- Email: [email protected]
Past, present, and future clinical trials of cardiovascular risk reduction—the hyperlipidemia perspective
International Congress Series 1262 (2004) 265 – 268
www.ics-elsevier.com
Past, present, and future clinical trials of cardiovascular risk reduction—the hyperlipidemia perspective Neil R. Poulter * Cardiovascular Studies Unit Department of Clinical Pharmacology Imperial College London, NHLI, Faculty of Medicine, St. Mary’s Campus, London W2 1PG UK
Abstract. In the 1990s, several randomized trials showed that long-term intervention with statin therapy reduces mortality and recurrent ischemic cardiovascular events both in individuals at increased risk of coronary heart disease (CHD) and in patients with established CHD. Since then, additional trials have illustrated the benefits of statin therapy in a variety of other high-risk patient populations. The HPS and ASCOT-LLA trials showed beneficial effects of statins in individuals with below average, average, or moderately elevated LDL cholesterol levels. The results of the ASCOT-LLA appear to conflict with those of the ALLHAT-LLT study, both of which were carried out among patients with hypertension. In the ALLHAT-LLT trial, significant cardiovascular benefits associated with statin use were not apparent. However, this appears to relate to the inadequate relative reduction in LDL and total cholesterol achieved. The cardiovascular benefits of statins also extend to the elderly and patients with diabetes. This review presents the latest data. D 2003 Elsevier B.V. All rights reserved. Keywords: Coronary heart disease; Statins; Cholesterol; Diabetes; Hypertension
1. Introduction During the 1990s, a number of large long-term randomized endpoint trials demonstrated conclusively that lowering serum cholesterol with a statin is associated with significant reductions in cardiovascular morbidity and mortality, both in subjects with, and at high risk of, coronary heart disease (CHD). This review will discuss recent statin trial data in a variety of high-risk patient populations, as well as identifying remaining uncertainties within the management of hyperlipidemia.
* Tel.: +44-207-594-3445; fax: +44-207-594-3411. E-mail address: [email protected] (N.R. Poulter). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2003.11.043
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N.R. Poulter / International Congress Series 1262 (2004) 265–268
2. Statin therapy in patients with normal cholesterol levels The Heart Protection Study (HPS) enrolled a wide range of patients, aged 40 –80 years, who were considered to be at substantial 5-year risk of death from CHD. Patients with total cholesterol levels of z 135 mg/dl ( z 3.5 mmol/l) were randomized to 40 mg simvastatin daily or placebo. HPS demonstrated that, regardless of baseline LDL cholesterol, 40 mg/day simvastatin significantly decreased the relative risk of major vascular events by 24% ( P V 0.0001) among the 20,536 men and women recruited into the trial. Moreover, there was no apparent cholesterol level below which benefits of statin therapy were not observed [1]. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) compared the effects of 10 mg atorvastatin and placebo on the primary endpoint of nonfatal myocardial infarction (MI) (including silent MI) or fatal CHD in 10,305 hypertensive patients with total cholesterol levels V 250 mg/dl (6.5 mmol/l). In September 2002, the ASCOT Data Safety Monitoring Board recommended that this arm of the trial be prematurely stopped after a median follow-up of 3.3 years. The primary endpoint (nonfatal MI and fatal CHD) was significantly reduced by 36% ( P = 0.0005) in the atorvastatin group (100 primary events) compared with the placebo group (154 primary events). Reductions were also seen in the rate of fatal or nonfatal stroke in the atorvastatin group (27%, P = 0.0236) [2]. A previously reported study, the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT-LLT), had also assessed the efficacy of statin therapy in patients with hypertension and moderate hypercholesterolemia. Treatment with 40 mg pravastatin produced nonsignificant reductions in coronary (9%) and stroke (9%) events compared with usual care, and no impact on the primary endpoint of allcause mortality [3]. The likely explanation for the apparently conflicting results obtained in ASCOT-LLA and ALLHAT-LLT is that, in the latter trial, 28.5% in the usual care group were receiving lipid-lowering drugs and 26.1% took a statin. As a result, the differences in total cholesterol (9.6%) and LDL cholesterol (16.7%) between the pravastatin and usual care groups in ALLHAT-LLT were less than half the equivalent figures in ASCOT-LLA (24% and 35%, respectively) [3,4]. Hence, the apparently disappointing clinical benefits noted in ALLHAT-LLT seem to merely reflect the dose response effect on cardiovascular events associated with achieved LDL cholesterol reduction. 3. Statin therapy in the elderly Until recently, there was little evidence that lipid-lowering may reduce the risk of CHD in individuals older than 70 years of age. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was the first study to examine the effects of statin therapy in an entirely elderly population (70 – 82 years at trial onset). The trial was of relatively short duration and included 5804 adults, of which the majority (n = 3000) were women. Pravastatin (40 mg) produced a 15% reduction in the primary endpoint of fatal and nonfatal coronary and stroke events ( P = 0.014) compared with placebo. Interestingly, all the benefit was achieved through reduction in coronary events [5].
N.R. Poulter / International Congress Series 1262 (2004) 265–268
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4. Is there an optimal target for lipid-lowering therapy? While the HPS and ASCOT-LLA data support the adoption of lower lipid-lowering treatment thresholds and target levels, the optimal cholesterol target for lipid-lowering therapy remains undefined. The Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid lowering (IDEAL), and the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trials will help to establish whether more aggressive lipid-lowering is associated with greater cardiovascular benefit. 5. Treating the patient with diabetes and dyslipidemia The best agent for diabetic patients with dyslipidemia remains unclear. The key atherogenic features of diabetic dyslipidemia are elevated levels of serum triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, and the preponderance of small, dense LDL. Given fibrates raise HDL cholesterol and lower triglycerides more effectively than statins, it might be expected that they form a central part of any lipid-lowering strategy in this group of patients. However, data comparing statins and fibrates in this context are currently unavailable so on the basis of best evidence to date, statins should be the treatment of choice in patients with diabetic dyslipidemia. Subgroup analyses of the statin trials have reported that statins produce equivalent reductions in CHD risk in diabetic compared with non-diabetic patients [6,7]. More recently, the effects of statins have been evaluated in much larger cohorts of patients with diabetes. For example, the HPS Group reported that allocation to 40 mg simvastatin daily for several years reduced the rate of first major vascular events by about a quarter in 5963 patients with diabetes (90% Type II diabetes), irrespective of their baseline cholesterol levels and whether or not they had existing arterial disease [8]. The relatively small number of patients with diabetes in the ASCOT-LLA was reflected by the non-significant effect of statins on the primary endpoint of fatal CHD and non-fatal MI among diabetics. However, total cardiovascular events and procedures were significantly reduced and to the same extent as among non-diabetic subjects [9]. More recently still, the Collaborative AtoRvastatin Diabetes Study (CARDS) Steering Committee recently stopped this 4-year study 2 years earlier than planned (June 2003) because of a significant benefit associated with atorvastatin therapy for the primary prevention of CHD in patients with Type II diabetes. CARDS recruited nearly 3000 patients aged 40 –75 years, without symptomatic CHD but with at least one other CHD risk factor and no previous history of heart disease or stroke [10]. Final results of the trial will be made public when available. 6. Conclusion Emerging data illustrate the benefits of statin therapy in a variety of patient populations. Furthermore, evidence is accumulating to support the idea that increasing benefits are likely to accrue from more aggressive cholesterol reduction, with no apparent LDL cholesterol threshold for initiating therapy. Looking to the future and the results of further studies, it seems inevitable that this drug class will eventually go ‘‘over the counter’’.
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References [1] Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial, Lancet 360 (2002) 7 – 22. [2] P.S. Sever, et alfor the ASCOT Investigators, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial, Lancet 361 (2003) 1149 – 1158. [3] The ALLHAT officers and co-ordinators for the ALLHAT collaborative research group, Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT), JAMA 288 (2002) 2998 – 3007. [4] R.C. Pasternak, The ALLHAT lipid lowering trial—less is less, JAMA 288 (2002) 3042 – 3044. [5] J. Shepherd, et alPROSPER study group, PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial, Lancet 360 (2002) 1623 – 1630. [6] K. Pyo¨ra¨la¨, et alfor the Scandinavian Simvastatin Survival Study (4S) Group, Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S), Diabetes Care 20 (1997) 614 – 620. [7] F.M. Sacks, et alFor the cholesterol and recurrent events Trial Investigators, The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels, N. Engl. J. Med. 335 (1996) 1001 – 1009. [8] Heart Protection Study Collaborative Group, MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial, Lancet 361 (2003) 2005 – 2016. [9] P.S. Sever, et alon behalf of the ASCOT investigators, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Author’s response, Lancet 361 (2003) 1986 – 1987. [10] H.M. Colhoun, et alCollaborative AtoRvastatin Diabetes Study (CARDS), Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, Diabet. Med. 19 (2002) 201 – 211.
www.ics-elsevier.com
Past, present, and future clinical trials of cardiovascular risk reduction—the hyperlipidemia perspective Neil R. Poulter * Cardiovascular Studies Unit Department of Clinical Pharmacology Imperial College London, NHLI, Faculty of Medicine, St. Mary’s Campus, London W2 1PG UK
Abstract. In the 1990s, several randomized trials showed that long-term intervention with statin therapy reduces mortality and recurrent ischemic cardiovascular events both in individuals at increased risk of coronary heart disease (CHD) and in patients with established CHD. Since then, additional trials have illustrated the benefits of statin therapy in a variety of other high-risk patient populations. The HPS and ASCOT-LLA trials showed beneficial effects of statins in individuals with below average, average, or moderately elevated LDL cholesterol levels. The results of the ASCOT-LLA appear to conflict with those of the ALLHAT-LLT study, both of which were carried out among patients with hypertension. In the ALLHAT-LLT trial, significant cardiovascular benefits associated with statin use were not apparent. However, this appears to relate to the inadequate relative reduction in LDL and total cholesterol achieved. The cardiovascular benefits of statins also extend to the elderly and patients with diabetes. This review presents the latest data. D 2003 Elsevier B.V. All rights reserved. Keywords: Coronary heart disease; Statins; Cholesterol; Diabetes; Hypertension
1. Introduction During the 1990s, a number of large long-term randomized endpoint trials demonstrated conclusively that lowering serum cholesterol with a statin is associated with significant reductions in cardiovascular morbidity and mortality, both in subjects with, and at high risk of, coronary heart disease (CHD). This review will discuss recent statin trial data in a variety of high-risk patient populations, as well as identifying remaining uncertainties within the management of hyperlipidemia.
* Tel.: +44-207-594-3445; fax: +44-207-594-3411. E-mail address: [email protected] (N.R. Poulter). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2003.11.043
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N.R. Poulter / International Congress Series 1262 (2004) 265–268
2. Statin therapy in patients with normal cholesterol levels The Heart Protection Study (HPS) enrolled a wide range of patients, aged 40 –80 years, who were considered to be at substantial 5-year risk of death from CHD. Patients with total cholesterol levels of z 135 mg/dl ( z 3.5 mmol/l) were randomized to 40 mg simvastatin daily or placebo. HPS demonstrated that, regardless of baseline LDL cholesterol, 40 mg/day simvastatin significantly decreased the relative risk of major vascular events by 24% ( P V 0.0001) among the 20,536 men and women recruited into the trial. Moreover, there was no apparent cholesterol level below which benefits of statin therapy were not observed [1]. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) compared the effects of 10 mg atorvastatin and placebo on the primary endpoint of nonfatal myocardial infarction (MI) (including silent MI) or fatal CHD in 10,305 hypertensive patients with total cholesterol levels V 250 mg/dl (6.5 mmol/l). In September 2002, the ASCOT Data Safety Monitoring Board recommended that this arm of the trial be prematurely stopped after a median follow-up of 3.3 years. The primary endpoint (nonfatal MI and fatal CHD) was significantly reduced by 36% ( P = 0.0005) in the atorvastatin group (100 primary events) compared with the placebo group (154 primary events). Reductions were also seen in the rate of fatal or nonfatal stroke in the atorvastatin group (27%, P = 0.0236) [2]. A previously reported study, the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT-LLT), had also assessed the efficacy of statin therapy in patients with hypertension and moderate hypercholesterolemia. Treatment with 40 mg pravastatin produced nonsignificant reductions in coronary (9%) and stroke (9%) events compared with usual care, and no impact on the primary endpoint of allcause mortality [3]. The likely explanation for the apparently conflicting results obtained in ASCOT-LLA and ALLHAT-LLT is that, in the latter trial, 28.5% in the usual care group were receiving lipid-lowering drugs and 26.1% took a statin. As a result, the differences in total cholesterol (9.6%) and LDL cholesterol (16.7%) between the pravastatin and usual care groups in ALLHAT-LLT were less than half the equivalent figures in ASCOT-LLA (24% and 35%, respectively) [3,4]. Hence, the apparently disappointing clinical benefits noted in ALLHAT-LLT seem to merely reflect the dose response effect on cardiovascular events associated with achieved LDL cholesterol reduction. 3. Statin therapy in the elderly Until recently, there was little evidence that lipid-lowering may reduce the risk of CHD in individuals older than 70 years of age. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was the first study to examine the effects of statin therapy in an entirely elderly population (70 – 82 years at trial onset). The trial was of relatively short duration and included 5804 adults, of which the majority (n = 3000) were women. Pravastatin (40 mg) produced a 15% reduction in the primary endpoint of fatal and nonfatal coronary and stroke events ( P = 0.014) compared with placebo. Interestingly, all the benefit was achieved through reduction in coronary events [5].
N.R. Poulter / International Congress Series 1262 (2004) 265–268
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4. Is there an optimal target for lipid-lowering therapy? While the HPS and ASCOT-LLA data support the adoption of lower lipid-lowering treatment thresholds and target levels, the optimal cholesterol target for lipid-lowering therapy remains undefined. The Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid lowering (IDEAL), and the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trials will help to establish whether more aggressive lipid-lowering is associated with greater cardiovascular benefit. 5. Treating the patient with diabetes and dyslipidemia The best agent for diabetic patients with dyslipidemia remains unclear. The key atherogenic features of diabetic dyslipidemia are elevated levels of serum triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, and the preponderance of small, dense LDL. Given fibrates raise HDL cholesterol and lower triglycerides more effectively than statins, it might be expected that they form a central part of any lipid-lowering strategy in this group of patients. However, data comparing statins and fibrates in this context are currently unavailable so on the basis of best evidence to date, statins should be the treatment of choice in patients with diabetic dyslipidemia. Subgroup analyses of the statin trials have reported that statins produce equivalent reductions in CHD risk in diabetic compared with non-diabetic patients [6,7]. More recently, the effects of statins have been evaluated in much larger cohorts of patients with diabetes. For example, the HPS Group reported that allocation to 40 mg simvastatin daily for several years reduced the rate of first major vascular events by about a quarter in 5963 patients with diabetes (90% Type II diabetes), irrespective of their baseline cholesterol levels and whether or not they had existing arterial disease [8]. The relatively small number of patients with diabetes in the ASCOT-LLA was reflected by the non-significant effect of statins on the primary endpoint of fatal CHD and non-fatal MI among diabetics. However, total cardiovascular events and procedures were significantly reduced and to the same extent as among non-diabetic subjects [9]. More recently still, the Collaborative AtoRvastatin Diabetes Study (CARDS) Steering Committee recently stopped this 4-year study 2 years earlier than planned (June 2003) because of a significant benefit associated with atorvastatin therapy for the primary prevention of CHD in patients with Type II diabetes. CARDS recruited nearly 3000 patients aged 40 –75 years, without symptomatic CHD but with at least one other CHD risk factor and no previous history of heart disease or stroke [10]. Final results of the trial will be made public when available. 6. Conclusion Emerging data illustrate the benefits of statin therapy in a variety of patient populations. Furthermore, evidence is accumulating to support the idea that increasing benefits are likely to accrue from more aggressive cholesterol reduction, with no apparent LDL cholesterol threshold for initiating therapy. Looking to the future and the results of further studies, it seems inevitable that this drug class will eventually go ‘‘over the counter’’.
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N.R. Poulter / International Congress Series 1262 (2004) 265–268
References [1] Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial, Lancet 360 (2002) 7 – 22. [2] P.S. Sever, et alfor the ASCOT Investigators, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial, Lancet 361 (2003) 1149 – 1158. [3] The ALLHAT officers and co-ordinators for the ALLHAT collaborative research group, Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT), JAMA 288 (2002) 2998 – 3007. [4] R.C. Pasternak, The ALLHAT lipid lowering trial—less is less, JAMA 288 (2002) 3042 – 3044. [5] J. Shepherd, et alPROSPER study group, PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial, Lancet 360 (2002) 1623 – 1630. [6] K. Pyo¨ra¨la¨, et alfor the Scandinavian Simvastatin Survival Study (4S) Group, Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S), Diabetes Care 20 (1997) 614 – 620. [7] F.M. Sacks, et alFor the cholesterol and recurrent events Trial Investigators, The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels, N. Engl. J. Med. 335 (1996) 1001 – 1009. [8] Heart Protection Study Collaborative Group, MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial, Lancet 361 (2003) 2005 – 2016. [9] P.S. Sever, et alon behalf of the ASCOT investigators, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Author’s response, Lancet 361 (2003) 1986 – 1987. [10] H.M. Colhoun, et alCollaborative AtoRvastatin Diabetes Study (CARDS), Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, Diabet. Med. 19 (2002) 201 – 211.