The long awaited results, of what has become a controversial drug trial, were announced recently, generating intense debate in medical circles, evoking widespread media speculation, and eliciting critical comments from the chair of the USA House of Representatives.
Controversies arising in the wake of a disappointing outcome for the ENHANCE TRIAL have provoked challenging commentaries from critical observers, and also defensive responses from the research team, seeking to minimise the impact of the trial’s shortcomings.
Numerous concerns have been expressed, arising from anomalies within the trial. These are considered here, together with their implications for health-care initiatives and primary care providers, and also for prospective users of the drugs in question.
The failure of Ezetimibe, an adjunctive cholesterol lowering agent , to produce a favourable result in this trial, has inescapable implications for prescribing doctors, for the drug manufacturer, and for the countless numbers of patients for whom LDL-C lowering drugs have been prescribed.
The Ezetimibe / Simvastatin combination was compared to Simvastatin alone, in a randomised trial involving 720 patients with Familial Hypercholesterolaemia (FH).
The aim was to show that by reducing atheroma burden, as measured by Carotid Intima Media Thickness (CIMT) , corresponding LDL-C lowering would be a justifiable strategic objective in attempting cardiovascular risk reduction.
As such, it was not a clinical outcome study, focusing instead on the progression of atherosclerosis in the carotid artery as a surrogate end point.
According to the lead investigator of the study, Dr. John Kastelein, this was the largest study of carotid IMT that has ever been conducted so far, involving 19 different centres of investigation.
The trial was commenced in 2002 and came to a conclusion in April 2006.
But the outcome was from what the trial researchers were hoping for. The anticipated favourable results were not observed.
This striking failure to produce favourable results provoked contrasting reactions from the trial researchers and from impartial observers.
Dr. P. Shah of Cedar Sinai Medical Centre is convinced that the drug will work, “because of its ability to lower LDL-Cholesterol”, he stated.
Dr Richard Lang, of Johns Hopkins, disagrees with this view, stating that there is “no evidence of extra benefit” to be derived from the use of this, or similar, drugs.
The fact that LDL-C lowering by the agents used, either in combination, or independently, had no effect on atheroma reduction has been interpreted by many observers as continuing evidence that LDL-C lowering does not confer clinical benefits.
The Enhance trial, in fact, enhances the conclusions from most of the major statin trials that there is no association between the degree of total cholesterol or LDL-C lowering and the CHD survival rate.
ATHEROMA BURDEN :
The reduction of atheroma burden, as reflected in CIMT reduction, is considered by many investigators to be a reliable prediction of improved outcome for high-risk patients with cardiovascular disease.
In the trial Ezetimibe / Simvastatin produced a 58% reduction of LDL-C from baseline, after 2 years, compared with a 41% reduction of LDL-C with Simvastatin alone.
Despite these marked LDL-C reductions, with an increase by 17% of LDL reduction in the combination therapy, there were no beneficial changes observed in CIMT, as measured by intravascular ultrasound (IVUS), thereby calling into question presumptions of clinical benefit for these drugs in particular, and for LDL-C lowering in general.
The trial has attracted intense media attention because of several concerns.
- The first of these was the delay in announcing the trial results, interpreted by some observers as a deliberate attempt to hide a negative result, and one which prompted the USA House of Representatives to challenge the drug manufacturers, Pfizer and Astra-Zenica, with accusations of impropriety.
- A second concern, which was also raised by the USA House of Representatives, was that the study was not registered with the ClinicalTrials.gov until after 31 October 2007, 18 months after completion of study.
- A third issue raising the ire of many observers was an attempt, before releasing any results, to change the end point of the trial, an act viewed by some as “an apparent manipulation of trial data”.
- A fourth concern was that of drug safety. Reports have emerged documenting liver damage to patients caused by the Ezetimibe / Simvastatin combination. Dr Mark Stolk reported 2 cases of Hepatitis in 2006 of which one was fatal.
Canada and Australia have both issued warnings regarding the risks of Ezetimibe which appear to have been ignored elsewhere.
- The fifth major concern arising from this trial was its clear failure to demonstrate the anticipated benefits in respect of atheroma reversal.
This negative finding has implications at several levels, viz.
a) For patients who currently use these agents in the belief that by so doing they will derive anticipated clinical benefits
b) For prescribing doctors who continue to focus efforts on LDL-C reduction strategies with little regard for lifestyle modifying strategies.
c) For the pharmaceutical industry and its insistance on marketing drugs without matching evidence of efficacy or safety.
d) For the prevailing paradigm that LDL-C is a “bad cholesterol”, a threat to wellness and longevity, and deserving the full weight of pharmacological intervention aimed at maximum suppression .
These implications bring into focus the underlying hypothesis that drives the war against cholesterol and shapes the prescribing habits and counselling objectives of many health professionals.
The popular perception, that high levels of circulating cholesterol are always harmful, serving as primary instigators for atherosclerotic disease, is not shared by all investigators.
Biological studies contradicting the prevailing paradigm underscore the arguments of those who refute claims that guidelines are evidence-based.
Dr Martin Krumholtz (Yale) speaks of “obscured evidence”” and Dr. Rodney Hayward (Michigan) reports, “current evidence supports ignoring LDL-C altogether”
LDL-C vs. OX-LDL :
The traditional focus on LDL-C reduction, as a strategy for minimising cardiovascular risk, ignores the biological evidence that oxidised-LDL (OX-LDL), a modification of circulating LDL-C, is a more potent pro-atherosclerotic stimulus than native LDL-C.
Evidence suggests that it is the former, rather that the latter, which imposes it’s deleterious effects on the vessel wall, through a complex cascade of pro-inflammatory processes, giving rise to a thickening of the arterial wall and ultimately plaque formation.
A study by Dr Frans van de Werf (Belguim) showed that LDL-C had no predictive value, but that OX-LDL was predictive of acute coronary syndrome and MI.
Several lines of study suggest that pro-oxidant factors alter a healthy endothelium,giving rise to modifications of circulating LDL-C and subsequent oxidised-LDL formation.
These factors have been shown to include cigarette smoking, poor glycaemic control, excessive refined dietary carbohydrate, homocysteine, iron overload, nutritional deficiency, nitric oxide depletion, microbial infection, an imbalance of Omega 6 and Omega 3, and psychological stress.
Several studies demonstrate that there is no association between OX-LDL and LDL-C, and that OX-LDL can be reduced by addressing causative factors, while circulating LDL-C remains unchanged .
Alternatively, the latter can be pharmacologically reduced without producing evidence of clinical benefit.
Japanese researchers have demonstrated a strong association between OX-LDL and advanced carotid plaques, and also a propensity for plaque rupture with elevated OX-LDL, rather than with LDL abnormalities.
The traditional perception of cholesterol laden debris accumulating on the vessel wall and progressively occluding the artery lumen to produce stenosis continues to dominate thinking in public and professional circles.
Current evidence dispels this notion as simplistic and inaccurate, offering instead a model of complex intra-arterial wall inflammation, as a consequence of repair mechanisms operating in response to oxidant induced damage.
Mounting evidence suggests that plaque formation and clinical outcome are not always correlated, and that coronary arteries with severe stenosis (>70%) do not cause the majority of myocardial infarctions that are documented.
Plaque formation may stabilise, or become unstable, leading to fragmentation and embolism, under pro-oxidant conditions.
Japanese researchers show that OX-LDL rather than LDL-C provides the conditions that predispose to plaque rupture and cardiac events.
The clinical benefits of HDL-C are well documented and have been explained by Mertens and Holvoet in terms of its antagonistic activity to OX-LDL.
By reversing the stimulating effect of OX-LDL on monocyte infiltration in the inflammatory process, HDL-C exerts a beneficial anti-inflammatory effect, which in turn prevents atherosclerosis.
The prevailing notion that circulating levels of cholesterol TC and LDL-C are the primary instigators for atherosclerosis, and that pharmacological reductions of LDL-C will reduce atheroma burden with improved clinical outcome is not supported by the ENHANCE TRIAL.
The results are due to be presented at the American College of Cardiology (ACC) in March this year (2008) for review and analysis and for further commentary.
Dr. Neville Wilson.
The Leinster Clinic – Medical Suite.