RECENT CHOLESTEROL-LOWERING DRUG TRIALS: NEW DATA, NEW QUESTIONS
Michel de Lorgeril and Patricia Salen
Laboratoire Coeur & Nutrition, Université Joseph Fourier - Grenoble 1,
CNRS, TIMC-IMAG, UMR 5525, Faculté de Médecine, Grenoble, France.
Correspondence : Michel de Lorgeril, MD, Coeur & Nutrition, Faculté de Médecine, Domaine
de la Merci, 38706 La Tronche, France
The cholesterol-lowering drug trials published in 2008-2009 were either negative (ENHANCE, SEAS, GISSI-HF, AURORA) or obviously biased and therefore not credible (JUPITER). How can we explain this wave of negative cholesterol-lowering drug trials? In this article, authors review and comment the results of these recent trials. It is also noteworthy that most cholesterol-lowering drug trials published between 2005 (the year of the Vioxx affair and of enforcement of new clinical trial regulations) and 2007 were also negative or ambiguous. Taken together, these recent trials, including those of 2008-2009, strongly suggest that the results of previous, highly positive trials with statins — particularly in the secondary prevention of coronary heart disease — published between 1994 and 2004 and that were used to issue guidelines for medical practitioners should be carefully re-examined by experts independent from the pharmaceutical industry. The next question would be whether it is not time for a full reappraisal of the theory according to which cholesterol-lowering results in a significant protection against cardiovascular morbidity and mortality.
Short title : Recent cholesterol-lowering drug trials
The years 2008 and 2009 have been very disappointing for cholesterol experts and the cholesterol drug industry, for at least four reasons. In fact, three events as important in terms of media coverage as of science and medicine are held each year around the issue of cholesterol: the annual meeting of the American College of Cardiology (ACC) in March, the annual meeting of the European Society of Cardiology (ESC) in August, and the American Heart Association (AHA) meeting in November. Because thousands of cardiologists from all continents are at the same place at the same time, each of these meetings is an opportunity to roll out cholesterol drug marketing campaigns. Today, marketing is primarily based on the publication of results of randomized trials. Thus every year, the three cardiology “world meetings” are the best time for the pharmaceutical industry and friends to re-launch the cholesterol-lowering drug machine. However, the years 2008 and 2009 have been sad years because trials results obviously did not support the theory according to which cholesterol-lowering results in significant benefits in the prevention of coronary heart disease (CHD), including the so-called “the lower the better theory”. To understand this course of events, a chronological account of events is needed.
Chapter One: The ACC meeting in March 2008
The results of the ENHANCE study conducted in patients with familial hypercholesterolemia (1) were published in March 2008—and were disappointing. Familial hypercholesterolemia is supposed to be a cholesterol-driven disease, with dramatically high LDL cholesterol levels. In ENHANCE, an association of ezetimibe, a cholesterol-lowering drug acting by decreasing the absorption of cholesterol in the digestive tract, and simvavastin, a statin that acts by decreasing the endogenous synthesis of cholesterol, was tested. For those who believe that cholesterol is the main cause of CHD, ENHANCE was designed not to fail. Actually, the association of the two drugs in the same patient results in a drastic reduction of cholesterol levels, in particular LDL cholesterol—the so-called “bad” cholesterol—levels. The test was not performed by measuring hard clinical endpoints such as cardiac death or myocardial infarction, but by repeated measurements of carotid intima-media thickness (IMT), a supposed marker of atherosclerosis progress.
Unexpectedly, the combination of the two drugs failed to provide incremental benefits over simvastatin alone, despite a drastic reduction of cholesterol (1). In addition, both treatments did not result in significant effects on the primary endpoints: not only did the change in IMT not differ over time, from baseline to 24 months, between the two study groups, but there was a slight increase in IMT in both groups: at 2 years, the estimates were of +0.0095±0.0040 mm in the simvastatin-only group (P=0.02 vs. baseline) and +0.0121±0.0038 mm in the combined-therapy group (P<0.01 vs. baseline), which suggests that the lower the cholesterol, the greater was the increase in IMT (1). These surprising and very disappointing data might explain why the results of ENHANCE were hidden from the medical community for nearly two years, while the drug was being used by millions of patients over the world, hoping that it was protecting their arteries and hearts (2-4).
Very surprisingly, after ENHANCE many cholesterol experts declared that familial hypercholesterolemia is not the adequate population to test the effects of cholesterol-lowering (2-4). Instead, a scientist would have concluded that if this potent association of drugs does not work in familial hypercholesterolemia, it can hardly be expected to work in any other case. Hence, ENHANCE was, by itself, a cause of confusion and debate among cholesterol experts. The data of ENHANCE led an ACC panel to urge physicians to only prescribe cholesterol-lowering medications with proven clinical effectiveness, i.e. proven effects on hard clinical CHD endpoints such as cardiac death, myocardial infarction and stroke (5). As a matter of fact, ezetimibe was approved and marketed in 2002 based solely upon a 20% reduction of cholesterol, but not on data related to its effectiveness on any clinical endpoint (6), as if cholesterol levels by themselves could be a surrogate of CHD. In addition, the effectiveness of the ezetimibe+simvastatin combination against hard clinical endpoints has never been demonstrated, as discussed below about the SEAS trial. As a consequence, many physicians and scientists rightly questioned why the combination tablet already was on the market if there was no proven effect on clinical CHD complications (4,5).
Finally, during the 2008 ACC meeting, a press release announced the premature termination of JUPITER, a trial testing rosuvastatin, presumably the most effective statin in terms of cholesterol-lowering, against a placebo in the primary prevention of CHD (7,8). With this announcement, the pharmaceutical company probably wanted to communicate that rosuvastatin, contrary to ezetimibe+simvastatin, resulted in an “unequivocal evidence of reduction in cardiovascular morbidity and mortality” as written in the press release (7,8). This was quite strategic for cholesterol experts at that particular time, because several trials testing cholesterol-lowering had been published during the previous years in various clinical circumstances — ASPEN, 4D, PREVENT IT, IDEAL, ILLUMINATE (9-13) — and also ENHANCE (1), and all of them reported no convincing protective effect against CHD complications (1,9-13). The failure of ENHANCE, in particular, generated unprecedented media coverage, patient and physician concerns, and the involvement of the US Congress over the use of cholesterol-lowering drugs to reduce CHD risk (2-5).
Following the publication of ENHANCE, two studies of cholesterol-lowering treatments following protocols approved by the FDA were either not published or abruptly terminated (14,15). CASHMERE tested atorvastatin in postmenopausal women. The trial results were unearthed by capital market analyst Robert Hazlett and showed no effect at all on IMT (14). ACHIEVE tested a novel combination tablet associating niacin and laropiprant (a prostaglandin D2 blocker used to prevent the flushing induced by niacin) in familial hypercholesterolemia (15). The trial was prematurely stopped because after the failure of ENHANCE in the same category of patients, sponsors and investigators thought that there was no hope to demonstrate a benefit (15). This indicated that even in 2008, trials that were obviously negative or tended in the wrong direction were still not publicly discussed by investigators and sponsors and sometimes were halted before completion. This gives an idea of what was being done before the new clinical research regulation came into force in 2005-2006, after the Vioxx affair (16), with the obligation of declaring all the clinical trials and of publishing the results even when they are not favorable to the tested drug (17,18). All these attempts to mislead the medical and scientific community have highlighted the fact that the alleged effectiveness of cholesterol-lowering to prevent CHD complications is very questionable for anyone wanting to open their eyes.
Chapter Two: The ESC meeting in August 2008
During the August ESC meeting, the results of two important trials were reported: SEAS and GISSI-HF (19,20).
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was a randomized, placebo-controlled study evaluating ezetimibe+simvastatin, like ENHANCE (1). This time, however, cholesterol-lowering was tested (against a placebo) by evaluating its effects on hard clinical endpoints, including aortic valve replacement and CHD complications in patients with aortic stenosis (19). The main assumption was that disease progression in aortic stenosis is strongly influenced by hypercholesterolemia (21,22) and often associated with CHD complications (23,24). Thus, double benefits were expected in these patients: first, by preventing CHD complication and second, by preventing aortic valve complications. The primary endpoint of the trial was therefore a combination of CHD and aortic valve complications.
To summarize SEAS results, drastic cholesterol-lowering had no significant effect on the primary endpoint (19). While the authors tried to present the SEAS data in a positive light by claiming that cholesterol-lowering had a significant effect on secondary endpoints such as coronary revascularization, SEAS actually confirmed the negative results of ENHANCE, but this time for of hard clinical endpoints (19).
From a scientific point of view, SEAS is a critical study for several reasons.
First, SEAS confirmed previous recent trials (9-13), including ENHANCE (1), and the inability of cholesterol-lowering to reduce the risk of CHD complications in certain populations. This raised the question of whether the failure of ezetimibe+simvastatin was due to some unknown side effects of the combined treatment or to the fact that cholesterol-lowering actually is beneficial in certain populations or patients and not in others. In fact, some experts have claimed that previous positive trials were not the result of cholesterol-lowering but of other properties of statins, the so-called pleiotropic effects (25). At this point in the controversy, cholesterol experts appeared to be divided into two groups: those who were claiming that cholesterol-lowering is still important whatever the results of ENHANCE and SEAS, and those claiming that cholesterol-lowering is not important as long as patients receive intensive statin treatment in order to induce pleiotropic protection (2-4,26).
Second, the control group in SEAS received a placebo, whereas in ENHANCE the comparison group received simvastatin alone. This means that the difference in LDL cholesterol between the experimental and the control group was huge in SEAS, close to 50%, but still did not provide any protection. Thus, ENHANCE and SEAS taken together should have logically led to reject the “the lower the better” theory that states that the lower the cholesterol, the better the protection (27,28).
Third, it is noteworthy that in SEAS, patients with low cholesterol levels in the experimental group had more cancers and died more frequently from cancers than those receiving the placebo (19) . Although it can be speculated that the increased cancer rate was a chance effect (29,30), this raises another critical question: may intensive cholesterol-lowering increase the risk of cancers in certain patients? No one can answer that question today. Given the millions of patients receiving intensive cholesterol-lowering treatment without any unambiguous cardiovascular benefits, the next critical question is whether we should not follow precautionary principles on this public health issue and at least fully inform the public about these questions.
The results of another important statin trial were reported during the 2008 ESC meeting.
GISSI-HF was a double-blind randomized trial testing whether 10 mg rosuvastatin compared with a placebo could reduce mortality and cardiac complications in patients with chronic heart failure (CHF) from various causes (20). Large observational studies, small prospective studies and post-hoc analyses (including meta-analyses) of large randomized trials have indeed suggested that cholesterol-lowering could be beneficial in CHF patients. Despite a 36% reduction of LDL cholesterol in the statin group compared with placebo, there was no difference between groups for total mortality (657 deaths versus 644 in the placebo group) and for other cardiovascular endpoints in GISSI-HF (20).
GISSI-HF thus confirmed the results of a previous trial published less than one year before, the CORONA trial (31). In CORONA, 10 mg rosuvastatin also were tested against placebo in patients with CHF aged 60 and more. Contrary to GISSI-HF, all patients in CORONA were CHD patients who had survived a previous myocardial infarction and presented left ventricular dysfunction. In other words, CORONA was a secondary prevention trial in high-risk patients because left ventricular dysfunction significantly increases the risk of CHD complications and cardiac death. Before CORONA, statin experts claimed that the higher the risk of cardiac death was, the higher the benefits of intensive cholesterol-lowering would be (32,33).
Official and international guidelines state that a statin should be given to all patients — whatever their cholesterol level — in high-risk secondary prevention, whereas in primary prevention, when the risk of cardiac death is lower, prescription should depend on the cholesterol level (28,34,35). In CORONA, the primary composite outcome was cardiac death, nonfatal infarction and nonfatal stroke (31). LDL cholesterol was reduced by 45% and CRP (an inflammatory marker) by 37% in the rosuvastatin group compared with placebo. CORONA was therefore designed not to fail. However, no significant difference was recorded for the primary composite outcome. Moreover, there were 488 and 487 cardiovascular deaths in the rosuvastatin and placebo groups, respectively. The numbers of deaths due to worsening heart failure were 191 and 193 in the placebo and statin groups, respectively. Thus, the unequivocal lessons of CORONA were that both drastic cholesterol-lowering and the supposed pleiotropic (anti-inflammatory) effect of the statin had no effect at all in the secondary prevention of CHD in high-risk patients.
CORONA and GISSI-HF therefore provided exactly the same information in two different populations, namely that cholesterol-lowering does not improve the prognosis for high-risk CHD patients. The theory that the higher the risk — notably in secondary prevention of CHD — the higher the benefit of cholesterol-lowering (28,32-35) should logically be rejected. Also, the theory according to which statin pleiotropy could have a significant clinical impact appears to be very elusive after GISSI-HF and CORONA.
Both GISSI-HF and CORONA raised many questions. The main, one however, was why the most recent statin trials conducted in secondary prevention and high-risk patients, including the patients with familial hypercholesterolemia recruited in ENHANCE and those with aortic valve disease recruited in SEAS, have been negative. An alternative question was whether there were some technical problems and potential biases in these 4 trials that could have explained the failure. If not, the same question should have been raised about the previous trials reporting high protection with statins, in particular those conducted during the 1990s, before the Vioxx affair and the new clinical research regulations (16,17). How can we explain the discrepancy between these older positive trials, in one hand, and CORONA, GISSI-HF, ENHANCE and SEAS, on the other hand?
Lastly, are the methods and results of previous trials reporting high benefits of cholesterol lowering verifiable today? Did the new regulations introduced after the Vioxx affair result in such a striking improvement of trial conduct that all trials are now negative?
Chapter Three: The 2008 AHA November meeting and the JUPITER trial
JUPITER tested the effects of 20 mg rosuvastatin in subjects without cardiovascular disease, normal cholesterol levels but relatively high CRP (36). The authors report a 50% decrease in LDL cholesterol, a 37% decrease in CRP and a decrease by about 50% in cardiovascular complications. However, there are methodological problems and major clinical inconsistencies in JUPITER.
The main methodological problem in JUPITER regards the premature trial termination (36). Investigators made the awkward decision to stop the trial after 393 cases of complications, before the calculated number of at least 520 events calculated in their analysis plan was reached (36). Taking only the hard complications of fatal and non fatal myocardial infarction and stroke into account, they actually stopped the trial after only 240 events! The ethical argument according to which patients in the placebo group could no longer be left untreated is not relevant, and even the opposite, as many scientific articles constantly stress (37,38) Scientific rigueur is the primary ethical rule that has to be followed in clinical research. Ethics required that the trial should not have been discontinued prematurely, as evidenced by the inconsistency of clinical results (see below).
The results of JUPITER are reproduced in the Table. They look dramatic. The primary endpoint (1st line) is a mix of diverse complications listed in the bottom lines of the table, although some of them such as revascularization are irrelevant because they are not complications but medical decisions. This being said, we actually observe an impressive difference between the two groups in terms of hard clinical complications, myocardial infarction and stroke (157 against 83, line 9). However, there are no clear data on cardiovascular mortality in the Table as well as the text of the article. One may infer from the Table (although this is not indicated in the text) that fatal myocardial infarction is the difference between “any myocardial infarction” and “nonfatal myocardial infarction”, giving total numbers of 9 (31 less 22) in the rosuvastatin group and 6 (68 less 62) in the placebo group. We can make the same calculation for fatal stroke (the difference between “any stroke” and “nonfatal stroke”), resulting in total numbers of 3 (33 less 30) in the rosuvastatin group and 6 (64 less 58) in the placebo group. Cardiovascular mortality (fatal stroke+fatal myocardial infarction) is therefore identical in the two groups (12 against 12).
The lack of effect on cardiovascular mortality associated with a miraculous effect on nonfatal complications is puzzling and should have led to suspect a bias and to the continuation of the trial instead of a premature ending. In addition, the numbers of fatal myocardial infarction in both groups (9 and 6) were unexpectedly low compared to nonfatal infarction (62 and 22), suggesting that JUPITER patients, particularly in the placebo group, withstood the consequences of myocardial ischemia and infarction extremely well. This was apparent even within the first hour following the first symptoms (the definition of sudden cardiac death), since curiously no sudden cardiac death was reported in the trial. Almost no (non sudden) cardiac deaths were reported either during in the following hours, days and weeks.
We were clearly facing a major clinical inconsistency.
Mortality from myocardial infarction is known to be very high. In fact, the “case fatality rate” in epidemiological reports has been reported in many populations with very different risks (39). Out of 100 patients who have a myocardial infarction, an average of 50 die immediately or within the 3-4 weeks that follow, and almost never less than 40 out of 100 even in populations with low cardiovascular mortality (39). In JUPITER, mortality during infarction (6 divided by 68 multiplied by 100) is 8.8% in the placebo group. This is extremely low, and here we have another major clinical inconsistency! But where does the error lie? Which are the false figures? The case fatality rate in the rosuvastatin group (9 divided by 22 multiplied by 100) is 29%, a figure that fits better (although not perfectly) with the expected variations but raises another question: would rosuvastatin have tripled myocardial infarction-related mortality?
Is this clinically consistent?
Another way to measure the trial's clinical consistency is to compare cardiovascular and total mortality. In most countries, cardiovascular mortality represents 45 to 60% of total mortality, rarely less than 35%. Yet in JUPITER, it represents only 6% of total mortality (12 divided by 190 x 100; see Table) in the statin group and 5% (12 divided by 235 x 100) in the placebo group. How incredibly low! This is another major epidemiological inconsistency.
Pending confirmation of JUPITER by a new trial that will—hopefully—follow traditional and validated clinical trial methods, the obvious conclusion is that JUPITER results are not clinically consistent and therefore not credible. We must bear in mind that two previous trials with rosuvastatin (CORONA and GISSI-HF) were negative for CHD prevention (20,31). Thus, no clinical trial so far had been published showing an unequivocal clinical benefit of rosuvastatin when JUPITER was published. And this right at the time where other anti-cholesterol drugs (tested in ENHANCE and SEAS) showed totally ineffective whatever the type of hard or surrogate endpoints used to test the effects of cholesterol-lowering (1,19).
Chapter Four: The 2009 ACC meeting and JUPITER follow-up
During the March ACC meeting, the results of one important trial, named AURORA, were reported (40). It was an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients who were undergoing maintenance hemodialysis. These patients are known to be at very high risk of CHD complications and a meta-analysis based on subgroup data extracted from previous trials did claim that cholesterol-lowering is effective to reduce CHD complications in these patients (41). In AURORA, patients were randomly assigned to receive rosuvastatin, 10mg daily, or placebo. The combined primary endpoint was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints included death from all causes. The mean reduction in LDL-cholesterol levels was 43% in patients receiving rosuvastatin. During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary endpoint (9.2 and 9.5 events per 100 patient-years, respectively; p=0.59). There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; p=0.51). Thus, in chronic kidney disease patients undergoing hemodialysis, cholesterol-lowering with rosuvastatin had no effect at all (40). This was not unexpected and confirmed the results of a previous negative trial in similar kidney disease patients where atorvastatin, instead of rosuvastatin, had been tested (10). Together the two trials confirmed that the failure of cholesterol-lowering was not medicament-specific but the consequence of the lack of effect of both cholesterol-lowering itself and of any “pleiomorphic effect” of statins.
At the same 2009 ACC meeting, JUPITER investigators presented data from secondary endpoints, symptomatic venous thromboembolisms (42). They were claiming on the basis of very weak data that rosuvastatin significantly reduces the occurrence of venous thromboembolisms forgetting that they were not included among the endpoints used to calculate the a priori hypothesis tested in the trial (36). It is perplexing to see leading medical journals publishing trials results which could lead naive practitioners to the foolish conclusion that rosuvastatin might have some anticoagulant properties.
During the same 2009 ACC meeting, JUPITER’s investigators reported analyses aimed at testing the hypothesis that the benefits observed in JUPITER were primarily the results of lowering both LDL cholesterol and high-sensitivity C-reactive Protein (CRP). It is not useless to recall that the JUPITER’s principal investigator has a personal conflict of interest as a co-holder of the patent for the CRP test (36) .
Authors reported that, although LDL and CRP reductions were only weakly correlated in individual patients, participants who achieved striking reductions of both LDL (less than 1.8mmol/L) and CRP (less than 1mg/L) had a 79% reduction of event rates (43). To further celebrate the magic usefulness of CRP testing in clinical practice, they also claimed that “achieved CRP concentrations were predictive of event rates irrespective of the lipid endpoint used” (43). Unfortunately, these weak data using subgroups extracted from an apparently biased dataset (see above) were in total contradiction with recent studies showing that CRP measurements are useless for improving our ability to evaluate CHD risk. For instance, a large study involving 28,112 cases and 100,823 controls showed a lack of concordance between the effects on CHD complications of CRP genotypes and CRP levels (44). This also strongly argued against a causal association of CRP with CHD (44).
The issue regarding subgroup analyses is particularly interesting regarding the effects of cholesterol-lowering in chronic heart failure patients. Indeed, cholesterol-lowering was claimed to be very effective in these high-risk and fragile patients on the basis of meta-analyses using subgroup data of previous trials (45). This was unchallenged by the medical community until the publication of well-designed negative trials (20,31) leading to opposite conclusions and rejection of the theory that cholesterol-lowering with statins is useful in this condition.
The heart and/or renal failure patients story is also an indication that meta-analyses, although often considered as golden-standard of medical sciences, can be strikingly flawed and misleading. An illustration of this is a recent article in the British Medical Journal (46) where JUPITER data were surprisingly included in a meta-analysis – although they are obviously not validated – to support the use of statins in primary prevention of CHD complications (46). Also in that study, authors wrongly used selected subgroup data to make their meta-analysis (46). It is worrisome to realize that the very process of reviewing and publishing itself can be biased, even in leading medical journals.
For cholesterol experts and the cholesterol industry, 2008 and 2009 have definitely been very disappointing years. The trials results reported at the four world cardiology meetings (ACC 2008, ESC, AHA and ACC 2009) were either negative (ENHANCE, SEAS, GISSI-HF, AURORA) or not clinically consistent and probably biased (JUPITER) because of premature termination. Taken together, in the light of other recent negative trials (CORONA, ASPEN, 4D, PREVEND IT, IDEAL, ILLUMINATE) published after the Vioxx affair in 2005 and the following new clinical research regulations, the 2008-2009 trials are puzzling. They suggest that the positive trials published before 2005 and the Vioxx affair should be urgently re-examined. A minimum would be that experts independent from the industry and free of conflict of interests should be committed to carefully check all the raw data recorded in the datasets and redo the statistical analyses. The next question would then be: is it not time for a full reappraisal of the cholesterol theory?
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46- Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009; downloaded from bmj.com on 1 July 2009.
Anthony N. DeMaria, MD, MACC, Editor-in-Chief, Journal of the American College of Cardiology
As I write this Editor's Page, Vioxx has just been withdrawn from the market by Merck, Inc., because of an increased risk of cardiovascular (CV) events. Given the number of patients involved (it is estimated that Vioxx was prescribed approximately 10 million times per month in the U.S.), the magnitude of sales of the agent ($2.5 billion/year), the financial impact upon Merck stock (a fall of 27% amounting to $27 billion), and the serious nature of the side effects (myocardial infarction and stroke), it is not surprising that this action received major media attention. The withdrawal provoked the immediate release of papers in the New England Journal of Medicine by prominent CV authorities questioning whether similar action should be taken for all selective cycloxygenase-2 inhibitors (COXIBs) and even calling for a Congressional investigation (1,2). Clearly, this matter has the potential for significant fallout in many areas.
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective agents, but are limited by potentially serious gastrointestinal (GI) ulcerations and bleeding. Vioxx was one of several COXIBs developed to exploit the anti-inflammatory effects of selective cyclooxygenase (COX)-2 inhibition while preserving the protective action of COX-1 on the GI mucosa. The VIGOR study (3), which documented the efficacy of Vioxx in reducing GI side effects, also yielded unexpected evidence of increased myocardial infarction and stroke. Although the relationship between the increased CV events observed and Vioxx was uncertain, a plausible explanation consisted of the unopposed prothrombotic effect of thromboxane A2 via the COX-1 pathway. Given the uncertainty regarding the findings from the VIGOR study, the apparent absence of similar adverse events from other studies, and the demonstrated GI benefit, the major alteration in prescribing recommendations was to urge that all patients with an indication for aspirin (usually for prophylaxis of CV disease) be given that agent with Vioxx. Two years after the VIGOR study was published, the Food and Drug Administration (FDA) instructed Merck to add a warning regarding the risk of CV disease to the package insert. Another two years passed until the results of a study of colon polyps documented the CV risk and resulted in the withdrawal of Vioxx from the market.
Reputation of the FDA in shambles after Vioxx scandal; calls for wholesale FDA reform gain momentum
Saturday, November 06, 2004
by Mike Adams, the Health Ranger
Editor of NaturalNews.com
"...the agency’s senior management is more concerned with external appearance than rigorous science." -- Dr. Richard Horton, editor, The Lancet
Perhaps the most relevant criticism of the agency comes from Dr. Richard Horton, editor of The Lancet, a well respected medical journal. After reading the Merck insider emails published in the Wall Street Journal showing how Merck sought to distort drug trials to hide evidence of heart disease, and after reviewing the same clinical trials on the drug that the FDA reviewed before approving it, Dr. Horton was outraged and called for FDA reform:
"In the case of Vioxx, the FDA was urged to mandate further clinical safety testing after a 2001 analysis suggested a 'clear-cut excess number of myocardial infarctions'. It did not do so. This refusal to engage with an issue of grave clinical concern illustrates the agency’s in-built paralysis, a predicament that has to be addressed through fundamental organizational reform."
But Dr. Horton didn't stop there. He also explained, "...with Vioxx, Merck and the FDA acted out of ruthless, short-sighted, and irresponsible self-interest." In other words, Merck and the FDA were playing the classic "cover your ass" game in trying to hide the destructive health consequences of Vioxx from the public for as long as possible. And they managed to pull it off for four years thanks to the gullibility of conventional doctors and the ignorance of the American public, who continue to believe in prescription drugs as "miracle cures" for just about every symptom or disease, even though the facts reveal that prescription drugs heal no one. More often than not, they actually kill people.