A Faulty Carnitine Clinical Study

:
A Common Example of Faulty Clinical Studies in General
BY STEPHEN L. DEFELICE, MD
’ve received a number of inquiries by concerned parties regard- media, know anything about this. Even many statisticians are not ing a recent clinical study at Cleveland Clinic which, sparked by expert in this field because probability statistics oftentimes the senior physician who participated in the study, was covered requires two extra years of probability specialty training to master heavily by the mass media, hailing it as a breakthrough medical difficult analytic problems. They are based on whether the results discovery. The message? Carnitine causes atherosclerosis. of a study are probably due to chance alone. If, for example the The day after the launch of the results of a study are not just by chance media coverage, I was still unaware of alone, then, depending on if it is a corall the controversy. Then, while enjoyrect clinical study design, you can be ing my morning coffee, I began reading reasonably sure that they are true. For articles in the Wall Street Journal and example, if the results of a study are due New York Times reporting on the study, to chance in one in a thousand, then echoing the message of the danger of you can be pretty sure that they weren’t carnitine. The coffee shot proprietor, due to chance and one can, with confiknowing of my carnitine history and dence, believe in the results. If, however, overhearing my disgruntled conversait’s one out of two, then it may be due to tion with myself, remarked, “Doc, it chance alone, and one, therefore, was all over the television news last should not accept such results night.” I correctly sensed that a media I first encountered all four factors in frenzy had begun. And so it did, from a single study when I was a young docDR DEFELICE: “The only solution is to cure the the Huffington Post to NPR, to almost tor investigating the role of aspirin for diseases and disabilities that ail us, which would everywhere. This has led to unwarrant- eliminate the need for these studies.” the treatment of diabetes, believing that ed confusion and concern by many it could prevent the all too common prescription carnitine takers, particularly the parents whose chil- vascular complications of this increasingly prevalent disease. A dren are taking carnitine due to life- threatening carnitine defi- multicenter clinical study, the UGDP, conducted with the oral anticiency states. diabetic drugs reported that these pharmaceuticals were harmful, This study is an increasingly common example of unrecognized causing deaths in a high percentage of patients. The media underfaulty clinical trials making unsubstantiated claims, creating mass standably sounded the alarm and caused lots of extreme, unwarconfusion rather than solutions to medical-health issues. ranted anxiety among diabetics and their families; and let’s not What are the reasons behind our ever forget the doctors who treat them! I growing medical-health Towers of remember very well sitting in a large conCarnitine is an ammonium compound Babble? Generally they are four interference room with an impressive number formed (biosynthesized) from the twined factors –poor study design, poor of diabetes experts, where the presentaamino acids lysine and methionine. In statistics, poor overall interpretation of tions of the results by the clinical investiliving cells, it is required for the transthe results and poor presentation of the gators were given. The statistical analysis port of fatty acids into the mitochonrisk/benefit ratio to consumers and docconcluded that it was highly improbable dria (part of the cell) during the breaktors. Before I move on, I want to emphathat the results of the study were due to down of lipids (fats) for the generation size the nature of statistics, for they are chance. In other words, the conclusions of metabolic energy. frequently used to justify the results of were justified. For certain reasons, many clinical studies, but also frequently misdiabetologists, including myself, were leading. It will surprise you to know that the application of statis- skeptical about the results. Largely because of this doubt, the study tics doesn’t prove anything. It only deals with probability. was reevaluated and the drugs were cleared of the false rap. This Paradoxically, neither doctors, scientists, consumers, nor the eye-opening case for me represented faulty protocol design, faulty

I

www.eparent.com/EP MAGAZINE • May 2013 43

statistics, faulty interpretation of the data voices are silent on this possibility. For the cular literature and Aristotle’s lessons on and faulty presentation of the risk/benefits record, I believe the case is not closed on logic, they concluded that carnitine is the of the drugs. It, indeed, was a critical career this issue. culprit. Not so. The high levels are a warnlesson for me. Here’s another eye-opener. It was, and ing sign or biomarker of a distressed heart, Examples of medical-media complex still is, very widely accepted and historical- be it coronary artery disease or cardiomycausing confusion ly supported by opathy, or weak heart. Since I am the docmany. For are and tor who brought carnitine into the United laboratory It will surprise you to know example, I am an clinical studies, States way back in 1965, I have a personal that the application of statistics endocrinologist that HDL choles- interest in this study and issued a press doesn’t prove anything, it only deals and clinical pharterol is cardiopro- release exposing its faults and clarifying with probability. macologist (an tective by remov- the truth. It is now posted on the FIM, The expert in clinical ing cholesterol Foundation for Innovation in Medicine research). Yet, I am still not sure of the risk- from artery walls. The higher the concen- website (www.fimdefelice.org). benefit of hormonal management of post- tration in the blood, the safer you are from There have been several published studmenopausal women. For many years, it the ravages of caries, warning us was believed that the benefit was obvious. diovascular disabout faulty cliniFactors contributing to Women felt better and, based on soft clini- ease. Not necescal studies which faulty clinical trials: cal data, it was believed that it decreased sarily so. In a more have been inex1. Poor study design the incidence of cardiovascular disease. definitive or conplicably and irre2. Poor statistics Then a large scale published study report- trolled s p o n s i b l y clinical 3. Poor overall interpretation of the results ed that hormonal therapy in post- study which evaluignored by the 4. Poor presentation of the risk/ benefit menopausal women increased their car- ated a drug that medical-media ratio (to consumers and physicians) diovascular risk. There understandably was elevated HDL, the complex. For a general response of grief and disbelief, results did not example, the even among doctors. Then a reanalysis of support this belief. Strangely enough, Greek physician, John Ionnidis, is perhaps the data was done, reporting that the clini- expert doctors in this field and the media the world’s authority on faulty conclusions cal design and stahave hardly cov- of clinical studies. He has published well tistical analysis of ered these find- over 1,300 papers with co-authors from According to one leading it were faulty and ings. For this rea- over 500 institutions in 43 countries. He authority, 90 percent of the only applied to son the vast has found that 90 percent of the concluconclusions of clinical studies, even in women who took majority of peo- sions of clinical studies, even in the most the most prestigious the hormones ple still are anx- prestigious medical journals, are somewhat medical journals, are somewhat flawed later on in the ious to know flawed and, oftentimes, incorrect. and, oftentimes, incorrect. post-menopausal So where does that leave us? about, and feel phase. The benesafer, when they Unfortunately, it is an unresolvable dilemfits only applied to women treated at an learn that their HDL blood levels are high ma, and we must live with it. The only soluearlier age. The result? Along with most of and embrace any substance that elevates tion is to cure the diseases and disabilities my colleagues and their patients, I am not them. How about you? that ail us, which would eliminate the need sure of the true risk/benefit of this therapy. for these studies. FIM has proposed the etting back to the Cleveland Clinic Doctornaut Act to accelerate the discovery There has been an insufficient attempt to study which claims that carnitine of such cures, as well as reduce health care explain to doctors and patients a clear prescauses atherosclerosis: As I said costs. For more information, take a look at: entation of the risks versus benefits of takbefore, the media went hog wild, spreading www.fimdefelice.org and watch the new ing such hormones. Let’s take vitamin E as another example: faulty information and scaring lots of folks, FIM video about Doctornauts. • Study after study reported that it was car- including not only patients who are carnidioprotective. Even doctors were con- tine takers, but parents of youngsters who ABOUT THE AUTHOR: vinced. Then a more “controlled” clinical have been on carnitine for years. This medStephen L. DeFelice, M.D., founded FIM, the study showed no such effect. All four fac- ical-media event is a classic and obvious Foundation for Innovation in Medicine, in 1976 tors are clearly in action in this case, and example of the negative side of the med- with the mission to accelerate medical discovery. the possibility that this vitamin being car- ical- media complex. The investigators FIM is now involved in the Cure Care vs. Health dioprotective still exists. However, medical measured carnitine blood levels in over Care initiative and the Doctornaut Act. Dr. DeFelice’s 40 year pioneering research on carnitine 2,000 patients and found that high levels led to its FDA approval as an orphan drug and were associated with cardiovascular dis- worldwide recognition. He also coined the term ease. Ignoring the vast carnitine cardiovas- nutraceutical, which is now in many dictionaries.

G

44 May 2013 • EP MAGAZINE/www.eparent.com