Show me the Evidence for
Cholesterol Reduction - Part 1

Today we accept that treating cholesterol pharmacologically will improve outcomes in a wide variety of patients both for primary and secondary prevention. This is a relatively new concept, only being conclusively demonstrated in the early 90s. Prior to the landmark 4S study there was evidence that cholesterol lowering reduced surrogate end points and even cardiovascular mortality in some studies, however a demonstration of reduction in all cause mortality was lacking. Indeed some argued that arthrosclerosis stared at a very young age with fatty streaks in the blood vessels and proceeded in a linear fashion until a build up of the fat plaque caused symptoms of angina or MI in later life. Once the patient presented with clinical disease they felt it was too late to treat the lipid abnormalities as the damage had already been done.

Our understanding of arthrosclerosis has evolved greatly in the last 20 years. We now understand that the event we see clinically as acute coronary syndromes, such as a STEMI or NSTEMI, is most often caused by unstable lipid rich non-occlusive plaques that have ruptured and caused an acute occlusion by triggering the coagulation cascade. We also have conclusive proof that lowering cholesterol, primarily with the statin class, will lower cardiovascular events and all cause mortality both in diabetic and non-diabetic populations.

Although there is a lot of evidence in the medical literature the Canadian Lipid Guidelines largely remain an evidence free zone. Clearly the evidence has been reviewed but there is no explicit grading for the level of evidence for each of their recommendations. Some of the recommendations are sound, such as treating diabetics as a high-risk group and treating dyslipidemia with a starting dose of simvastatin 40mg or its dosage equivalent. However the whole concept of treating high risk groups to a target LDL of 2.5mm/l has very little direct evidence behind it and the recommendations to treat lower risk groups to higher LDL targets has no evidence behind it that I can find.

In this article, I hope to present a short summary of the important papers of the last 20 years concentrating only on studies that have end points that patients care about such as morbidity and mortality, and avoiding studies that have surrogate end points such as angiographic changes or changes in lipid levels. I also hope to demonstrate that the key concept from the literature in treating dyslipidemia in high-risk patients is to treat to dose rather than treat to a target.

Multiple guidelines suggest that type II diabetic patients without prior cardiovascular disease be considered as high risk as non-diabetic patients who have already had an MI. What evidence is this conclusion based on?

Perhaps the best place to look for an answer is a Finnish prospective cohort observational study published in 1998³. A prospective cohort study is the best design to answer questions about prognosis. Between 1982 and 1984 researchers assembled a cohort of 1,059 type 2 diabetics aged 45 to 64 years of age and a random control group of 1,373 non-diabetics of the same age range living in the same districts. 115 of the diabetics and 51 of the non-diabetics had a history of a prior MI at base line. The groups were followed prospectively for the next seven years. Since this study was done in the '80s only 9 diabetics were receiving lipid lowering drugs at baseline. Follow up ended in 1990 and the results were quite conclusive. The seven-year incidence rate for fatal and non-fatal MI in non-diabetic subjects with and without prior MI were 18.8% and 3.5% respectively (p < 0.001). The seven-year incident rate of fatal and non fatal MI in the diabetic subjects with and without MI at baseline were 45% and 20.2% respectively (p < 0.001). So the diabetics without a history of MI at baseline had the same incidence of fatal and non fatal MI as did the non-diabetics with a previous MI and diabetics with a history of MI were at an extreme risk of having another one. Death from cardiovascular causes and fatal and non-fatal stoke all followed this same pattern. This study was done in an era prior to widespread statin therapy.

4S²

Prior to this trial drug therapy for hypercholesterolemia had been controversial, mainly due to a lack of evidence for all cause mortality reduction. Previous trials had demonstrated reduction in cardiovascular mortality only.

In this double blind placebo controlled trial 4,444 patients from Scandinavia, aged 35-70y with angina or previous MI, serum cholesterol of 5.5-8.0 mmol/l and triglycerides < 2.5mmol/l, on a lipid lowering diet were randomly assigned to take simvastatin 20mg or placebo. They were followed for a median of 5.4 years. The goal of treatment was to reduce total cholesterol to 3.0-5.2 mmoles/l. The dose was adjusted to 40 mg or 10 mg by a computer program without breaking blinding. The primary end point was total mortality with a variety of secondary end points. In the active treatment group 37% of patients took 40 mg of simvastatin with almost all of the rest taking 20 mg daily. Only 2 patients took 10 mg. Total cholesterol was reduced by 25%, LDL by 35% and HDL raised by 8% in the active treatment group.

The results were dramatic and conclusive. All cause mortality was reduced by 30% p=0.0003 (RR 0.7 ARR 3.7% NNT 27) All coronary mortality was reduced by 42% (95% CI 27-54) (ARR 3.5% NNT 29). Non-cardiovascular mortality was the same in the 2 groups.

What about diabetics?

There were 202 diabetics and 4,242 non-diabetic patients in this trial. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in non-diabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001).⁴

As can be seen the diabetic sub group benefited even more from lipid lowering than the non diabetics. The total mortality reduction is not significant here due to the small diabetic sub group(beta error).

The Pravastatin Trials

Through the rest of the 1990s, there were several papers published using pravastatin at a fixed dose of 40 mg in the evening, compared to placebo. These trials furthered our understanding and created some controversies, which have been settled by later trials. We will look at them chronologically.

WOSCOPS⁵

This trial was done in the west of Scotland hence the name. Researchers randomly assigned 6595 men 45 to 64 years old free of prior MI and a LDL >4.0, and <6.0, on a lipid lowering diet, to pravastatin 40mg vs placebo for 5 years. They had to be otherwise healthy with at most minor EKG changes. Men with angina and no hospitalizations in the last year were eligible and made up 5% of the study population. Diabetics made up 1% of the study population. Therefore this was a primary prevention trial. The primary end point was a combination of nonfatal and fatal MI with an intention to treat analysis. Pravastatin reduced total cholesterol by 20% and LDL by 26% and an increase in HDL of 5%, with no change in the placebo group. There was a 30% drop out rate in both the active treatment and placebo groups by 5 years.

There was a 31% reduction (p < 0.001) in the primary endpoint of fatal and non-fatal MI (RR 0.69 ARR 2.4% NNT 42). There were similar reductions in non-fatal MI and death from all cardiovascular causes, coronary angiographies and revascularization procedures. There was no difference in stroke. Death from non-CV causes was similar in the 2 groups with all cause mortality reduced by 22% P=0.051 (NNT 111) which is technically not significant by convention (P < 0.05). This was the first primary prevention trial involving a statin but it only included men.

CARE⁶

A total of 4,169 patients (14% women), aged 21 to 75y, with a prior MI between 3 and 20 months before randomization, a cholesterol of < 6.25, LDL between 3.0 and 4.5, triglycerides < 4.0, and ac glucose < 12.2mmoles/l, no clinical CHF and an EF > 25% were randomized 40mg of pravastatin or a matching placebo. If in either group, on treatment LDL > 4.5 the subject received cholestyramine. The trial lasted 5 years with an intention to treat analysis. The primary end point was fatal or non-fatal MI.

By the last year of follow up 86% of placebo group and 94% of the treatment group were taking their study drugs. The frequency of the primary end point of fatal or nonfatal MI was 10.2% in the pravastatin group and 13.2% in the placebo group (RRR 24% RR 0.76 ARR 3% NNT 33 p=0.005). Diabetics, who made up about 15% of the study population, had a similar reduction in their event rate as the non-diabetics. There was a 9% reduction in all cause mortality, which did not achieve statistical significance.

Sub group analysis generated some insights and controversy. Men derived only a 20% reduction in major coronary events (NNT 20) whilst women had a 46% reduction (NNT 8). Patients with a starting LDL < 3.25 derived no benefit what-so-ever from the pravastatin. There was no statistical difference in non-CV deaths. There was one breast cancer diagnosis in the placebo group and 12 in the pravastatin group (p=0.002) and was a cause of concern at that time.

This secondary prevention trial was done in people with a lower starting lipid level than the 4S cohort with a less potent statin and gave a less spectacular result.

LIPID⁷

This trial was conceived in 1989 and recruited patients between June 1990 and December 1992. It ended in May 1997 by the safety monitoring committee due to clear benefit. Mean follow up was for 6.1 years. 9,014 people (17% female) 31 to 75 y, with a total cholesterol between 4 and 7 mmoles/l on a lipid lowering diet, and prior acute MI or hospitalized unstable angina between 3 to 36 months before study entry, were randomly assigned to 40 mg of pravastatin or matching placebo. The patient's usual care allowed institution of other lipid lowering drugs as large trials with statins were being reported in this time frame. Analysis was by intention to treat. The primary endpoint was death from CHD. There was a 18% reduction in total cholesterol and 25% reduction in LDL, triglycerides were reduced by 11% and HDL increased by 5%. In the first 6 months cholesterol was down 21% but the difference shrank to 13% at 6 years due to the use of open label statins in the placebo group and discontinuations of pravastatin in the treatment group.

Death from CHD occurred in 8.3% of patients assigned to the placebo group and 6.4% of patients assigned to the treatment group. (p < 0.001 RRR 24% ARR 1.9% NNT 53) All cause mortality was reduced 22% (p < 0.001 NNT 32) and stroke was reduced 19% (NNT 125). There was no difference in cancer incidence or death including breast cancer. Patients with a starting LDL < 3.5 had a 16% reduction in the primary endpoint which did not achieve statistical significance. So again we see with pravastatin that patients with a low starting LDL are not benefiting. Was this due to a J-shaped curve for cholesterol lowering, a type II error in this study or poor effects of this statin in this population? Further studies would reveal the answer.

- Farokh Buhariwalla CCFP

Thanks to Hector Baillie FRCP and Richard Lewanczuk FRCP for reviewing the draft copy of this article.

. . . Part II

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