- Email: [email protected]
Past, present, and future clinical trials of cardiovascular risk reduction—the hypertension perspective
International Congress Series 1262 (2004) 261 – 264
www.ics-elsevier.com
Past, present, and future clinical trials of cardiovascular risk reduction—the hypertension perspective Toshiro Fujita * Department of Internal Medicine, Chief, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan
Abstract. The relationship between blood pressure (BP) and risk of cardiovascular (CV) events is continuous, consistent, and independent of other risk factors—the higher the BP, the greater the CV risk. Over the past few decades, numerous clinical trials have shown that reducing BP can reduce the risk of CV events. A wide variety of different antihypertensive drugs were examined in these trials, including ‘‘older’’ BP-lowering agents such as diuretics and h-blockers, and ‘‘newer’’ agents, including ACE inhibitors and calcium channel blockers. The recent ALLHAT trial compared the effects of older with newer antihypertensive agents on CV events in hypertensive patients. Although it remains uncertain whether one antihypertensive drug has superiority over another for CV protection, it is clear that monotherapy is not sufficient to attain currently recommended BP targets in the majority of patients with hypertension; in ALLHAT, for example, a combination of at least two antihypertensive agents was necessary to produce the largest reductions in CV risk. The question of which combination of antihypertensive drugs is most effective will be addressed by the next generation of randomized controlled trials, including the ASCOT trial. D 2003 Elsevier B.V. All rights reserved. Keywords: Hypertension; Cardiovascular disease; Antihypertensive therapy; Calcium channel blockers; ACE inhibitors
1. Introduction Over the past few decades, numerous clinical trials have shown that reducing blood pressure (BP) can reduce the mean incidence of stroke by 35 – 40%, myocardial infarction (MI) by 20– 25%, and heart failure by more than 50% [1]. A wide variety of different antihypertensive drug regimens were examined in these trials. It is currently unclear, however, whether any one class of antihypertensive agent, or combination of classes, is superior in efficacy to another. This review will discuss recent and upcoming trials of antihypertensive agents that may influence our future management of hypertension. * Tel.: +81-3-5800-9735; fax: +81-3-5800-9736. E-mail address: [email protected] (T. Fujita). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2003.11.041
262
T. Fujita / International Congress Series 1262 (2004) 261–264
2. Blood pressure and the risk of CVD In patients between the ages of 40 – 70 years old, the risk of cardiovascular disease (CVD) doubles with every 20/10 mm Hg increase in BP [2]. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states that BP should be treated to < 140/90 mm Hg, unless an individual has diabetes or chronic renal disease, in which case the target is < 130/85 mm Hg [3]. With increasing age, there is a gradual shift from diastolic BP (DBP) to systolic BP (SBP) as the best predictor of CVD risk. In particular, the greatest burden of CV events occurs in elderly subjects with isolated systolic hypertension (ISH) (SBP>160 mm Hg and DBP < 90 mm Hg). The Systolic Hypertension in the Elderly Program (SHEP) trial was a landmark, double-blind placebo-controlled outcome trial (n = 4736) examining the effects of lowering SBP using a diuretic –based treatment in patients over the age of 60 with ISH [4]. After an average of 4.6 years follow-up, the mean BP in the treatment group was 11/4 mm Hg lower than placebo. This was associated with significant reductions in all CV events (32%), stroke (36%) and left ventricular failure (54%). The Systolic Hypertension in Europe trial (Syst-Eur) was the first trial to examine the effects of a calcium channel blocker (CCB), nitrendipine, on the risk of stroke in elderly patients with ISH [5]. In this 2-year study, almost 4700 patients were randomly assigned to a CCB, with the possible addition of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, or matching placebos. Mean BP was reduced by 10.1/4.5 mm Hg and this was associated with a 42% reduction in total stroke rate ( P = 0.003) and a 44% reduction in non-fatal stroke rate ( P = 0.007). Despite the clinical benefits associated with treating high SBP, fewer than 70% of patients < 60 years old, 48% of patients aged 61– 75 years, and 34% of patients aged over 75 years are currently treated to target SBP [6]. 3. ‘Old’ versus ‘new’ antihypertensive therapies Both ‘‘newer’’ drugs (ACE inhibitors, angiotensin-receptor blockers (ARBs), CCBs) and ‘‘older’’ drugs (diuretics, h-blockers) are available for the treatment of elevated BP. Recent meta-analyses of BP-lowering trials have provided little evidence that any antihypertensive agent is more or less effective than another in reducing the incidence of CVD [7]. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) was the largest randomised, controlled trial (n = 33,357) to compare newer drugs with old. ALLHAT examined the effects of a CCB (amlodipine), a diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) on the risk of fatal coronary events and nonfatal MI in patients with hypertension and a high risk of coronary heart disease [8]. After an average of 4.9 years follow-up, no significant difference was observed between amlodipine and chlorthalidone for the primary outcome, or for the secondary outcomes of all-cause mortality, stroke, angina, coronary revascularization, peripheral arterial disease, cancer, or end-stage renal disease. For lisinopril versus chlorthalidone, however, the lisinopril group had a 15% higher risk of stroke ( P = 0.02), although no significant difference was observed between lisinopril and chlorthalidone for the primary outcome.
T. Fujita / International Congress Series 1262 (2004) 261–264
263
This difference in stroke outcome may be partially accounted for by the 2 mm Hg difference in SBP between the lisinopril and chlorthalidone groups. The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study reported that the ARB, losartan, significantly reduced the incidence of CV mortality, stroke, or MI, compared with the h-blocker, atenolol, in patients aged 55 –60 years with essential hypertension (sitting BP 160– 200/95 – 115 mm Hg) and left ventricular hypertrophy [9]. Follow-up was for a minimum of 4 years, until 1040 patients had a primary CV event (death, MI, or stroke). Despite similar reductions in BP in each treatment group (30.2/16.6 mm Hg for losartan vs. 29.1/16.8 mm Hg for atenolol), the ARB was associated with a 25% reduction in the risk of fatal and non-fatal stroke, compared with the h-blocker ( P = 0.001). 4. Combining therapies for the treatment of hypertension While the evidence for the superiority of one antihypertensive drug over another for CV protection is not compelling, it is clear that monotherapy is not sufficient to attain BP targets in the majority of patients with hypertension. For example, in the ALLHAT and Syst-Eur trials, a combination of at least two antihypertensive agents was often necessary to produce the largest reductions in stroke risk [5,8]. The question of which combination of antihypertensive drugs is most effective will be addressed in part by the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Having enrolled 19,342 patients with untreated SBP z 160 mm Hg or DBP z 100 mm Hg, or treated SBP z 140 mm Hg or DBP z 90 mm Hg, and at least three other pre-specified CV risk factors, ASCOT will compare a newer antihypertensive regimen consisting of the CCB amlodipine (with or without the ACE inhibitor, perindopril) to an older antihypertensive regimen consisting of the h-blocker, atenolol (with or without the diuretic bendrofluazide) for the primary prevention of CVD [10]. ASCOT is expected to be completed in 2005. 5. Conclusions Several classes of drug are available for the treatment of hypertension but it is not clear whether any one class, or combination of classes, is superior to another. However, since most patients do not reach target BP with a single drug, combinations of drugs from different classes should be used to reduce CV risk. The optimal combination will be examined in the ASCOT trial, which is due to be completed in 2005. References [1] B. Neal, et al., Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood pressure lowering treatment trialists’ collaboration, Lancet 356 (2000) 1955 – 1964. [2] J.L. Izzo Jr., et al., Clinical advisory statement. Importance of systolic blood pressure in older Americans, Hypertension 35 (2000) 1021 – 1024. [3] A.V. Chobanian, et al., National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National High Blood Pressure Education
264
[4]
[5] [6] [7] [8]
[9]
[10]
T. Fujita / International Congress Series 1262 (2004) 261–264 Program Coordinating Committee, The seventh report of the Joint National Committee (JNC) on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report, JAMA 289 (2003) 2560 – 2572. SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP), J. Am. Med. Assoc. 265 (1991) 3255 – 3264. R.H. Fagard, et al., Treatment of isolated systolic hypertension in the elderly: the Syst-Eur trial. Systolic Hypertension in Europe (Syst-Eur) trial investigators, Clin. Exp. Hypertens. 21 (1999) 491 – 497. D.M. Lloyd-Jones, et al., Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community, Hypertension 36 (2000) 594 – 599. J.A. Staessen, et al., Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003, J. Hypertens. 21 (2003) 1055 – 1076. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), JAMA 288 (2002) 2981 – 2997. B. Dahlo¨f, et al., LIFE Study Group, Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 359 (2002) 995 – 1003. P.S. Sever, et al., Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators, J. Hypertens. 19 (2001) 1139 – 1147.
www.ics-elsevier.com
Past, present, and future clinical trials of cardiovascular risk reduction—the hypertension perspective Toshiro Fujita * Department of Internal Medicine, Chief, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan
Abstract. The relationship between blood pressure (BP) and risk of cardiovascular (CV) events is continuous, consistent, and independent of other risk factors—the higher the BP, the greater the CV risk. Over the past few decades, numerous clinical trials have shown that reducing BP can reduce the risk of CV events. A wide variety of different antihypertensive drugs were examined in these trials, including ‘‘older’’ BP-lowering agents such as diuretics and h-blockers, and ‘‘newer’’ agents, including ACE inhibitors and calcium channel blockers. The recent ALLHAT trial compared the effects of older with newer antihypertensive agents on CV events in hypertensive patients. Although it remains uncertain whether one antihypertensive drug has superiority over another for CV protection, it is clear that monotherapy is not sufficient to attain currently recommended BP targets in the majority of patients with hypertension; in ALLHAT, for example, a combination of at least two antihypertensive agents was necessary to produce the largest reductions in CV risk. The question of which combination of antihypertensive drugs is most effective will be addressed by the next generation of randomized controlled trials, including the ASCOT trial. D 2003 Elsevier B.V. All rights reserved. Keywords: Hypertension; Cardiovascular disease; Antihypertensive therapy; Calcium channel blockers; ACE inhibitors
1. Introduction Over the past few decades, numerous clinical trials have shown that reducing blood pressure (BP) can reduce the mean incidence of stroke by 35 – 40%, myocardial infarction (MI) by 20– 25%, and heart failure by more than 50% [1]. A wide variety of different antihypertensive drug regimens were examined in these trials. It is currently unclear, however, whether any one class of antihypertensive agent, or combination of classes, is superior in efficacy to another. This review will discuss recent and upcoming trials of antihypertensive agents that may influence our future management of hypertension. * Tel.: +81-3-5800-9735; fax: +81-3-5800-9736. E-mail address: [email protected] (T. Fujita). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2003.11.041
262
T. Fujita / International Congress Series 1262 (2004) 261–264
2. Blood pressure and the risk of CVD In patients between the ages of 40 – 70 years old, the risk of cardiovascular disease (CVD) doubles with every 20/10 mm Hg increase in BP [2]. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states that BP should be treated to < 140/90 mm Hg, unless an individual has diabetes or chronic renal disease, in which case the target is < 130/85 mm Hg [3]. With increasing age, there is a gradual shift from diastolic BP (DBP) to systolic BP (SBP) as the best predictor of CVD risk. In particular, the greatest burden of CV events occurs in elderly subjects with isolated systolic hypertension (ISH) (SBP>160 mm Hg and DBP < 90 mm Hg). The Systolic Hypertension in the Elderly Program (SHEP) trial was a landmark, double-blind placebo-controlled outcome trial (n = 4736) examining the effects of lowering SBP using a diuretic –based treatment in patients over the age of 60 with ISH [4]. After an average of 4.6 years follow-up, the mean BP in the treatment group was 11/4 mm Hg lower than placebo. This was associated with significant reductions in all CV events (32%), stroke (36%) and left ventricular failure (54%). The Systolic Hypertension in Europe trial (Syst-Eur) was the first trial to examine the effects of a calcium channel blocker (CCB), nitrendipine, on the risk of stroke in elderly patients with ISH [5]. In this 2-year study, almost 4700 patients were randomly assigned to a CCB, with the possible addition of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, or matching placebos. Mean BP was reduced by 10.1/4.5 mm Hg and this was associated with a 42% reduction in total stroke rate ( P = 0.003) and a 44% reduction in non-fatal stroke rate ( P = 0.007). Despite the clinical benefits associated with treating high SBP, fewer than 70% of patients < 60 years old, 48% of patients aged 61– 75 years, and 34% of patients aged over 75 years are currently treated to target SBP [6]. 3. ‘Old’ versus ‘new’ antihypertensive therapies Both ‘‘newer’’ drugs (ACE inhibitors, angiotensin-receptor blockers (ARBs), CCBs) and ‘‘older’’ drugs (diuretics, h-blockers) are available for the treatment of elevated BP. Recent meta-analyses of BP-lowering trials have provided little evidence that any antihypertensive agent is more or less effective than another in reducing the incidence of CVD [7]. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) was the largest randomised, controlled trial (n = 33,357) to compare newer drugs with old. ALLHAT examined the effects of a CCB (amlodipine), a diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) on the risk of fatal coronary events and nonfatal MI in patients with hypertension and a high risk of coronary heart disease [8]. After an average of 4.9 years follow-up, no significant difference was observed between amlodipine and chlorthalidone for the primary outcome, or for the secondary outcomes of all-cause mortality, stroke, angina, coronary revascularization, peripheral arterial disease, cancer, or end-stage renal disease. For lisinopril versus chlorthalidone, however, the lisinopril group had a 15% higher risk of stroke ( P = 0.02), although no significant difference was observed between lisinopril and chlorthalidone for the primary outcome.
T. Fujita / International Congress Series 1262 (2004) 261–264
263
This difference in stroke outcome may be partially accounted for by the 2 mm Hg difference in SBP between the lisinopril and chlorthalidone groups. The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study reported that the ARB, losartan, significantly reduced the incidence of CV mortality, stroke, or MI, compared with the h-blocker, atenolol, in patients aged 55 –60 years with essential hypertension (sitting BP 160– 200/95 – 115 mm Hg) and left ventricular hypertrophy [9]. Follow-up was for a minimum of 4 years, until 1040 patients had a primary CV event (death, MI, or stroke). Despite similar reductions in BP in each treatment group (30.2/16.6 mm Hg for losartan vs. 29.1/16.8 mm Hg for atenolol), the ARB was associated with a 25% reduction in the risk of fatal and non-fatal stroke, compared with the h-blocker ( P = 0.001). 4. Combining therapies for the treatment of hypertension While the evidence for the superiority of one antihypertensive drug over another for CV protection is not compelling, it is clear that monotherapy is not sufficient to attain BP targets in the majority of patients with hypertension. For example, in the ALLHAT and Syst-Eur trials, a combination of at least two antihypertensive agents was often necessary to produce the largest reductions in stroke risk [5,8]. The question of which combination of antihypertensive drugs is most effective will be addressed in part by the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Having enrolled 19,342 patients with untreated SBP z 160 mm Hg or DBP z 100 mm Hg, or treated SBP z 140 mm Hg or DBP z 90 mm Hg, and at least three other pre-specified CV risk factors, ASCOT will compare a newer antihypertensive regimen consisting of the CCB amlodipine (with or without the ACE inhibitor, perindopril) to an older antihypertensive regimen consisting of the h-blocker, atenolol (with or without the diuretic bendrofluazide) for the primary prevention of CVD [10]. ASCOT is expected to be completed in 2005. 5. Conclusions Several classes of drug are available for the treatment of hypertension but it is not clear whether any one class, or combination of classes, is superior to another. However, since most patients do not reach target BP with a single drug, combinations of drugs from different classes should be used to reduce CV risk. The optimal combination will be examined in the ASCOT trial, which is due to be completed in 2005. References [1] B. Neal, et al., Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood pressure lowering treatment trialists’ collaboration, Lancet 356 (2000) 1955 – 1964. [2] J.L. Izzo Jr., et al., Clinical advisory statement. Importance of systolic blood pressure in older Americans, Hypertension 35 (2000) 1021 – 1024. [3] A.V. Chobanian, et al., National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National High Blood Pressure Education
264
[4]
[5] [6] [7] [8]
[9]
[10]
T. Fujita / International Congress Series 1262 (2004) 261–264 Program Coordinating Committee, The seventh report of the Joint National Committee (JNC) on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report, JAMA 289 (2003) 2560 – 2572. SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP), J. Am. Med. Assoc. 265 (1991) 3255 – 3264. R.H. Fagard, et al., Treatment of isolated systolic hypertension in the elderly: the Syst-Eur trial. Systolic Hypertension in Europe (Syst-Eur) trial investigators, Clin. Exp. Hypertens. 21 (1999) 491 – 497. D.M. Lloyd-Jones, et al., Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community, Hypertension 36 (2000) 594 – 599. J.A. Staessen, et al., Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003, J. Hypertens. 21 (2003) 1055 – 1076. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), JAMA 288 (2002) 2981 – 2997. B. Dahlo¨f, et al., LIFE Study Group, Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 359 (2002) 995 – 1003. P.S. Sever, et al., Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators, J. Hypertens. 19 (2001) 1139 – 1147.