects of Statin Drugs

Posted by medconsumers on November 1, 2006

This is an excellent Web site for anyone who is currently on a statin drug or who has stopped taking one because of a serious adverse reaction. Although cholesterol-lowering statin drugs first went on the market 20 years ago, there are major information gaps concerning their adverse effects.

Beatrice A. Golomb, MD, PhD, who heads the UCSD Statin Study at the University of California at San Diego, has been working for years to change things by collecting information directly from the public. She has recently launched a new online survey (www.statineffects.com) “for people who have had adverse responses to statins or to other cholesterol-lowering drugs, and also [for] people who have done well on these drugs.” Statins are a class of cholesterol-lowering drugs that includes atorvastatin (Lipitor), simvastatin (Zocor), pravastatin (Pravachol) fluvastatin (Lescol), lovastatin (Mevacor), and rosuvastatin (Crestor).

The very existence of this study is tacit acknowledgment of deficiencies both in the FDA drug approval process and in its post-market surveillance system. Drug trials are designed to prove a benefit and typically do not provide a full picture of harm. Add to the mix the fact that most statin drugs are taken by older people. Many report to Dr. Golomb that their doctors attribute such problems as joint pain and memory deficits to aging and do not consider the possibility of statin side effects.

The site is more than a survey opportunity. It has information on known adverse effects divided into two sections: “Side Effects Your Doctor Will be Familiar With (muscle symptoms and changes in liver function, as noted in a blood test)” and “Lesser Known Side Effects” (e.g., peripheral neuropathy, memory loss, thinking and concentration problems), as well as a description of symptoms that should be reported immediately to your doctor.

Maryann Napoli, Center for Medical Consumers ©

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Protopic and Elidel: Eczema Drugs Have a Cancer Risk

Posted by medconsumers on May 1, 2006

Early this year, the Food and Drug Administration issued a warning about two prescription topical creams for the common skin disease, eczema. Both Elidel and Protopic must now include written material for professionals and patients that warns of a cancer risk based on “information from animal studies, case reports in a small number of patients, and knowledge of how drugs in this class work.”

Though the warning says, “a small number” of people who have used the products “have had cancer (for example, skin or lymphoma),” evidence from the FDA’s own reporting system indicates that this may be an understatement. Pretty alarming for drugs that are applied to the skin, primarily for young children. Doubly so, considering the fact that less than 10% of all serious adverse drug reactions are reported to the FDA.

People with eczema, also known as atopic dermatitis, and parents of children with this chronic skin disorder are often desperate for a treatment that alleviates the severe itchiness and inflammation. Eczema primarily afflicts babies and children, but can continue into adulthood in about 50% or show up  (rarely) for the first time in adulthood. There is no cure. A drug might beat it back for a short time, but flare-ups are common.

Elidel (generic name: pimecrolimus) and Protopic (generic name: tacrolimus) control eczema by suppressing the immune system, and they can be extremely effective in producing improvements. Until they came along, corticosteroid cream was the standard treatment. Hopes for the newer drugs stem from fears about the side effects of corticosteroid cream like thinning of the skin and adrenal gland suppression. Novartis, the company that makes Elidel, and Astellas Pharma (formerly Fujisawa), maker of Protopic, fed these fears by promoting their products as “steroid-free.”

One example is Fujisawa’s fraudulent ad for Protopic that appeared six years ago in Prevention magazine stating, “Breakthrough research has finally uncovered a new kind of medicine for eczema. Made of a natural substance, this new treatment is steroid free.” The ad implies safety. But in reality both Elidel and Protopic are in the same drug class as Prograf, a powerful immunosuppressant drug that prevents liver or kidney transplant rejections. In fact, Protopic and Prograf (generic name: tacrolimus), which comes with a warning of “infection and development of lymphoma,” are the same drug!

FDA Explains Itself

Why hasn’t the FDA withdrawn the drugs, given their obvious dangers and the existence of a safer alternative? “FDA believes that the benefits of Elidel and Protopic outweigh the risks of these products,” responded Julie Beitz, MD, of the FDA’s Center for Drug Evaluation and Research, who would answer questions only by e-mail by way of a press officer. “The  new warnings in the professional labels and in the Medication Guides* for these products convey what our concerns are, however, a causal link has not been established between the reports of cancer and use of these products.”

The FDA warning states that it may “take human studies of ten years or longer to determine whether Elidel or Protopic is linked to cancer.” Despite the lack of long-term data and what is surely an undercount of cancers associated with use of these drugs, Dr. Beitz defends the FDA position, “While there is under-reporting of adverse events to the FDA, we also know that use of these products is great, so relative to all users, the number of reports we have received is small.”

To some dermatologists, the question of whether Elidel and Protopic pose more than a rare cancer risk seems to hinge on how much is absorbed into the skin. In a January 19, 2006 press release that disagrees with the  FDA’s decision to issue an warning, Clay J. Cockerell, MD, president of the American Academy of Dermatology, said, “Because these medications are applied to the skin, virtually none of it gets inside the body.”

That statement was quoted to Dr. Beitz, who commented, “We agree that very little of the drug is absorbed in general, however, we have data to show that some patients do absorb the drug to greater degrees. Additional factors to consider: 1) how long the patient is using the product; 2) how large an area of skin the product is being applied to; and 3) the fact that areas affected with atopic dermatitis are not normal and may allow for more absorption.” Babies under two should not be treated with either drug, according to the FDA warning.

“Infants have higher surface area to volume so they will have higher blood levels of the drug and their skin is more permeable,” said Peter M. Elias, MD, professor of dermatology, University of California, San Francisco, in a telephone interview. “The companies have over-marketed these drugs suggesting, for example that they are safe for infants by showing images of infants [in promotional materials].” The ads implying Elidel and Protopic are safer than corticosteroids are ridiculous, he continued, adding that neither drug has been shown to be safer or more effective than topical steroids in a head-to-head comparison as maintenance therapy for eczema. “Low- to mid-potency steroids are quite safe in eczema, although many clinicians prefer an even less potent agent, such as hydrocortisone, in infants,” said Dr. Elias.

When the FDA was deciding whether to approve these drugs in 2000, Dr. Elias wrote a letter to the agency expressing concerns, particularly about Protopic, which he described as “a powerful and potentially toxic immunosuppressive drug.” In the letter, which remains on the FDA Web site, Dr. Elias told the agency that he is “alarmed at what appears to be a potentially cavalier and uncritical attitude about the indications and long-term safety of topical tacrolimus [generic name for Protopic]. [This drug] is absorbed into the circulation through inflamed skin, and in low-body weight children it can produce transient therapeutic (transplant) drug levels.”

Dr. Elias sees a limited role for the drugs, “Protopic should be reserved for severe, recalcitrant flares of eczema in children and adults, and Elidel for similar bad flares in infants. Elidel might also be useful for periorbital dermatitis due to risk of glaucoma from steroids. But in all these examples, the use should be short term—days, weeks, but not months—and only in conjunction with sunscreens, which should always be used when these drugs are applied to sun-exposed skin. There is no rationale for long-term therapy with either drug.”

Pressure Not to Warn the Public

In the five to six years since the FDA approved each drug, Novartis and Astellas/Fujisawa mounted a massive, often misleading, advertising campaign aimed at doctors and the public. And in the last two years, both companies waged an aggressive campaign against the FDA’s planned warning. Under great pressure not to act, the FDA went ahead and called a meeting of its pediatric advisory committee in February 2005, which recommended a label change warning doctors and patients about the risk associated with both Elidel and Protopic.

The next month, a cancer warning appeared on the FDA Web site. (It is not known how many doctors or patients would think to look on the FDA’s Web site for new warnings.) As of January 2006, a Medication Guide for patients with the warning is supposed to be included with all prescriptions of Elidel and Protopic. The Guide does not spell out the safe duration (if there is one) of short-term use, though makes it clear that neither drug should be the first-choice treatment for eczema.

There are reasons to think that these efforts will go unheeded. Several studies show that only one in ten doctors read the drug label which is the most complete source of information about a drug’s use and harms. (Consumers are not much better.) A recent survey showed doctors are overwhelmed with drug warnings and have difficulty keeping them all straight. In the case of Protopic and Elidel, the dermatologists’ professional organizations were actively working against the FDA’s plan to issue a  warning. The Society for Pediatric Dermatology, in a letter dated November 30, 2005, advised its members to write the FDA to tell the agency that warnings are not warranted because “abrupt discontinuation of these medications out of fear [will result] in disease flares in many children.” Furthermore, the letter claimed that an analysis of the clinical data presented to the FDA have not supported a malignancy risk.

“The great resistance in the dermatologic community to the FDA warning is based in part on the fact that many of the opinion leaders are in conflict of interest situations that too often go undisclosed,” said Dr. Elias, referring to funding from Novartis and Astellas that pays for the speakers bureau, conferences, and continuing education. And he doesn’t think much of the evidence cited to support objections to the FDA warning about Elidel and Protopic. “There are 55 articles about the safety of both drugs that claim to be long term,” Dr. Elias explained. “However, they are not, in fact, long term; the longest study lasted only six months; many are repeats—the same study published in multiple journals—and others are written by the drug company journal editor.” [Note: There are longer studies indicating the drugs are safe and effective, but they are funded by either Astellas or Novartis.]

It is quite possible that one day lawsuits will generate  the publicity needed to adequately warn the public about inappropriate use of Elidel and Protopic. Several law firms now have Web sites specifically devoted to the drugs. One such firm headed by Larry M. Roth has a Web site (www.protopiclawyers.com) that features his detailed article on the history of FDA approval of topical immunosuppressants and reports of serious reactions, complete with extensive footnotes. It describes cancers, deaths, and other severe  reactions reported to the FDA.

In a telephone interview, Laurilyn Cook-Arrington, a paralegal at Larry M. Roth, PA, said the law firm had retrieved this information from the FDA’s Adverse Events Reporting System with a Freedom of Information Act request. (Manufacturers are required “by regulation” to report serious drugs reactions to AERS.) Ms. Cook-Arrington said the firm has been gathering information on topical immunosuppressant drugs for three years. “Hundreds of potential claimants have contacted our firm in the last year. And many of these claims include deaths. Almost 50% of them are made on behalf of children. They involve skin cancers, as well as systemic malignancies like leukemia, Hodgkin’s disease, and multiple myeloma.”

What to do:

  • If you are using Elidel or Protopic, inform yourself about these medications. Start with the warnings at the FDA Web site (www.FDA.gov). Consumers and doctors can report serious adverse drug reactions to the FDA’s Medwatch Program 1(800) FDA-1088.
  • Ask your doctor about prescription emollients to reduce the amount of topical drugs needed to control eczema. According to Dr. Elias, “Topical prescription emollients alter biochemical abnormalities in the skin, lead to fewer flare ups, and fight off infection.” They can be used as the first treatment or as maintenance after short-term treatment with an immunomodulator, explained Dr. Elias, who is also chief science officer at Ceranix, makers of a yet-to-be-available emollient, EpiCeram.

Maryann Napoli, Center for Medical Consumers ©
May 2006

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Adverse Drug Reactions

Posted by medconsumers on July 19, 2005

Remarks of Maryann Napoli at a Meeting of the Institute of Medicine ‘s (IOM’s) Committee on the Assessment of the US Drug Safety System, July 19, 2005.

I have been a consumer advocate for nearly 30 years, writing about medical research and critically appraising clinical trials. I’m still surprised that I could have been at it so long without fully understanding-until about two years ago-that it is not unusual for drug company-sponsored trials to withhold data about adverse drug reactions. I am referring to trials published in high-profile medical journals.

I learned this while writing about the cholesterol-lowering drugs, statins, when I was putting together a poster for the Cochrane Collaboration’s 2003 conference. My work has long focused on the selling of drugs to healthy people-drugs to reduce a risk factor, drugs that healthy people will take for the rest of their lives. I have always been interested in the way we Americans have come to accept the idea that a risk factor should be treated as if it were a disease. Bisphosphonate drugs for bone loss, postmenopausal estrogen to improve lipid profiles-that sort of thing. The emphasis-when selling healthy people the idea of lifelong preventive drug therapy-is on the benefits. We don’t hear much about the drugs’ risks.

For my Cochrane Poster, I summarized the proven benefits of statins for people who do not have heart disease-just a few risk factors like high cholesterol. I found only one review of the five major mostly primary prevention trials that had compared a statin drug with a placebo. All five were drug company-sponsored and published in leading medical journals. Here’s what jumped out at me. The authors of that review, who are based at the University of British Columbia , wrote in their on-line publication, Therapeutics Initiative, that only two of the five trials had reported their serious adverse events (SAE). The UBC authors reported that they had asked the investigators from other three trials for their SAE data and were refused. Working with what they had (data from only two of the trials), the UBC authors found that the benefit of statins was far more modest than doctors and the general public have been led to believe. There was approximately a 1.8% lower rate of non-fatal heart attacks in the male study participants, but this was offset by the 1.4% increase in SAE among the statin users. SAE were defined as “any untoward occurrence that results in death, is life-threatening, requires hospitalization or results in prolonged hospitalization, or significant disability.” [1]

It troubled me to see that statins aren’t anywhere near the lifesaving medications they’re purported to be. In fact, this review showed that for primary prevention, only middle-aged men under 70 benefited from these drugs. Not only was the benefit small, it was canceled by the risks. But it was far more alarming to learn that we do not have the full story on the safety of statins because three of the trials had refused to release all their SAE data [2] .so it is quite possible that the risks could considerably outweigh the benefits. But we simply do not know. Keep that in mind the next time you see a doctor quoted in the media, telling us that statins are safer than aspirin. I would learn later that this withholding of data is not unusual. In fact, sometimes the lead investigator has received only incomplete data on the drug.

I have since relayed my “revelation” to other experienced consumer advocates and every one of them said that they never heard that published drug trials often provide incomplete data about safety. I have also reported this to physicians and researchers who also say that they never heard of this withholding of SAE data. In fact, most deny that it is so.

How can healthy people who are on lifelong drug therapy make an informed decision about their medications when drug companies are allowed to withhold such important information? To go beyond statins for a moment, I’ve found that it is not unusual for anti-hypertensive drug trials to show that the cardiovascular death rate is reduced by the drug. But the overall death rate is no different from that of placebo group. Often this finding goes unexplored.

How prevalent is the non-reporting of SAE? A study by Ioannidis and Lau surveyed the safety reporting of new medications in 192 randomized drug trials, which altogether included over 130,000 participants. Only 46% of these trials reported or specified the drugs’ SAE. Overall, the researchers found the space allocated to safety results was equal to the amount of space devoted to contributor names and affiliations. The conclusion: “The quality and quantity of safety reporting vary across medical areas, study designs, and settings, but they are largely inadequate.” 3 I hope that the IOM report will shine a light on this issue and related questions like:

Why do medical journal editors let the trial sponsors get away this these glaring omissions of important data? Why aren’t these omissions “redflagged” in the abstract of every published trial that fails to provide complete safety data? Why do these editors allow drug company-sponsored trials to express their results in relative risk reduction terms and omit the more-understandable-to-consumers absolute risk reduction? Is it any wonder that many consumers overestimate the effectiveness of their prescription drugs?

We must find a better way to quickly detect SAE once drugs are on the market.

I urge the IOM to encourage more government-funding of epidemiological studies like the one announced last year by Kaiser Permanente. It found a greater incidence of heart attacks and sudden deaths among the enrollees who had been taking higher than normal doses of Vioxx. Everything should be done to encourage Center for Medicare and Medicaid Services to continue using its database to determine the safety and effectiveness of drugs prescribed to people on Medicare and Medicaid. And registries should be established for all clinical trials from their onset to prevent drug companies from hiding the existence of clinical trials that show negative results and from withholding SAE data from their trials [see related article].

I thank this committee for taking on this important issue and giving me the opportunity to present my perspective.

[1] Therapeutics Initiative Evidence Based Drug Therapy. Do statins have a role in primary prevention? University of British Columbia . Vancouver , April-May-June 2003. www.ti.ubc.ca The reviewers attempted to answer the question: What is the overall health impact when statins are prescribed for primary prevention? ” In the 2 trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9% . This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations.”

[2] Walsh J and Pignone M. Drug treatment of hyperlipidemia in women. JAMA, May 12, 2004. “For women without cardiovascular disease, lipid lowering does not affect total or CHD mortality. Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively.”.. The risk for total mortality was not lower in women treated with lipid-lowering drugs, regardless of whether they had prior cardiovascular disease or not. In the primary prevention studies, there was no reduction in either CHD or total mortality. This may be because lipid lowering does not affect total mortality in women or because there were few deaths in the small, relatively healthy cohorts of women studied, even after summarizing study findings. In most of the studies, the length of follow-up was only 2.8 to 6 years. It is possible that a reduction in total mortality might have been observed with a longer duration of follow-up. For secondary prevention, CHD mortality is reduced, but total mortality is not. Possible explanations include chance, the limitation that not all studies reported both CHD and total mortality, or not all studies could be included in each summary estimate. Another potential explanation might be an increase in a competing cause of mortality, for example, an increase in hemorrhagic stroke with lipid-lowering therapy. However, information on the causes of non-CHD mortality is not available for all the trials, so this possibility cannot be proven. Publication of cause-specific mortality for many of the larger trials could help to clarify the association between lipid-lowering therapy and total mortality.”

[3] Loannidis JME, Lau J. Completeness of safety reporting in randomized trials of seven medical areas. JAMA 2001, Jan 24-31.

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Many People Stop Taking Anti-Hypertensive Drugs because the Dose is too High

Posted by medconsumers on August 1, 2003

At least half of all people stop taking their blood pressure medications because of the side effects that typically include fatigue, lethargy, dizziness, and sexual dysfunction. Jay S. Cohen, MD, knows the reason why—-the dose is set too high. He takes issue with the prevailing belief among doctors and drug manufacturers that side effects are inevitable and unavoidable. In his book Over Dose: The Case Against Drug Companies (New York: Jeremy P. Tarcher/Putnam, 2001), Dr. Cohen says that the drug companies set the dosage for all prescription drugs at a high level because it is more convenient for doctors. The source of information that most doctors turn to for dose recommendations is the Physicians’ Desk Reference, which is published by the pharmaceutical industry with oversight by the FDA.

Dr. Cohen, a research physician at the University of California, San Diego, has published numerous medical journal articles on the subject of drug dosage. He has found that most side effects never occur when people are started at a low dose that is slowly increased if needed. Nowhere is that more apparent than in the treatment of hypertension.

Every five years, the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC) is convened to reassess the standard therapies for hypertension. The JNC usually gets a lot of media attention with its pronouncements, but Dr. Cohen observes that the guidelines have little effect on physician prescribing habits where it concerns dosage.

When the JNC last published guidelines, Dr. Cohen did his own survey comparing the doses recommended by the JNC with the doses recommended by the drug companies. The JNC experts recommended substantially lower initial doses for 23 out of 40 anti-hypertensive drugs. Asked about the latest JNC guidelines in a telephone interview, Dr. Cohen said that most of the guidelines are exactly the same, though a few new drugs have been added. “A lot of the [recommendations] come out again with the same standard ‘one size fits all’ dosing. Young and old, big and small, healthy and unhealthy, and people who take ten medicines and those who take one medicine,” he answered. “Whenever I’m talking about this on a radio show, veterinarians and farmers usually call in to say they always adjust medicine doses for animals.” Dr. Cohen emphasized that he is not suggesting everyone needs low doses. Only about 20-40% of all people do. “It’s usually the small, female, [and/or] elderly,” he said, “People who are sensitive to medicine–they know who they are.”

After many years of treating high blood pressure, doctors have become more amenable to lowering the dosage once they prescribe drugs in combinations of two or three, explained Dr. Cohen. To illustrate how long it takes to identify the safest and most effective dose, Dr. Cohen used diuretics as an example. “Those drugs can have major side effects that usually aren’t obvious,” he explained. “They were first marketed at doses of 50-100 mg a day, and now the standard dose is 12.5 mg. It took them decades to figure that out. 12.5 mg is fine for most people, but for those who are sensitive, there is no harm in starting lower.”

Dr. Cohen has advice for people who want to avoid high blood pressure or lower mild hypertension without drugs. “Lose weight, eat a good diet that emphasizes vegetables, fruits, whole grains, fish, poultry, and low-fat dairy products. This has been proven to lower blood pressure as much as a mild blood pressure pill.” Those who follow this type of diet, however, will still need magnesium supplementation, according to Dr. Cohen, who estimates that 80% of the population is magnesium deficient. To help people understand why, Dr. Cohen wrote a booklet called Magnesium for High Blood Pressure, which he said is available at many health food stores. “Magnesium does exactly the same thing as these expensive calcium channel blockers doctors prescribe for hypertension,” he explained. “It calms the nervous system, and relaxes the musculature, and stabilizes blood vessel function.”

For More Information:
Visit Dr. Cohen’s Web site (www.medicationsense.com) to sign up for a free electronic newsletter and learn more about his work.

Maryann Napoli, Center for Medical Consumers(c)

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