The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient

Transcription

1 Q J Med 2005; 98: Advance Access publication 8 July 2005 doi: /qjmed/hci093 Commentary The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient H.T. ONG From the HT Ong Heart Clinic, Penang, Malaysia Summary The landmark HMG-CoA reductase inhibitor (statin) studies have practical lessons for clinicans. The 4S trial established the importance of treating the hypercholesterolaemic patient with cardiovascular heart disease. Next, WOSCOPS showed the benefit of treating healthy, high-risk hypercholesterolaemic men. CARE, a secondary prevention trial, showed the benefit of treating patients with cholesterol levels within normal limits. This was confirmed by the LIPID trial, another secondary prevention study, which enrolled patients with cholesterol levels mg/dl (4 7 mmol/l). The importance of treating patients with established ischaemic heart disease, and those at high risk of developing heart disease, regardless of cholesterol level, was being realized. In the MIRACL trial, hypocholesterolaemic therapy was useful in the setting of an acute coronary syndrome, while the AVERT study showed that aggressive statin therapy is as good as angioplasty in reducing ischaemic events in patients with stable angina. By showing the value of fluvastatin after percutaneous intervention, LIPS confirmed that benefit is a class action of the statins. The HPS randomized over patients, and showed beyond doubt the value of statins in reducing cardiovascular events in the high-risk patient. Although PROSPER showed benefit in treating the elderly patients above 70 years, statin therapy in this trial was associated with an increase in cancer incidence. The comparative statin trials, PROVE-IT, REVERSAL, Phase Z of the A to Z, ALLIANCE and TNT, all showed that highdose statins will better reduce cardiovascular events in the high-risk patient, although the adverse effects of therapy will also be increased. ALLHAT- LLT, ASCOT-LLA and CARDS showed that for statin therapy to demonstrate a significant benefit, hypertensive or diabetic patients must be at sufficiently high risk of cardiovascular events. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not the lipid level of the patient. No therapy is free of adverse effect. Treatment of those most at risk will bring the most benefit; treatment of those not at high risk of cardiovascular disease may expose patients who would not benefit much from therapy to its adverse effects. Introduction There has been an explosion of data and trials in the 1990s on the role of cholesterol reduction in the management of patients with ischaemic heart disease (IHD) or those at risk of future development of IHD. It was barely a decade ago that the value of hypolipidaemic therapy was questioned, and its Address correspondence to Dr H.T. Ong, HT Ong Heart Clinic, 251-C Burmah Road, Penang, Malaysia. htyl@pd.jaring.my! The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 600 H.T. Ong possible consequence in increasing non-cardiac mortality was raised. 1,2 In reviewing the developments leading up to the present day, we come to appreciate that many of the questions and suspicions of hypolipidaemic therapy have been answered. Clinicians need to familiarize ourselves with the evidence accumulated, so that we can appropriately advise patients who may be incorrectly informed by the lay literature or press releases. The beginnings: 4S, WOSCOPS and CARE The Scandinavian Simvastatin Survival Study (4S) ushered in the era of mega-trials on hypolipidaemic therapy. 3 A total of 4444 patients with angina or prior myocardial infarction and serum cholesterol mg/dl ( mmol/l) were put on either simvastatin (dose range mg) or placebo and followed up for a median of 5.4 years. Total cholesterol was reduced by 25%, and LDL cholesterol by 35% in the treatment group. Treatment with simvastatin significantly reduced the primary end-point of total mortality (RR 0.70, 95%CI ), as well as major coronary events (defined as coronary death, myocardial infarction, or resuscitated cardiac arrest, RR 0.66, 95%CI ), and coronary mortality (RR 0.58, 95%CI ). Furthermore, therapy also reduced the need for coronary revascularization with bypass surgery or angioplasty (RR 0.63, 95%CI ). There was no difference in noncardiovascular deaths in the treated and placebo groups. This study established clearly that hypolipidaemic therapy was safe and reduced morbidity and mortality in hypercholesterolaemic patients with IHD. It is thus reasonable to conclude that all patients with significantly elevated cholesterol levels and known prior cardiovascular heart disease should have their hypercholesterolaemia treated to reduce future adverse events. A subsequent substudy confirmed the value of therapy in diabetic patients. 4 In hindsight, the 4S trial was a very wellconceived study recruiting a large number of participants with an adequately long follow-up. It addressed the question for which a positive answer was most likely, by asking whether patients who were already suffering from IHD and had definitely elevated cholesterol levels could benefit from a reduction of their lipid levels. These ambulatory patients with stable coronary disease are similar to many of those seen in a busy outpatient department or a general practice clinic. The intervention studied was simple and easy to replicate. When intervention was found to produce a clear-cut benefit with no significant adverse effects, a new era of therapy with the statins was ushered in. The next major study was the West of Scotland Coronary Prevention Study (WOSCOPS). 5 This addressed a different question from 4S, and investigated whether hypolipidaemic therapy was beneficial in hypercholesterolaemic men without a prior history of myocardial infarction. A total of 6595 men aged years were put on either pravastatin 40 mg/day or placebo, and followed up over an average of 4.9 years. Total cholesterol was reduced by 20% and LDL cholesterol reduced by 26% with treatment. Although this was a primary prevention study, the subjects enrolled were actually at high risk of coronary events, being middle-aged men having markedly elevated lipid levels with mean total cholesterol mg/dl ( mmol/l) and elevated BMI ( kg/m 2 ), and over a third were current smokers. In this high-risk group, pravastatin therapy reduced the primary end-point of non-fatal myocardial infarction or coronary deaths by 31% (95%CI 17 43%), revascularization procedures by 37% (95%CI 11 56%) and cardiovascular mortality by 32% (95%CI 3 53%). There was no difference in non-cardiovascular mortality, and the reduction in total mortality of 22% was of borderline significance (p ¼ 0.051). This suggests that in these subjects with no definite prior ischaemic heart disease, treatment of elevated lipid levels does not bring about as great a benefit as it would in a group known definitely to have cardiovascular disease, as in the 4S population. Nevertheless, the reduction of coronary events in WOSCOPS was impressive, and the message was clear that the high-risk hypercholesterolaemic patient not previously known to have IHD would benefit from treatment of hyperlipidaemia. The goalpost has been moved the strategy is now to seek out the high-risk hypercholesterolaemic patient, who has been shown to benefit from statin therapy. The following year saw the publication of the Cholesterol and Recurrent Events (CARE) study. 6 This studied patients with a past history of a myocardial infarction, but who had average cholesterol levels of mg/dl ( mmol/l). A total of 4159 patients had a median follow-up for 5 years. Total cholesterol was reduced by 20% and LDL cholesterol by 28%. Compared to placebo, pravastatin 40 mg daily therapy reduced the primary end-point (defined as coronary death or non fatal myocardial infarction) by 24% (95%CI 9 36%). In this study, there was no significant

3 The statin studies 601 difference in cardiovascular, non-cardiovascular or total mortality; it was myocardial infarction that was markedly reduced, and this accounted for the significant reduction in the primary end-point. The need for revascularization procedures and the incidence of strokes were also lowered significantly with pravastatin therapy. The inescapable conclusion was that in patients with a prior myocardial infarction (secondary prevention), hypolipidaemic therapy is important even if cholesterol levels are not highly elevated. However, the absence of coronary mortality reduction, and the lower percentage reduction of major coronary events in the CARE study compared to 4S, suggests that it is the patient who is both hyperlipidaemic and high-risk who will benefit most from therapy. The historical impact of these three trials, published over a 2-year period, is especially remarkable when one considers what was available in the two decades prior to their appearance. Hypocholesterolaemic drug trials achieved only a modest reduction of total cholesterol levels of about 10%, compared to a 20 30% reduction with the statins. These drugs produced significant unpleasant adverse effects, suggested an increase of non-cardiac mortality and appeared to have no impact on total mortality The disappointing results of drug trials supported the drive to study dietary and lifestyle changes. 11,12 However, dietary and lifestyle changes are difficult to implement and maintain on a large scale. Moreover, the difference between a diet with under 10% of total calories from saturated fat, and one with under 7% of total calories from saturated fat, may be more significant to the researcher and dietician than to the clinician or the patient. This is not to negate the value of dietary and lifestyle changes, and even recently, more evidence on the importance of healthy living in reducing cardiovascular disease has emerged Today, clinical guidelines call for a therapeutic lifestyle change and healthy eating habits to be implemented for all. However, the safety, efficacy and tolerability of the statins are so well established that these guidelines all devote more attention to pharmacological therapy than to dietary advice in the primary and secondary prevention of cardiovascular disease It was these three statin trials that laid the foundation of our fundamental change in practice habits. The next generation: LIPID and AFCAPS/TEXCAPS The Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) study emphasized the importance of hypolipidaemic therapy in the secondary prevention setting. 19 Patients enrolled had a history of myocardial infarction or unstable angina with a very broad range of initial total cholesterol levels varying from 155 to 271 mg/dl ( mmol/l). A total of 9014 patients were enrolled in this placebo-controlled study and followed-up over a mean of 6.1 years. Pravastatin 40 mg daily reduced total cholesterol by 18%, and LDL cholesterol by 25% compared to placebo. The primary end-point was coronary mortality and this was reduced with pravastatin treatment by 24% (95%CI 12 35%). Total mortality was reduced by 22% (95%CI 13 31%). There was also a significant reduction of major coronary events (coronary death and non fatal infarction) by 24%, coronary revascularization by 20% and strokes by 19%. A later paper showed that the stroke reduction was due to a reduction of non-haemorrhagic strokes, with no effect on haemorrhagic strokes. 20 Although subgroup analysis of LIPID showed the benefit of hypolipidaemic therapy to extend over all ranges of total cholesterol levels, there was a suggestion that benefit was most in those with the highest LDL cholesterol. It stands to reason that even in secondary prevention, it is those at highest risk of another coronary event who will benefit most from intervention. The focus returned to primary prevention, in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS), a placebocontrolled randomized trial to investigate the effects of lovastatin mg/day on an averagerisk healthy population with normal total cholesterol levels of mg/dl ( mmol/l) but having low HDL cholesterol: 545 mg/dl for men (1.16 mmol/l) and 547 mg/dl (1.22 mmol/l) for women. 21 After 1 year, lovastatin treatment significantly reduced total cholesterol levels by 18%, LDL cholesterol by 25%, and increased HDL cholesterol by 6%. After a mean follow-up of 5.2 years in a total of 5608 men and 997 women, the primary end-point of first major coronary event, defined as myocardial infarction, unstable angina or sudden death, was highly significantly reduced (RR 0.63, 95%CI ). A similar marked improvement was seen in risks of myocardial infarction, unstable angina and coronary revascularization. Although no adverse effect of therapy was seen in comparison with the placebo group, there was no difference in the total mortality between the two groups. 22 In fact, there were 80 deaths in the lovastatin group, and 77 in the placebo group (RR 1.04, 95%CI ). What was equally striking was that of the total deaths in both the treatment and placebo groups of 157, over

4 602 H.T. Ong two-thirds (115) were from non-cardiovascular causes. This emphasizes the point that in a group of people not at high risk of coronary deaths, therapy to lower cholesterol cannot do very much to lower mortality, as the patients are more likely to succumb to non-cardiovascular causes. Previous experience with non-statin hypocholesterolaemic drugs have revealed similar findings of a reduction in cardiac end-points without total mortality reduction in primary prevention trials. AFCAPS/TEXCAPS thus emphasizes the point that in primary prevention, targeting patients at higher risk will bring a bigger impact at lower cost. 23,24 Furthermore, the safety and efficacy of lovastatin is most welcome, given its lower cost compared to the other patented statins. The 4S recruited patients from throughout the Scandinavian countries. WOSCOPS enrolled Scottish patients, CARE and AFCAPS/TEXCAPS were North American studies, and the patients for LIPID were from Australasia. That patients from various regions throughout the world similarly benefit from statin therapy is reassuring, but not surprising. The Seven Countries Study clearly showed that the relationship of increasing cholesterol levels and increasing coronary heart disease mortality holds true across various regions of the world, although different regions are at different absolute risk of disease. 25 Thus it is reassuring to find that treatment of hypercholesterolemia is also similarly useful in various parts of the world. The challenge for clinicians is to get the correct message from these various statin trials. The publication of LIPID and AFCAPS/TEXCAPS confirm that patients at high risk should receive therapy to reduce adverse cardiovascular events, even if their actual cholesterol level is not in the elevated range. The shifting of concern from the actual cholesterol level to the risk profile of the patient is logical when one remembers that hypercholesterolaemia by itself is asymptomatic, and it is the cardiovascular disease (which the hypercholesterolaemic patient is prone to) that brings morbidity and mortality. Getting aggressive: MIRACL and ADVERT Besides lowering cholesterol levels, statins are known to modify endothelial function and stabilize plaques, as well as reducing inflammation and thrombus formation. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study 26 looked at the effect of atorvastatin used early in the acute coronary syndromes (ACS). A total of 3086 patients with unstable angina or non-q-wave myocardial infarction were randomly assigned to placebo or atorvastatin 80 mg/day at h of admission. Atorvastatin treatment reduced total cholesterol by 34% and LDL cholesterol by 52%. After a follow-up of 16 weeks, atorvastatin therapy produced a significant reduction in the primary end-point, which was defined as death, non-fatal myocardial infarction, cardiac arrest or recurrent symptomatic ischaemia (RR 0.84, 95%CI ). Unfortunately, there was no significant change in death, non-fatal myocardial infarction or cardiac arrest, and the benefit was seen in the reduction of recurrent ischaemia. Thus, while this study established the safety and efficacy of statins in the acute coronary setting, it also suggests that more benefit will come from other therapeutic interventions when dealing with unstable angina and myocardial infarction. 27,28 The patient with an ACS is facing life-threatening consequences of the sudden occlusion of coronary blood flow. For treatment to make the most impact, it must result in quick and significantly increased coronary flow; this is something hypolipidaemic therapy does not do. The value of aggressive cholesterol reduction was investigated in comparison with coronary angioplasty in the Atorvastatin Versus Revascularization Treatment (AVERT) study. 29 Patients with stable angina recommended for percutaneous intervention were studied. Out of 341 patients recruited, 177 had an angioplasty as advised initially; the other 164 did not have an angioplasty but were instead initiated on 80 mg/day atorvastatin. Atorvastatin patients had a reduction of total cholesterol by 31%, and LDL cholesterol by 46%. After a follow-up of 18 months, 13.4% of patients assigned to the aggressive lipid-lowering therapy had had an ischaemic event, compared to 20.9% of patients in the angioplasty group (risk reduction 36%, p ¼ 0.048, not significant after adjustment for interim analysis). The time to reach an ischaemic event was significantly longer in the atorvastatin group (RR 0.64, , p ¼ 0.03). The safety of aggressive lipid reduction therapy was confirmed, and there is a suggestion that it may be as efficacious as percutaneous intervention in managing patients with stable angina pectoris. In fact, trials of angioplasty vs. medical therapy in stable angina pectoris have shown that angioplasty does not reduce the incidence of myocardial infarction, and has no effect on coronary mortality. 30,31 In fact, most myocardial infarctions are due to the sudden disruption of the mildly stenotic lesions, and not the progression of previously severely narrowed plaques. 32 Since angioplasty

5 The statin studies 603 treats only those severely stenotic lesions and does nothing to the mildly stenotic plaques, it thus cannot have a big impact in reducing myocardial infarction. Moreover, there is increasing evidence that acute coronary syndromes develop in the setting of a systemic inflammatory state. 33,34 Since the statins also have an anti-inflammatory and plaque stabilization effect, it stands to reason that they would be better able to prevent plaque rupture than angioplasty, which only targets a local stenotic plaque Further work is needed in this area, but it does seem that drug therapy has much to offer in preventing the adverse effects of atherosclerosis. Resolving all doubts: HPS and LIPS The publication of the Heart Protection Study (HPS) firmly establishes the benefit of statin therapy in preventing adverse events in patients at high risk of atheromatous disease, regardless of initial lipid levels. 38 Patients recruited were defined as being at high risk of coronary mortality because of prior coronary disease (secondary prevention), presence of non-coronary atheromatous disease or diabetes. A total of patients were enrolled and followed-up for a mean of 5 years. Patients were randomized to receive simvastatin 40 mg/day or placebo. Compared to placebo, after 5 years, simvastatin reduced total cholesterol by a mean of 1.2 mmol/l (20.3%) and LDL cholesterol by 1.0 mmol/l (29.4%). Primary end-point was total mortality. Simvastatin produced a highly significant reduction in total mortality (RR 0.87, 95%CI , p ¼ ), in major coronary events (RR 0.73, 95%CI , p ), in strokes (RR 0.75, 95%CI , p ) and in revascularization procedures (RR 0.76, 95%CI , p ). There was no increase in non-haemorrhagic stroke and no effect on noncardiac mortality. Benefit was seen clearly in women, in the elderly and in patients with prior non-cardiac atheromatous disease. Any remaining doubts about the value of statin therapy in diabetic patients was settled with the clear reduction of cardiovascular disease in the 5963 diabetics recruited into the HPS study. 39 Benefit also extended to those patients with initially low total and LDL cholesterol levels. In fact, the proportional reduction in adverse events was the same in all categories of lipid levels in the patients studied, even in those with initial LDL cholesterol 53 mmol/l and total cholesterol 55 mmol/l. There can now be no doubt of the strategy to take. All patients at high risk of atheromatous disease must be given statin therapy, which will reduce adverse coronary and other vascular events. Baseline cholesterol levels are just one of the many risk factors in atheromatous disease, and any decision on therapy should be based on an assessment of overall risk, not just the lipid level. With the publication of the HPS, it is hard to argue with the conclusion that statin therapy is safe. Statin trials have now randomized well over patients, and statin therapy has been available to clinicians for over two decades. No therapy is free of adverse effects, and the cerivastatin saga highlights the importance of proper patient monitoring and the need for caution with newer formulations, and in combining drugs. 40 Nevertheless, the acceptability of the statins contrasts significantly with the poor palatability and high discontinuation rates of niacin and the sequestrant formulations. 41 Although expensive, statin therapy for hyperlipidaemia is cost-effective if the right patient group is targeted The evidence from the trials is that all patients with atheromatous disease or who are at high risk of future atheromatous disease need statin therapy. Less emphasis should be placed on the actual lipid level, and more consideration must be given to the cardiovascular risk profile of the patient. Under-use of statin therapy remains prevalent today and is a practice that needs to be discouraged, as it is far better to prevent coronary disease than to treat its consequences. 46 The Lescol Intervention Prevention Study (LIPS) was a secondary prevention study, and thus it is unsurprising that fluvastatin was found to successfully lower the risk of major adverse cardiac events (MACE), defined as cardiac death, non-fatal myocardial infarction or re-intervention. 47 Patients were recruited after having undergone percutaneous coronary intervention (PCI), had a baseline total cholesterol ranging from mg/dl ( mmol/l) and were randomized to fluvastatin 80 mg/day (n ¼ 844) or a placebo (n ¼ 833). LDL cholesterol was reduced by 22% on fluvastatin treatment. After a median follow-up of 3.9 years, 21.4% of the fluvastatin patients experienced at least one MACE compared to 26.7% of the placebo group (RR 0.78, 95%CI , p ¼ 0.01). The results of this study thus reinforced the usefulness of statin therapy in patients with established coronary atherosclerosis who would thus be at high risk for future adverse cardiovascular events. By showing the efficacy of fluvastatin treatment, LIPS also supports the view that the protective effect of the statins is a class effect.

6 604 H.T. Ong Some surprises: PROSPER and ALLHAT-LLT The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial randomized 5804 patients aged years to either pravastatin 40 mg/day or placebo. 48 Patients recruited either had a history of existing vascular disease (coronary, cerebral or peripheral) or were at risk of such disease (because of smoking, hypertension or diabetes). This was thus a mixed secondary and primary prevention study, and it sought to finally address the question of hypocholesterolaemic therapy in older patients. After 3 months follow-up, pravastatin therapy reduced LDL cholesterol by 34%, and increased HDL cholesterol by 5%. The primary end-point was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. After an average follow-up of 3.2 years, therapy significantly reduced the primary end-point (RR 0.85, 95%CI , p ¼ 0.014). The reduction was due to the lowered risk of coronary death and non-fatal myocardial infarction (RR 0.81, 95%CI , p ¼ 0.006); there was no significant change in stroke incidence (RR 1.03, 95%CI , p ¼ 0.8). However, new cancer diagnoses were more frequent in the pravastatin-treated patients (RR 1.25, 95%CI , p ¼ 0.02), apparently supporting the previous concern about the potential carcinogenic dangers of statin therapy. 49,50 The authors then performed a metaanalysis of previous statin trials, and showed no overall increase in cancer occurrence whether patients were on pravastatin or other statin drugs. It may be useful to consider this increased cancer incidence in PROSPER with the results of some of the other statin studies. The HPS recruited 5806 patients aged 470 years, and this group made up 28% of the total study population. The reduction in major vascular events was as marked in these elderly patients as in those aged 565 and those aged between 65 and 70 years. There was no agebased breakdown provided for cancer incidence. However, there was an apparent excess of nonmelanoma skin cancer in the simvastatin-treated group, compared to placebo (2.4% vs. 2.0%, p ¼ 0.06). Neoplasias other than non-melanoma skin cancer were similar in the simvastatin and placebo groups (7.9% vs. 7.8%, p ¼ 0.9). Looking back at the 4S study, which also involved simvastatin, there were 21 patients with non-melanoma skin cancer in the statin group, compared to seven in the placebo group; there were also 89 patients with other types of cancer in the statin treated group compared to 96 in the placebo group. 51 In the CARE study, which involved pravastatin, the occurrence of 12 cases of breast cancer in the statin-treated group compared to one case in the placebo group was attributed to a chance occurrence. Thus, although no statistically significant evidence exists that neoplasias are increased with statin therapy, the cautious clinician will not totally dismiss this possibility, given these anecdotal reports. We have changed our emphasis in lipid management from our prior concern with just the absolute lipid level of the patient, to targeting the elevated risk of developing clinical atherosclerotic disease; trials are now studying the effects of treatment on high-risk patients, regardless of lipid levels. 52,53 Patients at highest risk will benefit most from statin therapy, which has been clearly shown to reduce adverse clinical events. Similarly, the fair-minded practical clinician must be concerned about possible adverse effects of statin therapy, especially since cholesterol is needed to maintain the integrity of the cell membrane. The increased cancer incidence in the PROSPER trail raises the possibility that in those at increased risk of neoplasia, such as the elderly population, statin therapy might indeed result in an increase of clinical cancers. The importance of targeting the right patient group thus needs to be re-emphasized. Treating those at high risk of atheromatous disease will reduce the occurrence of clinical cardiovascular events; treating those at high risk of cancer occurrence may bring about an increase in neoplasia incidence. The balance of risk and benefit must thus be assessed carefully in each individual patient. The Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Lipid Lowering Trial component (ALLHAT-LLT) randomized patients aged 455 years with hypertension and one other risk factor to either pravastatin mg/day (n ¼ 5170) or usual care (n ¼ 5185). 54 This was a mixed primary and secondary prevention trial, with 14% of patients having had prior coronary disease, and 35% being diabetics. Compared to placebo, there was only a modest reduction with pravastatin: total cholesterol by 10% and LDL cholesterol by 17%. After a mean follow-up of 4.8 years, there was no difference in the primary end-point of all-cause mortality between the pravastatin and usual care groups (RR 0.99, 95%CI , p ¼ 0.88). Coronary heart disease events were also not significantly different (RR 0.91, 95%CI , p ¼ 0.16). As this is essentially a primary prevention study, with 86% of patients having no prior coronary disease, the failure to demonstrate a significant reduction in all-cause mortality with

7 The statin studies 605 statin therapy is not surprising. Cholesterol-lowering therapies in primary prevention trials have consistently struggled to show a reduction in total mortality. Such generally healthy patients are also at risk of dying from non-cardiovascular causes, and thus any benefit of a reduction in coronary mortality from statin therapy is obscured when considering the total mortality rate of whole population studied. The unexpected failure of ALLHAT-LLT to show a reduction in coronary heart disease events was attributed to the increased use of statin and other hypolipidaemic therapy in the usual care patients. After 6 years, 26.1% of the usual care patients were on statins and 2.4% were on other hypolipidaemic drugs. On the other hand, after 6 years, 16.2% of the pravastatin group ended up on no lipid-lowering therapy at all. Thus, the difference in cholesterol levels in the two groups of patients was not as large as expected, and it was probably this failure to produce a marked difference in lipid levels in the two groups that resulted in the failure to demonstrate coronary event reduction. 55 It appears that the time for placebocontrolled trials with statin therapy has passed, whether on practical or ethical grounds. Is higher dose statin better? The results of the MIRACL trial established the value of high-dose aggressive hypolipidaemic therapy in patients presenting with an ACS. 26 The next useful question to consider was whether especially high-risk patients would actually derive more benefit from higher-dose aggressive statin therapy. Fiver studies reported in the last couple of years sought to answer this question, and gave almost consistent results. The Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 (PROVE-IT) investigators enrolled 4162 patients who had an ACS episode within the prior 10 days. 56 They were randomized to standard therapy with 40 mg/day pravastatin, or to intensive therapy with atorvastatin 80 mg/day. The primary end-point was the composite of death, myocardial infarction, hospitalized unstable angina, revascularization and stroke. The median LDL cholesterol was 95 mg/dl (2.46 mmol/l) with standard therapy, and 62 mg/dl (1.60 mmol/l) with intensive therapy (p ). At the end of 2 years, the primary endpoint event rate was 26.3% with pravastatin and 22.4% with atorvastatin (p ¼ 0.005; RR 0.84, 95%CI ). Although the benefit of intensive therapy appeared as early as 30 days, it reached statistical significance only after follow-up of 180 days. Treatment of patients with LDL cholesterol of at least 125 mg/dl appeared to produce more benefit than in patients of LDL cholesterol 5125 mg/dl (HR 34% vs. 7%, p ¼ 0.02). Elevation of alanine aminotransferase to more than three times upper limit occurred in 1.1% of patients with standard pravastatin and in 3.3% with intensive atorvastatin (p ). Nevertheless, discontinuation of treatment, myalgias and creatine kinase elevation were all similar in the two groups. Thus, in patients with an ACS, initiation of a more intensive dose statin therapy appeared to confer greater protection against death and major cardiovascular events, compared to usual dose treatment. Phase Z of the A to Z trial recruited 4479 ACS patients and randomized them to either early and intensive (EI) or delayed and conservative (DC) simvastatin therapy. 57 Patients on the EI treatment arm were immediately (mean time from symptom onset of 3.7 days) given 40 mg/day simvastatin for a month, followed by 80 mg/day simvastatin. The DC treatment involved placebo therapy for 4 months, followed by 20 mg/day simvastatin. The primary end-point was a composite of cardiovascular death, non-fatal myocardial infarction, ACS admission and stroke. Total and LDL cholesterol, as well as C-reactive protein levels, were significantly lower in the EI treatment arm after 4 and 8 months from randomization. After a median follow-up of 2 years, the primary end-point occurred in 16.7% of the DC patients compared to 14.4% of the EI patients (HR 0.89, 95%CI ; p ¼ 0.14). Further analysis showed that there was no difference during the first 4 months of treatment, but from 4 months until the end of follow-up, the EI treatment group saw a statistically significant reduction in primary end-point (9.3% vs. 6.8%, HR 0.75, 95%CI ; p ¼ 0.02). Cardiovascular death reduction in the EI treatment arm just about reached statistical significance (5.4% vs. 4.1%, HR 0.75, 95%CI ; p ¼ 0.05). The higher risks of intensive statin therapy was also shown up, with myopathy occurring significantly more often in the EI treatment group. In showing a trend favouring early and intensive statin therapy that was more pronounced over a longer follow-up period, the A to Z trial supports the findings of MIRACL and PROVE-IT which similarly studied ACS patients. It is also important to remember that although ACS patients will benefit clinically from high-dose statin therapy, liver and muscle enzymes should be carefully monitored given the increased incidence of adverse effects, and the benefit from statins would probably not match the immediate symptomatic and prognostic benefit from an interventional strategy. 58

8 606 H.T. Ong The question of whether an intensive statin strategy would be beneficial in the stable nonacute coronary patient was addressed by the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. 59 Patients aged years, who on angiography had luminal stenosis of between 20% to 50%, were put on either moderate therapy with 40 mg/day pravastatin or intensive therapy with 80 mg/day atorvastatin. Intravascular ultrasound was used to assess atheroma load with 502 patients studied both at baseline and after 18 months of treatment. LDL cholesterol was significantly lower in the intensive group [79 mg/dl (2.05 mmol/l) vs. 110 mg/dl (2.85 mmol/l), p ], with more reduction also seen in the C-reactive protein levels ( 36.4% vs. 5.2%, p ). The primary end-point was percentage change of atheroma volume. Compared to baseline, atheroma volume increased significantly by 2.7% in the pravastatin patients (95%CI 0.2% 4.7%; p ¼ 0.001), while it was not significantly different over the 18 months in the atorvastatin patients ( 0.4%, 95%CI 2.4% to 1.5%; p ¼ 0.98). A significantly lower progression rate in atheroma volume was thus seen with more intensive statin therapy ( p ¼ 0.02). Adverse events and drug discontinuation rates did not differ in the two groups, although elevation of alanine aminotransferase to three times the upper limit occurred in 2.3% of intensive atorvastatin patients compared to 1.6% of standard pravastatin patients. Although the study was not large enough to demonstrate a difference in clinical events, REVERSAL makes a case for intensive statin therapy in atherosclerotic coronary patients, as this appeared to successfully halt atheroma progression. The Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study sought to answer the question of whether an aggressive statin treatment strategy in coronary patients would actually be beneficial in a real world setting. 60 The trial looked at 2442 patients with coronary disease under managed care or the Veterans Affairs system, and randomized them to either atorvastatin 80 mg/day or to usual-care lipid therapy. Aggressive hypolipidaemic therapy reduced total cholesterol by 24.1% and LDL cholesterol by 34.3%, compared to total cholesterol reduction of 15.5% and LDL cholesterol reduction of 23.3% under usual care. NCEP guideline targets were met in 72.4% of the atorvastatin patients and in 40.0% of usual care. After a median follow-up of 54.3 months, the primary end-point of first cardiovascular event occurred in 23.7% of atorvastatin patients and in 27.7% of usual care patients (RR 0.83, 95%CI , p ¼ 0.02). There was no significant elevation of liver enzymes, rhabdomyolysis or increased cancer incidence with atorvastatin treatment. The study suggests that an aggressive statin treatment strategy would be safe and significantly reduce cardiovascular events in patients with known coronary disease. The Treating to New Targets (TNT) study recruited patients with clinically stable IHD whose LDL cholesterol was less than 130 mg/dl (3.4 mmol/l) while on atorvastatin 10 mg/day. 61 They were then either continued on atorvastatin 10 mg/day, or were put on atorvastatin 80 mg/day. The primary end-point was occurrence of first cardiovascular event, defined as coronary death, non-fatal myocardial infarction, resuscitated cardiac arrest or stroke. Mean LDL cholesterol was 77 mg/dl (2.0 mmol/l) with 80 mg atorvastatin, vs. 101 mg/dl (2.6 mmol/l) with 10 mg atorvastatin. After a median follow-up of 4.9 years, the primary end-point occurred in 10.9% of the 10 mg atorvastatin group, and 8.7% of the 80 mg atorvastatin group (HR 0.78, 95%CI , p ). Significant reductions were noted in the incidence of myocardial infarction (HR 0.78, 95%CI , p ¼ 0.004), cerebrovascular events (HR 0.77, 95%CI , p ¼ 0.007) and in hospitalized heart failure (HR 0.74, 95%CI , p ¼ 0.01). However, adverse events related to treatment occurred in 8.1% while on 80 mg atorvastatin, but in only 5.8% on atorvastatin 10 mg (p ); the incidence of persistent liver enzyme elevation being 1.2% in the high-dose atorvastatin group vs. 0.2% in the lowdose group (p ). The number needed to treat (NNT) to produce one treatment-related adverse event in this trial was 43, compared with the NNT to reduce one cardiovascular event of 45. There was no difference in total mortality between the high-dose and low-dose groups, with the reduction in cardiac mortality by 26 being balanced by the increase in non-cardiac mortality of 31 in the patients on 80 mg atorvastatin daily. 62 Thus, while high-dose statin does reduce cardiovascular outcomes, there is no doubt that it is associated with a higher incidence of adverse effects, and the worry remains that it may adversely affect noncardiovascular mortality. It is vitally important to treat the correct patient with high doses of statin, to maximize the risk-benefit ratio. Special high risk groups: hypertensives and diabetics The Anglo-Scandinavian Cardiac Outcomes Trial- Lipid Lowering Arm (ASCOT-LLA) recruited hypertensive patients with at least three other

9 The statin studies 607 cardiovascular risk factors. 52 Although this was a primary prevention study, patients had a mean of 3.7 risk factors and were thus at higher risk of cardiovascular events than those in ALLHAT-LLT, which recruited hypertensive patients with one other risk factor. 54 ASCOT-LLA randomized patients to either 10 mg/day atorvastatin or placebo, with a primary end-point of nonfatal myocardial infarction and fatal coronary heart disease. After a median follow up of 3.3 years, 100 events occurred in the atorvastatin group, with 154 events in the placebo group (HR 0.64, 95%CI , p ¼ ). Strokes, incidence of chronic stable angina, and total coronary events, as well as total cardiovascular events and procedures, were all significantly reduced. The reduction in total mortality did not reach statistical significance (HR 0.87, 95%CI , p ¼ 0.16). Taken together, ALLHAT-LLT and ASCOT-LLA suggest that the high-risk hypertensive patient will benefit from statin therapy, while the hypertensive with no prior cardiovascular disease and who is at low risk will not. The importance of risk stratification in the individual patient is reiterated. The Atorvastatin Diabetes Study (CARDS) recruited 2838 diabetic patients aged years with no prior cardiovascular disease, and randomized them to atorvastatin 10 mg/day or placebo. 63 The primary end-point was occurrence of an acute coronary event, coronary revascularization or stroke. Treatment with atorvastatin reduced total cholesterol by 26%, and LDL cholesterol by 40%. After a median follow-up of 3.9 years, the atorvastatin patients had an event rate of 1.54 per 100 person-years, while placebo patients had an event rate of 2.46 per 100 patient-years (RR 37%, 95%CI 17 52%, p ¼ 0.001). The reductions in acute coronary events and strokes were significant, but the reductions in coronary revascularization and total mortality failed to reach statistical significance. The reduction in primary endpoint occurred throughout the whole range of baseline lipid levels; patients with presenting LDL cholesterol 43.1 mmol/l had a reduction in hazard ratio of 0.62, those with LDL cholesterol 53.1 mmol/l saw a reduction of 0.63 (p ¼ 0.96). Unlike the importance seen for risk stratification, the actual lipid level of the diabetic patient is not predictive of whether there will be benefit from statin therapy. Statin treatment cannot be recommended for the primary prevention of cardiovascular disease in all diabetics, but their risk status will need to be carefully assessed and therapy initiated for those high-risk diabetics who will benefit from treatment. 64 Resolving conundrums and answering questions With the enormous amount of information accumulated from these large studies over the last decade, it is useful to try to resolve conundrums and seek answers for practical questions clinicians are often faced with. (i) Who should receive statins, and when? The statins should no longer be seen as treatment for hyperlipidaemia per se. Hyperlipidaemia increases the risk of cardiovascular disease, and statins should be viewed as treatment to reduce and prevent clinical cardiovascular events. Thus, those requiring statins are those at high risk of cardiovascular events, regardless of the baseline lipid levels. 6,19,39,52,63 The assessment of risk in the individual patient is a matter to be decided by the clinician, but in all methods of risk assessment, lipid levels form only one of the many clinical parameters to be taken into consideration. 18,65,66 Such a strategy of treatment based on risk will ensure that patients likely to suffer from adverse cardiovascular outcomes will be treated regardless of their initial lipid level, and avoid the unnecessary treatment of the young hyperlipidaemic patient, who may not benefit from therapy. The question of at what lipid level to initiate treatment has to be replaced by at what cardiovascular risk should statins be started. The initial confusion about whether some groups such as females or the elderly might respond differently has now been convincingly resolved with the large numbers recruited into the trials. 38,48 Male or female, young or old, diabetic or not, it is the overall cardiovascular risk of the individual presenting patient that should decide the need for statin therapy. Similarly, it is the propensity of the individual patient to possible adverse consequences of treatment (hepatitis, myositis, mood changes) that necessitates caution in initiating and increasing statin usage. (ii) What level of lipids should be the target for statin treatment? None of the trials sought to answer the question of what lipid level should be the target for with statin usage, unlike the UKPDS and HOT studies with diabetes and hypertension The statin trials all either used a fixed dose of statin, or else increased dosage according to a pre-defined protocol. The recent comparative statin trials contrasted a low-dose with a high-dose regimen, and did not actually seek to compare patients treated

10 608 H.T. Ong to different target LDL cholesterol levels. It was only on post hoc review that the lipid levels of the two treatment groups were calculated. Thus, the latest guideline advice to seek very low lipid levels of 570 mg/dl (1.8 mmol/l) for those at very high risk is actually an extrapolation of the studies, and of epidemiological data, rather than a direct evidence-based conclusion derived from the trials. 70,71 Clearly, the higher the dose of statin used, the more cardiovascular outcomes will be reduced. 56,57,59 61 Equally clearly, there is an increase in the incidence of adverse effects with higher doses of statins. 56,57,61,62 Thus, the higher the risk of cardiovascular events in the presenting patient, the higher the dose of statin that should be used. The higher the presenting lipid level, the more likely it would be that a higher dose of statin can be used. In any patient, reaching an LDL cholesterol of 70 mg/dl (1.8 mmol/l) will indicate the level when statin dosage should not be further increased. The onset of clinical or biochemical adverse effects, or financial strain, would similarly suggest that the upper limit of statin dose has been reached. Such an individualized approach to statin therapy would reinforce the need for the physician to manage the whole patient clinically, rather than to be excessively distracted by any arbitrarily defined laboratory lipid levels. (iii) Are there alternatives to conventional statin treatment? There can be no doubt that statin therapy in conventional doses studied in the trials, (daily simvastatin mg, pravastatin mg, atorvastatin mg, lovastatin mg and fluvastatin 80 mg), will reduce future cardiovascular events. Thus, when used for the appropriately high risk patient, a favourable risk-benefit ratio will be obtained. It is interesting to consider the alternatives to conventional dose statin therapy that have been studied. Ethnic differences in drug efficacy have been demonstrated, as in the reduced effects of agents targeting the renin-angiotensin system amongst African-American patients. 72,73 A Japanese study of patients found that just 5 mg daily of simvastatin reduced total cholesterol by about 20%, and LDL cholesterol by about 25%; the effects were seen after just 6 months and persisted for the 6 years of the trial. 74 The Food and Drug Administration caution physicians that serum levels of rosuvastatin amongst Asians are double those of Caucasians, and advised that initiating doses of the drug should be halved in Asian patients. 75 The possibility exists that the smaller and lighter Asian patients may benefit from lowdose statin therapy, an idea that would be welcomed in these generally less affluent parts of the world. A meta-analysis of different hypolipidaemic strategies involving over 275^000 patients showed that it was only the statins (RR 0.87, 95%CI ) and n-3 fatty acids (RR 0.77, 95%CI ) that produced a reduction in total mortality. 76 Cardiovascular mortality was reduced with the statins (RR 0.78, 95%CI ), resins (RR 0.70, 95%CI ) and n-3 fatty acids (RR 0.68, 95%CI ). While both the statins and resins had a significant hypolipidaemic effects, n-3 fatty acids did not significantly affect cholesterol levels, suggesting that their cardiovascular protective effect may be mediated by other means. 77 In the 17 fibrate trials recruiting patients, non-cardiovascular mortality was increased in the treated group compared to controls (RR 1.13; 95%CI ). Although dietary intervention was found not to reduce mortality in this review, ample evidence exists that dietary restraint and exercise will be beneficial in coronary artery disease An additional strategy in hypolipidaemic therapy is the use of the cholesterol absorption inhibitor ezetimibe together with a statin to enhance cholesterol reduction. 78,79 A further reduction of 20% in the LDL cholesterol level can be achieved by co-administering ezetimibe with the existing statin. However, there are as yet no reports on whether this addition of ezetimibe will result in a further reduction of clinical cardiovascular events. (iv) The future of statin research There are a few more ongoing comparative statin trials addressing the question of whether high-dose therapy is better. 80 IDEAL will study 7600 patients with a prior myocardial infarction, randomized to either atorvastatin 80 mg/day or simvastatin mg/day, with coronary death or non-fatal myocardial infarction as the primary end-point. SEARCH is another secondary prevention trial, and will randomize patients in a 22 factorial design to simvastatin 80 mg/day or simvastatin 20 mg/day with or without folate/vitamin B12; the primary end-point is also coronary death or nonfatal infarction. BELLES will recruit 600 patients on either atorvastatin 80 mg/day or pravastatin 40 mg/day, with the difference in calcium content of the coronary arteries being the primary end-point. Given the compatible results of the five reported comparative statin trials, it is likely that these ongoing studies will report that higher dose statin

11 The statin studies 609 will result in a lower incidence of coronary outcomes, at the expense of higher statin-induced adverse effects. 56,57,59 61 The role of inflammation in atherosclerotic cardiovascular disease is being increasingly recognized. 81 By reducing inflammation, as reflected by its reduction of C-reactive protein, statin therapy also reduces clinical cardiovascular outcomes, independent of the reduction of lipid levels. 82,83 Besides its effects on clinical cardiovascular events, statin therapy also reduces objectively assessed myocardial ischaemia This has led to increasing research and reports on the effect of statins in reducing endothelial dysfunction and in enhancing vasodilatation. 87,88 It is being increasingly suggested that pathophysiologically, statins are especially suited for the therapy of atherosclerosis, and the pleiotrophic effects of the statins will no doubt be the focus of intensive research in the years to come. 89 Conclusions There has been a significant philosophical shift in the approach to dyslipidaemias over the last decade. From concentrating solely on lipid levels, the emphasis is now on risk stratification, with the realization that treatment will be most effective in the group of patients at high risk of clinical cardiovascular disease. As shown in Tables 1 and 2, the benefit of statin treatment is greater in secondary prevention studies, with the mean number needed to treat (NNT) to reduce a primary end-point being 38 (range 19 56), compared to a mean NNT of 85 (31 250) in the primary prevention studies. The importance placed by the National Cholesterol Education Program in risk stratification is shown by the increase to four risk categories in its latest guidelines for different treatment strategies. 70 Doctors and patients must realize that no decision can be made about the need for statin therapy based solely on lipid level; all therapeutic decisions must be based on the risk the patient has for future cardiovascular events. Recent studies suggest that in patients with a prior ACS or established coronary disease, a more aggressive statin treatment strategy will better reduce cardiovascular events. As shown in Table 3, the benefit from a more aggressive statin therapy in these patients appear to exceed even those in the Table 1 Placebo-controlled secondary prevention statin trials 4S CARE LIPID n Follow-up (years) Statin used Sim 5 40 mg Pra 40 mg Pra 40 mg Reduction from baseline Total cholesterol 25% 20% 18% LDL cholesterol 35% 28% 25% Primary end-point Total mortality Coronary mortality, non-fatal MI Coronary mortality RR with statin treatment (95%CI) 0.7 ( ) 0.76 ( ) 0.76 ( ) p NNT HPS MIRACL LIPS n Follow-up (years) 5 16 weeks 3.9 Statin used Sim 40 mg Ator 80 mg Flu 80 mg Reduction from baseline Total cholesterol 20% 34% Nil LDL cholesterol 29% 52% 22% Primary end-point Total mortality Mortality, non-fatal MI, Ca, MACE recurrent ischaemia RR with statin treatment (95%CI) 0.87 ( ) 0.84 ( ) 0.78 ( ) p NNT MI, myocardial infarction; CA, cardiac arrest; MACE, major adverse cardiac events; NNT, number needed to treat to prevent one primary end-point; Sim, simvastatin; Pra, pravastatin; Ator, atorvastatin; Flu, fluvastatin.