CURRENT ISSUES

LDL-cholesterol reduction - outcome of choice in prevention of CHD?

- Amanda Cameron -

Low-density lipoprotein (LDL)-cholesterollevels have been used as a surrogate marker and have been the focus of the management of coronary disorders for some time. In a 2-hour

debate at the recent APOR'" Lipid Conference [November 1997; Florida, US], worldwide experts discussed the role of LDL-cholesterollowering and the relevance of other risk factors in the management of coronary heart disease (CHD). Dr Evan Stein, President of Medical Research Laboratories, Kentucky, US, argued that LDL-cholesterol reduction is the outcome of choice in CHD prevention, while Dr Jim Shepherd from the University of Glasgow, Scotland, argued that, in addition to LDL-cholesterol reduction, there are other outcomes that should be considered.

LDL-cholesterol 'the major culprit' Dr Stein pointed out that 200 or more risk factors

have been implicated in the development of CHD, and that the aim of his presentation was 'not to bury the other risk/actors but to . .. prove that WL is the major culprit' .

The strength of association between a risk factor and a disease can be established using 9 criteria adapted from the list published by G Heiss and HA Tyroler, said Dr Stein [see boxed text]. Of all the risk factors associated with CHD, only raised LDL­cholesterol levels satisfies all 9 criteria and can be considered causative, he stated.

Criteria for assessing the relationship between a risk factor and a disease

• strength of association • independence of association • biological consistency • observational consistency (Le. consistency across all

studies) • measurement validity (Le. risk factor able to be

measured) • temporal relationship (i.e. individuals wrth that risk factor

will develop that disease if followed over time) • evidence from animal models • evidence from genetic human models • evidence of interventional benefrt.

Link with atherosclerotic lesions ... Of these criteria, the demonstration of

interventional benefit is of the most interest to clinical decision-makers. And when it comes to demonstrating interventional benefit, there is no other risk factor and disease that can show as consistent a relationship as that between LDL-cholesterollevels and CHD, said Dr Stein.

It is flOw' know·n L'lat everj at.ltercsclerotic lesion, big or small, is related to cardiovascular events. Early angiographic studies showed that lowering LDL­cholesterol levels by whatever means (be it a low-fat diet, a resin such as cholestyramine, or an HMG CoA reductase inhibitor), resulted in a halt or a reversal in the development of atherosclerotic lesions. Notably, the variety of treatments studied all lowered LDL­cholesterol levels, but had variable effects on other lipoproteins.

1173-550319810144-00031$01.000 Adis International Limited 1998. All rights r_rved

... and cardiovascular events Since 1972, a consistent relationship between LDL­

cholesterol reduction and a reduction in cardiovascular events has been demonstrated in large outcome trials, such as 4S**, CAREt, and WOSCOPS~, pointed out Dr Stein.

Together, these clinical trial findings indicate that LDL-cholesterol reductions of 25-35%, as a result of HMG CoA reductase inhibitor therapy, produce a consistent reduction in the incidence of cardiovascular events [including coronary mortality, nonfatal myocardial infarction (MI), unstable angina pectoris, and bypass surgery], in patients with moderate-to­severe hypercholesterolaemia All-cause mortality was significantly reduced in both primary and secondary prevention trials.

The clinical benefits were often detected soon after the initiation of HMG CoA reductase inhibitor therapy (perhaps within 12-18 months), pointed out Dr Stein.

LDL-cholesterollowering consistently beneficial

Notably, the cardiovascular benefits of HMG CoA reductase inhibitor therapy that were demonstrated in the 4S, CARE and WOSCOPS trials occurred across a range of mean baseline LDL-cholesterollevels (140-200 mg/dl). Furthermore, lowering LDL­cholesterol levels improved cardiovascular outcome regardless of the effects of lipid-lowering therapy on triglyceride and high-density lipoprotein (HDL)­cholesterol levels, and occurred irrespective of patient gender, age, or the presence of other risk factors such as diabetes mellitus, hypertension or a smoking habit.

Other outcomes important Providing a counterpoint to Dr Stein's argument,

Dr Jim Shepherd told delegates at the conference that

* The Association for Phannacoeconomics and Outcomes Research (ArORj and the iniemui;ufwl Society for Economic Evaluation of Medicines (ISEEM) have joined forces to become the International Society for Phannacoeconomics and Outcomes Research (ISPOR). The new name became effective as of January 1,1998. ** Scandinavian Simvastatin Survival Study; see PhannacoResources 43: 7, 16 Dec 1995; 800404411 t Cholesterol and Recurrent Events trial :t West of Scotland Coronary Prevention Study; see PhannacoEconomics & Outcomes News 143: 9, 20 Dec 1997; 800654406

PhannacoEconomics & Outcomes News 10 Jan 1998 No. 144

3

4 CURRENT ISSUES

LDL-cholesterol reduction - outcome of choice in prevention of CHD?

'although WL may be at the root of the [CHD] problem, it is not the only issue which governs the pathogenesis of atherosclerosis and ... the likelihood of [having] a myocardial infarction'.

This opinion is based on the findings of a posthoc analysis of the WOSCOPS study results. However, Dr Shepherd was quick to point out that posthoc analyses are hypothesis-generating rather than hypothesis-proving, and therefore their findings need to be tested a priori.

LDL-cholesterol reduction poor predictor of coronary risk

The results of this analysis indicate that LDL­cholesterol reduction is a 'pretty poor' predictor of coronary outcome, according to Dr Shepherd. He and his colleagues found that there was no direct relationship between LDL-cholesterol reduction and the risk of having a fatal/nonfatal MI in the middle­aged men with hypercholesterolaemia who received either pravastatin or placebo in the WOSCOPS study.

After dividing the group who received pravastatin into quintiles based on the extent of LDL-cholesterol reduction (10, 23, 29, 34 and 41 %, respectively), the investigators found that the risk of MI was nearly 2-fold lower among those who achieved maximum LDL-cholesterol reduction (quintile 5; 4% risk) than among those who achieved minimum LDL-cholesterol reduction (quintile 1; 7.3% risk). However, the MI risk for patients in quintile 5 was not significantly different from that in each of quintiles 2, 3 and 4.

Thus, although LDL-cholesterollowering is an 'important contributor' to MI risk reduction, the reduction in the risk of MI that is achieved by lowering LDL-cholesterol by about 25% is not significantly altered by lowering LDL-cholesterol any further, concluded Dr Shepherd.

Other anomalies Interestingly, Dr Shepherd and colleagues also found

that, although around 400 pravastatin and 400 placebo recipients had similar LDL-cholesterollevels (159 and 162 mgldl, respectively) during the last 4.5 years of the 5-year study, these 2 groups had a significantly different rate of MI (3.8 and 5.6%, respectively) over this time.

Furthermore, when data from the WOSCOPS study were incorporated into the Framingham equation, predicted risk reduction in coronary events was less than that actually seen with pravastatin therapy. That is, the 46% risk reduction that was actually observed with pravastatin in the WOSCOPS study was more than 2-fold greater than the 26% risk reduction that was predicted by the Framingham equation. For the WOSCOPS results to be consistent with the Framingham study, total cholesterol and HDL­cholesterol levels had to be used as the lipid predictors in the calculation.

PharmacoEconomics & Outcomes News 10 Jan 1998 No. 144

Factors other than LDL-cholesterol reduction at work?

The observation that the extent of coronary event reduction achieved with pravastatin is greater than that expected, means that it is necessary to exclude the idea that LDL-cholesterol alone is all-important in the prevention of CHD by HMG CoA reductase inhibitors, declared Dr Shepherd.

For example, pravastatin significantly reduced the viscosity of plasma and whole blood in the WOSCOPS study, and it was calculated that these effects probably accounted for around 25% of the total reduction in coronary events. It is also possible that the drug's effects on thrombosis, endothelial function, smooth muscle cell function, and inflammation contributed to a reduction in coronary events.

Global promotion of Bristol-Myers Squibb's pravastatin

Bristol-Myers Squibb is using the results of the posthoc analyses of the WOSCOPS study in a worldwide promotion of pravastatin [,Pravachol'j.l The results of the event reduction analysis support Bristol-Myers Squibb's contention that 'all statins are not the same' and indicate that 'there's more to tell than LDL', says Dr Richard Hinson, Senior VP-US Primary Care Marketing & Medical for the company. The obvious implication is that pravastatin has the edge over other statins because of its effects above and beyond LDL ~Iesterol reduction.

1. Bristol Pravacbol event reduction analysis suggests benefits beyond LDL lowering; Avapro v. Cozaar trials could be added to labeling in 1998. FOC Reports - Pink Sheet - Prescription Pbarmaceuticals and Biotechnology 59: 19-20, 15 Dec 1997

Dr Shepherd also thinks that HMG CoA reductase inhibitors have their effect by changing the athero­genicity of the entire lipoprotein profile.

'There are things that are happening with [HMG CoA reductase inhibitors] that go beyond WL', concluded Dr Shepherd, 'and just to measure LDL as a surrogate of what Idnd of benefit you are going to get is not really good enough - you have to go beyond it' .

800458983

1173-5503'9810144-00041$01.00° Adi. International Limited 1998. All rights reserved