http://www.redflagsweekly.com/rosch/2003_jul21.html

PAUL ROSCH, MD

July 21, 2003

CONVERTING MILLIONS OF HEALTHY PEOPLE INTO PERPETUAL PATIENTS

By Paul J. Rosch, MD, F.A.C.P.
THE AMERICAN INSTITUTE OF STRESS

Paul Rosch, MD, FACP, is clinical professor of medicine and psychiatry at New York Medical College and is President of the American Institute of Stress, and Honorary Vice-President of the International Stress Management Association.

This column will also appear in a future edition of the Health and Stress monthly newsletter of the American Institute of Stress

Forget about the alchemist's magical "Elixir of Life" and Ponce De Leon's "Fountain of Youth". These fantasies have recently been replaced by a combination pill concocted not by some "kook", but two distinguished scientists, Nicholas Wald, Professor and Head of the Wolfson Institute of Preventive Medicine in London and Malcolm Wald, a Professor at the University of London and University of Auckland in New Zealand. These researchers believe they can prevent almost nine out of ten heart attacks as well as four out of five strokes in anyone with cardiovascular disease and everyone age 55 and older. All you need to do is to take their powerful Polypill daily.

So what's in this latest magic bullet? A statin to lower LDL, three different antihypertensive drugs (a beta blocker, diuretic and ACE inhibitor), aspirin to reduce clotting tendencies and folic acid to prevent high homocysteine levels. There is no vitamin C or vitamin E, omega-3 fatty acids, Coenzyme Q10 or other ingredients that have also been shown to reduce heart disease. There are no dietary restrictions or recommendations nor any apparent need to exercise more or stop smoking.

The Polypill was introduced with much fanfare in a lead article entitled "A strategy to reduce heart disease by more than 80%". It appeared in the June 28 issue of the British Medical Journal accompanied by two enthusiastic editorials. Richard Smith, the editor, started out by stating that this was possibly the most important issue of the journal in the last 50 years. He suggested that everyone save their copy since it would likely become a collector's item. A guest editorial by Anthony Rogers, co-director of the Clinical Trials Research Unit, University of Auckland was not quite as gushy. However, it also seemed to endorse the authors' claim that the Polypill would have "a greater impact on the prevention of disease in the Western world than any other known intervention"! Not surprisingly, the professors filed a patent application for their formulation and a trademark application for the name Polypill over three years ago

Their contention is that one in three people over the age of 54 could look forward to an additional 11 or 12 years of life free from cardiovascular disease by taking a daily Polypill. All the ingredients are readily available and not protected by patent so the price of the pill would be minimal, especially when purchased in huge quantities. There is apparently little concern about safety because of the relatively low dosages of the various drugs, which apparently does not reduce their effectiveness.

These conclusions seem somewhat premature, if not preposterous, for several reasons. The first is that no studies have ever been done with the Polypill since it does not exist. It is not clear if this will be manufactured as a tablet, capsule containing powder or gelcap, and the various different fillers required or formulation of the covering may not be compatible with all the constituents. Proximity to meals and time of day of administration may influence efficacy. Simvastatin and beta blockers are more effective when given in the evening, but a thiazide diuretic taken at the same time could significantly interfere with a good night's sleep. Some of the ingredients have significant side effects or are relatively contraindicated in common conditions like diabetes and asthma. In addition, desired responses may be suppressed and/or unwanted actions augmented when certain of these drugs are taken simultaneously.

The claims for efficacy and safety of the Polypill are based solely on meta-analyses and statistical evaluations of more than 750 clinical trials involving some 400,000 participants. Many of these study groups involved individuals with evidence of or at increased risk for coronary heart disease and hypertension. Extrapolation of such results to populations with no increased risk for cardiovascular disease other than having reached the age of 55 seems unwarranted and potentially dangerous. They hardly justify converting millions of healthy people into perpetual patients, some of whom may well develop complaints like chronic cough and bleeding tendencies. The promises that 88% of heart attacks and 80% of strokes will be prevented are based on statistics that reflect relative risk reduction, which is very different than absolute risk reduction. This is a great example of Harry Truman's advice, "If you can't convince them, confuse them".

For example, your doctor tells you that there is a new blockbuster statin drug with no side effects and if you take it every day for the next five years it will significantly "reduce your risk" of heart attack. How likely is it that you would take the drug based on the following clinical studies?

1. Over five years, patients taking this drug had 34% fewer heart attacks compared to controls who took a placebo. (Sounds pretty convincing)
2. Over five years only 2.7% of patients taking this drug had a heart attack compared to 4.1% taking a placebo. (Also not too bad)
3. If seventy-one people take this drug every day for five years it will prevent one of them from having a heart attack. However, there is no guarantee that you will be that person. (These odds are not very attractive)

All these scenarios are accurate and are based on the same data but the statistics have been presented in very different ways. To avoid becoming confused, it is essential for you to be able to distinguish between relative risk reduction, absolute risk reduction and number-needed-to-treat.

Scenario 1: 4.1% taking the placebo had heart attacks; compared to only 2.7% for those taking the drug, a 34% Relative Risk Reduction of 34%.

Scenario 2: When you compare the percentage of the 4.1% in the placebo group who had heart attacks with the 2.7% of statin-takers who had heart attacks, the Absolute Risk Reduction is only 1.4%!

Scenario 3: How many people need to take the drug to prevent just one heart attack? Your doctor would have to treat 71 people just like you for five years to prevent one of them from having a heart attack but there is no way of knowing who this will be. This is called the Number Needed To Treat and would probably not persuade many healthy patients to take this pill for the rest of their life.

Statin manufacturers are able to persuade physicians to prescribe their products by citing Relative Risk Reduction statistics and these are also featured in direct advertising to consumers, who may not be aware of their true significance. The fact is that none of the primary prevention statin trials have demonstrated a decrease in overall mortality rates and most show no significant decrease in the incidence of heart attacks or strokes. The Polypill proponents have done the same thing. Many will interpret their claims to mean that taking a pill every day for the rest of their lives will reduce the likelihood of having a heart attack by 88 per cent and lower their chances for stroke by 80 per cent. If the meta-analyses statistics were reported instead as Absolute Risk Reduction percentages and Number Needed To Treat, quite a different picture would be painted. According to a rapid response posted on the BMJ web site by two British physicians entitled "Patients Before Populations",

"We are duty bound to inform our healthy 55-year-old that if he or she takes the Polypill for the next 10 years there will be less than 1% chance per year of benefit and a 6% overall chance of side effects, some of which (e.g. aspirin related GI haemorrhage) may be life threatening. Furthermore if the Polypill is successful, our patient’s chance of dying from cancer, trauma and degenerative brain disease will increase pari passu with the effectiveness of the Polypill, as sadly even on the Polypill, mortality will remain stubbornly around the 100% mark."

Not mentioned were the possible adverse effects of statin induced Coenzyme Q10 depletion, beta blocker fatigue and impotence, etc. The selection of three antihypertensive drugs at "half standard doses" shotgun approach is based on the erroneous premise that most patients will eventually require three or more medications to achieve satisfactory blood pressure control. It also assumes that this particular combination will provide a satisfactory synergistic effect while significantly reducing individual side effects. Calcium channel blockers were apparently excluded to keep costs down but they can also conflict with thiazides. However, beta blockers may deplete levels of Co Q10 and potentiate other adverse statin side effects like fatigue. There could be additional complications from unanticipated interactions between the constituents of this crazy concoction.

Extrapolating the results from epidemiologic studies of large populations to treat individual patients is dangerous, especially when based on meta-analyses of groups that may not be relevant. This approach also ignores comorbidity problems due to other conditions that may affect metabolism and excretion or require conflicting medications. A good example of this is the current confusion about treating elevated blood pressure, which is also usually a trial and error buckshot approach. A bullet will do the trick, since 60% of all hypertensive patients can be controlled on one medication permanently by renin profiling to determine whether the problem is salt (volume) related or due to activation of the renin-angiotensin-aldosterone system. As will be explained in a subsequent article, this testing is now readily available. Until then it would be wise to heed the "Patients Before Populations" advice of other Polypill critics.