Cholesterol lowering, sudden cardiac death and mortality

Abstract

Sudden cardiac death is the main cause of cardiac mortality. Is blood cholesterol a determinant of sudden cardiac death? Does cholesterol lowering result in fewer sudden cardiac deaths? Answering these two questions may shed a new light on the epidemiology of coronary heart disease and on prevention options. In fact, careful analysis of the available data, including randomised trials, indicates that, contrary to a widespread opinion, cholesterol lowering does not appear to be a very effective way of reducing cardiac and overall mortality in the general population.

• Cholesterol
• statins
• sudden cardiac death
• myocardial infarction
• mortality

Coronary heart disease (CHD) is the Number One “serial killer” in developed and developing countries. Obviously, any treatment or preventive strategy against CHD should be assessed according to its effect on mortality. All the other parameters of treatment efficacy are, at best, secondary or surrogate endpoints. Because of potential short- and long-term non-cardiovascular side effects that may conceal the benefits of any treatment against CHD, both CHD and overall mortality should be carefully analysed, and no clinical (and, all the more, public health) recommendation should ever be made without having first scrutinised these two endpoints.

The next question is: what is CHD death? In other words, how do people dying from CHD actually die?

Sudden cardiac death: An unrecognised tragedy

According to recent data standardised to the 2000 US population, about 65% of 719 456 cardiac deaths among adults aged >35 years in 1998 were defined as sudden cardiac deaths (SCD). In that study, SCD was defined as death occurring out of the hospital or in the emergency room, or as “death on arrival” with an underlying cause reported as a cardiac disease. Among those aged 35 to 55, about 75% of cardiac deaths were SCDs 1. This means that the vast majority of premature CHD deaths in our societies, in particular among apparently healthy populations, are SCDs. It is also noteworthy that from 1989 to 1999, age-specific death rates for SCD increased by about 20% among women aged 35 to 45 years 1. Efforts to identify potential risk factors of that specific CHD complication in particular groups are therefore urgently needed.

Is high blood cholesterol a risk factor of sudden cardiac death?

Since most SCDs occur as the first presentation of CHD, a major question is whether we are able to identify people at risk of SCD in the general, apparently healthy, population. In other words, are the traditional and easily measured risk factors of CHD predictive of SCD? Several studies have recently tried to answer this question. For instance, in a prospective study on healthy men, investigators found that only C-reactive protein (CRP) was significantly associated with the risk of SCD, whereas blood homocysteine and all lipid parameters, including serum total and LDL cholesterol levels, were not 2. In another study investigating the determinants of SCD in women, diabetes and smoking created a markedly higher risk of SCD, while high blood cholesterol did not increase the risk 3. Thus it seems that a high cholesterol level is not a risk factor of SCD in the general population, while SCD does appear to be the main cause of CHD death. These surprising findings are in apparent contradiction with the widespread idea that high cholesterol is a major risk factor of CHD death.

If these epidemiological data are true, the next obvious question is whether (or to what extent) lowering cholesterol levels helps reduce the risk of SCD, and thus the risk of CHD death and death from any cause. Is there a cause-effect relationship between cholesterol lowering and reduced mortality?

Does cholesterol lowering result in fewer sudden cardiac deaths?

Curiously, most trials (and all recent trials) testing the effects of cholesterol-lowering diets or drugs do not report about SCD. In addition, the effects on overall mortality were usually small or non significant in primary prevention (in apparently healthy populations), and a recent meta-analysis of randomised trials reported a risk ratio of 1.02 (95% confidence intervals 0.89 to 1.15), which amounts to no effect at all 4.

Considering that statins are the best cholesterol lowering drugs available (in terms of cholesterol levels), it is important to specifically look at SCD data (and CHD mortality data) in recently published statin trials. In these trials, the recruited patients were a mix of patients with established CHD (and in theory with optimal drug and non-drug treatment of CHD) and patients at high risk of having CHD but no symptom yet. Curiously again, all recent statin trials contain no data regarding the effect of statins on SCD. This suggests, as expected from epidemiological data, that statins (and cholesterol lowering in general) have had no significant effect on SCD. In fact, if there had been any significant effect on SCD, the investigators would probably have commented about it at great lengths. Given the importance of SCD as a cause of CHD death (as underlined above), one can therefore suspect that the effect of statins on CHD death and on overall mortality was, at best, modest.

In fact, when carefully looking at the published trials, it appears that the effect of statins on mortality actually was either small or non significant Table I. For instance, in HPS, PROSPER, ALLHAT-LLT, ASCOT-LLA and ALLIANCE, the death rate ratios were 0.87 (indicating a relative risk reduction of 13%), 0.93 (non significant), 0.99 (non significant), 0.87 (non significant) and 0.92 (non significant) respectively 5–9. It is noteworthy that when a 13% reduction of the relative risk of dying from any cause in HPS is translated in reduction of absolute risk, it is almost negligible in terms of public health. Furthermore, the specific effect of statins in women has been recently analysed using a meta-analysis of 13 studies from the Cochrane database 10. The authors conclude that in both primary and secondary prevention, statins had no significant effect on mortality in women 10. Also, a careful analysis of the trial results suggests that statins had no effect on mortality among elderly people (>70 years), as specifically tested in the PROSPER trial 6.

Table I.  Description of four recent statin trials in homogeneous populations (country, population, trial year). The effects on mortality were small, especially in terms of reduction of the absolute risk, or non significant.

	HPS	PROSPER	ALLHAT	ASCOT-LLA
Drug	Simvastatin	Pravastatin	Pravastatin	Atorvastatin
Country	UK	UK & The Netherlands	USA	UK & Scandinavia
Publication year	2002	2002	2002	2003
Population	High risk**	High risk**	High risk**	High risk**
Sample size	20 536	5 804	10 355	19 342
Patient age	>40y	>70y	>55y	>40y
Effect on overall mortality (RRR)^&	−13%	−7%*	−1%*	−13%*

*: non significant.

**: “High risk” means patients with established CHD or patients with risk factors of CHD and at high risk of having CHD but no symptom.

^&: “RRR” means Reduction of the Relative Risk.

A first conclusion based on results of randomised trials is that cholesterol lowering had no significant effect on mortality in primary prevention, in women and in the elderly, thus in a very high percentage of the adult population.

It can be argued that we should also consider the oldest statin trials 11–13 conducted in survivors of recent acute myocardial infarction (AMI) although at that time (recruitment during late eighties) most patients did not benefit from the most modern treatments of the acute (artery re-opening) and post-acute (anti-thrombotic) phases of AMI as well as of the post-AMI chronic phase including dietary prevention which actually is the most effective form of secondary prevention of CHD 14, 15. In fact, mortality data in these old trials were quite confusing with significant effect on mortality in 4S and LIPID (−30% and −22% respectively) but no significant effect in CARE 11–13, giving in average a rather modest effect in this particular subset of patients (specific geographic area, post-AMI, large majority of middle-aged men). It is therefore important to first consider the most recent trials in patients with optimal drug and non drug (dietary prevention) treatment in order to update clinical recommendation for the present time. Actually, in recent statin trials focusing on patients with acute CHD syndromes and early and intensive lipid lowering therapy (MIRACL, PROVE-IT, A to Z Trial), the effects on mortality were also small or non significant 16–18. Considering that several thousand patients were recruited for these trials, it would be scientifically (and ethically) irrelevant to ascribe this failure to a lack of statistical power. Indeed, as a last example, in the so-called TNT study testing the effect of intensive cholesterol lowering in more than 10 000 patients with stable CHD followed up for a median period of 4.9 years, 284 deaths were recorded in the intensive treatment group and 282 in the “classical” treatment group 19. This raw comparison of figures does not require commenting, and it is actually in line with other previous trials 5–9, 16–18. What is really surprising, however, and so far unexplained, is that in this statin trial, like in most others, there were both a striking reduction of the risk of non fatal complications of CHD and no clinically significant effect on mortality. An urgent (scientific?) explanation is required here, because it would be socially difficult to explain why we call for expensive measures to arrest a serial killer while there is no hope of reducing the number of victims. It would also be very difficult to motivate our patients to take anti-cholesterol drugs over a long period of time if we cannot reassure them that this will improve their life expectancy.

Summary and conclusion

Thus, contrary to widespread opinion, cholesterol lowering (with statins or other means) does not appear at the present time to be a very effective way of reducing CHD and overall mortality in our populations. Specifically, we know that SCD is the main cause of cardiac death in the general population but raised cholesterol is not a risk factor of SCD. On the other hand, lowering cholesterol has not even been shown to decrease overall mortality in recent trials, the only exception being in secondary prevention in men in the absence of optimal drug and non drug (dietary) prevention. This raises the major question of whether it may not be time to adopt a new paradigm, both to explain the CHD epidemics and to organise prevention in the general population.