The most common cause of death in industrialised societies continues to be coronary heart disease, and the burden placed on health care systems by all types of vascular disease is formidable. Vascular disease does not occur at random, however, and a variety of risk factors, some modifiable and some not, have been identified.
We can calculate the risk of vascular disease in individuals with the aim of trying to identify those who will benefit from intervention. New evidence for the potential benefit of cholesterol reduction, or more specifically the use of statins, has re-opened the question of what constitutes ïhigh-riskÍ and who should be treated.
A multitude of factors have been associated with vascular disease. Very many of these are of little relevance to clinical practice, and those that matter most are the familiar ones: increasing age, male sex, smoking, hypertension, family history and diabetes. A standard rundown of risk factors for vascular disease rapidly reaches cholesterol.
The evidence that cholesterol is a major risk factor is good. Epidemiological evidence from such studies as the Seven Countries Study, suggests that the lower the population cholesterol, the lower the incidence of coronary deaths.1 In the MRFIT study, coronary heart disease death rate was strongly related to baseline total cholesterol,2 with a curvilinear relation suggesting a great increase in risk above a total cholesterol of around 5.3mmol/l. Reduction in cholesterol reduces coronary risk in proportion.3
It is true to say that this interpretation of the data is not universally accepted. A small but vociferous minority continues to assert that the relation between cholesterol and coronary disease is not proven.4 However, the overwhelming majority of researchers are convinced of the relation between cholesterol and coronary disease.
A significant reduction in cholesterol can rarely be achieved by lifestyle changes alone. Most patients with coronary heart disease are reluctant to take the measures necessary, and it is unrealistic to expect that the population at risk of coronary disease is likely to make such changes. Radical interventions, such as bowel shortening surgery,5 can have dramatic effects on cholesterol levels and subsequent coronary events, but are not realistic options for all but the worst affected patients.
This leaves pharmacological therapy as the only therapeutic option likely to have an impact. Bile acid sequestrants have had some effects, as have fibrates. However, it was not until 1999 that a fibrate, gemfibrozil, was shown to have a beneficial effect on outcomes - and that in a group of patients with low HDL cholesterol, rather than high total cholesterol.6
The introduction of 3-hydroxy-3-methyl-glutaryl co-enzyme A reductase inhibitors (statins) has dramatically changed the management of cholesterol as a risk factor, and the number of patients potentially eligible for statin treatment continues to grow.
Statins work by inhibiting the rate-limiting step of endogenous hepatic cholesterol synthesis. In response, the liver up-regulates cell-surface LDL receptors, thereby removing more LDL from the circulation. In passing, it is worth noting that patients with homozygous LDL receptor deficiency derive limited benefit from statins.
The beneficial effects of statins are usually attributed to their cholesterol lowering properties, which has, indeed, been the principle underlying the trials. However, statins have additional properties,3 being anti-inflammatory8-10 and antithrombotic.11-13
The first cluster of clinical trials with statins chose to look at patients at high risk of coronary events - those with established coronary artery disease (Table 1, below). The ground-breaking 4S study14 looked at those with a cholesterol between 5.5 and 8.0mmol/l (mean 6.74mmol/l) and demonstrated a 30% reduction in risk of death compared with placebo.
|Table 1: Comparison of landmark statin trials|
|Study||N||Age||Male (% )||Cholesterol||Angina||MI||Statin||Risk reduction (death)|
|*not statistically significant|
In CARE,15 the primary end-point was fatal coronary event or non-fatal MI for which there was a 24% relative risk reduction in patients with previous MI with a cholesterol below 6.2mmol/l (average 5.4mmol/l). There was no significant reduction in risk of death.
The LIPID study16 in patients with established coronary disease demonstrated a 22% reduction in relative risk of mortality. In this study, patients had to have a cholesterol above 4.0mmol/l to be included.
In interpreting these findings, most clinicians now take the view that all patients with established coronary disease should be treated with a statin unless there is good reason not to do so. Patients with established coronary disease are at high risk of future events, and whatever the absolute cholesterol value, it is too high for them. The only exception is that small group of patients with a total cholesterol of less than 4.0mmol/l.
The role of statins in primary prevention has been explored principally in the West of Scotland study (WOSCOPS)17 and AFCAPS/TexCAPS.18 WOSCOPS studied men at risk of coronary disease by virtue of a total cholesterol above 7.0mmol/l and reported an approximately 30% reduction in coronary end-points but no significant change in total mortality. AFCAPS/ TexCAPS studied individuals with a lower total cholesterol (average 5.71mmol/l) and again markedly reduced coronary end-points, but with no overall effect on total mortality.
Faced with this level of evidence, most authorities have suggested that in the management of those without established coronary disease, it is important to place the patient in the context of their overall risk before deciding on treatment. Various tables of different levels of complexity have been derived to estimate a patientÍs risk.19 Treatment is recommended for individuals at high risk (e.g. 15% risk over 10 years). This has led to much confusion about which patients should start treatment that is destined to be lifelong with a fairly expensive agent.
The Heart Protection Study
The Heart Protection Study20 was predicated on the hypothesis that the reduction in risk seen with statin use is related to the initial overall risk of cardiovascular disease, not simply the risk conferred by an individualÍs cholesterol.
More than 20000 individuals were randomly assigned to receive either simvastatin 40mg per day or placebo for an average of 5 years (see Table 1). Patients were randomised if they were at high risk of cardiovascular disease and if their treating physicians felt that there was no indication for statin use. ïHigh riskÍ meant: presence of coronary artery disease, other arterial disease, diabetes and male hypertensive >65 years of age. Mortality was the primary end-point.
Some 65% of those randomised had a history of coronary disease. Of the remainder, 25% had had a stroke, 38% peripheral arterial disease and 57% diabetes (some had more than one condition), with only 237 being randomised on the basis of hypertension alone.
Average cholesterol at randomisation was 5.9mmol/l and it fell by an average of 1.2mmol/l in the simvastatin group compared with placebo. The headline result was a 13% reduction in total mortality, driven predominantly by a 17% reduction in vascular death (predominantly coronary). There was no difference in death from other causes. Figure 1 (below) shows the results of the landmark statin trials, including the Heart Protection Study.
|Figure 1: landmark statin trials|
Other findings included a marked reduction in myocardial infarction, stroke and revascularisations of any kind. These findings were consistent regardless of the initial ïhigh riskÍ factor that led to inclusion in the trial, and regardless of initial cholesterol level, age or sex.
It is noteworthy that these dramatic findings underestimate the benefit of statin therapy: around 15% of the patients randomised to receive simvastatin stopped taking treatment, and by the end of the study, 32% of the placebo group were taking non-trial statin. This suggests that the benefits shown are around two-thirds of the true effect that would have been seen with rigid adherence to the trial allocation.
Patients with heart failure face a particularly high risk for vascular death. It is noteworthy that the trials of statin use following myocardial infarction have all excluded patients with heart failure or significant left ventricular dysfunction. In the 4S study, heart failure requiring treatment was a specific exclusion criterion;21 in LIPID, patients with NYHA class III or IV heart failure were excluded and 90% were in class I.22 In CARE,15 patients with congestive heart failure, or a left ventricular ejection fraction <25% were specifically excluded (in the event, 4% of randomised patients did have heart failure).
There are some data to suggest that statins may be of benefit in patients with heart failure, for example simvastatin caused a reduction in mortality in patients who developed heart failure during the course of the 4S trial.23
The high risk patient
Perhaps oddly, we have few qualms about starting indefinite treatment for hypertension with the aim of reducing long term risks of vascular damage, and this is often done with little regard to the overall risk a patient faces. For example, a 40-year-old woman with a blood pressure of 150/90mmHg undoubtedly has a higher risk than her friend with a blood pressure of 130/80mmHg, but the absolute risk to her is low, and the benefits of treatment are far from certain.
When treating with a statin we are asking patients to take potentially toxic therapy life-long, so we need to be sure that the risk-benefit ratio is known. For example, there has been some question about the possibility of an increase in the risk of violent deaths and suicides with cholesterol reduction. The phenomenon appears to be real, but has not been shown when cholesterol reduction is achieved with statins.20,24
What does this mean for the individual patient? The absolute reduction in risk of death in the Heart Protection Study was small: thus for an individual the ñchance not to die in five years without statin treatment is 85.4% and simvastatin treatment can increase this to 87.1%.î25 However, this is to underestimate the benefit for patients. Vascular events of all sorts are reduced by statin use, and the Heart Protection Study suggests that treating 1000 individuals for 5 years can prevent up to 100 first vascular events, and indeed, the risk of subsequent events.20
We can pick out the patient at high risk of vascular disease. Patients with established vascular disease (coronary, cerebral or peripheral) and those with diabetes are at high risk of future events. These individuals should now all be treated with a statin regardless of their absolute cholesterol levels.
- Pyorala K. Interpopulation correlations between serum cholesterol level and the occurrence of coronary heart disease. Eur Heart J 1987; 8(Suppl E): 23-30.
- Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet 1986; 2: 933-6.
- The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365-74.
- Ravnskov U. The Cholesterol Myths. Washington DC: New Trends Publishing, 2000.
- Buchwald H, Varco RL, Matts JP, Long JM et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990; 323: 946-55.
- Rubins HB, Robins SJ, Collins D, Fye CL et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341: 410-8.
- Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-19.
- Walter DH, Fichtlscherer S, Britten MB, Rosin P et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation. J Am Coll Cardiol 2001; 38: 2006-12.
- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100: 230-5.
- Ridker PM, Rifai N, Clearfield M, Downs JR et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959-65.
- Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279: 1643-50.
- Osamah H, Mira R, Sorina S, Shlomo K, Michael A. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets. Br J Clin Pharmacol 1997; 44: 77-83.
- Aviram M, Hussein O, Rosenblat M, Schlezinger S et al. Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiovasc Pharmacol 1998; 31: 39-45.
- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.
- Sacks FM, Pfeffer MA, Moye LA, Rouleau JL et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001-9.
- Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339: 1349-57.
- Shepherd J, Cobbe SM, Ford I, Isles CG et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301-7.
- Downs JR, Clearfield M, Weis S, Whitney E et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279: 1615-22.
- Grundy SM, Pasternak R, Greenland P, Smith S Jr, Fuster V. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999; 100: 1481-92.
- MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.
- Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol 1993; 71: 393-400.
- Design features and baseline characteristics of the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) Study: a randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris. Am J Cardiol 1995; 76: 474-9.
- Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997; 3: 249-54.
- Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle SH. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials. Br Med J 2001; 322: 11-15.
- Ravnskov U. Statins as the new aspirin. Conclusions from the heart protection study were premature. Br Med J 2002; 324: 789.