The Blood Pressure Lowering Treatment Trialists' Collaboration - Second Cycle of Analyses&#
The Blood Pressure Lowering Treatment Trialists' Collaboration - Second Cycle of Analyses
Presenter: Stephen MacMahon, PhD, Institute for International Health, University of Sydney (Sydney, Australia, UK)
The second cycle of analyses of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) has confirmed that ACE inhibitors, calcium channel blockers (CCBs), and diuretics/beta-blockers have similar effects on total cardiovascular events. However, CCBs appear to be less effective for prevention of heart failure, although the analysis also suggests that they may be effective in preventing stroke. Angiotensin-receptor blockers (ARBs) have been confirmed as effective in reducing total cardiovascular events. The analysis also confirmed that the size of the blood pressure reduction achieved is important in reducing the risk for stroke and coronary heart disease (CHD) but not in reducing the occurrence of heart failure.
The BPLTTC -- established in 1995 (at a European Society of Hypertension meeting) by the principal investigators of all the ongoing large scale trials of blood pressure lowering -- aims to determine the effects of various blood pressure-lowering regimens on major cardiovascular outcomes and death. Unlike many other meta-analyses and systematic overviews, this is a prospectively planned series of overviews (meta-analyses), with prespecified hypotheses, inclusion criteria, and outcomes. The BPLTTC is supported by the National Health & Medical Research Council of Australia and the World Health Organization-International Society of Hypertension Liaison Committee.
With > 160,000 patients enrolled in the program, the BPLTTC is the largest single analysis of any intervention in cardiovascular disease.
Completed in 2000, the first cycle of analyses included the 15 trials (N = 74,696) listed below. (See Trial Glossary for expansion of acronyms.)
For the second cycle, the following 14 trials were added (N = 87,669).
The second-cycle analysis aimed to compare the effects of the following treatments on mortality and major morbidity:
Three types of treatment comparisons were made:
1. Active vs control (Table 1)
Table 1. Active vs Control
ACEI, ACE inhibitor; CCB, calcium channel blocker
2. Active vs active (head to head comparisons of drugs; Table 2).
Table 2. Active vs Active
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
3. ARB vs other regimen. (The ARBs were analyzed separately since the design of several of these trials differed from that of any of the other trials.)
The prespecified primary outcomes of the analysis were stroke (fatal and nonfatal), CHD-related death and nonfatal myocardial infarction (MI), heart failure (fatal and hospitalized), total cardiovascular events, cardiovascular mortality, and total mortality. Data on cardiovascular mortality and total mortality were not presented, but were consistent with the other results, according to Dr MacMahon. All analyses presented were intention-to-treat. Relative risks and 95% confidence interval were calculated using a fixed-effects model, and each study was weighted by inverse of variance.
Drug Treatment Effects for Primary Outcomes Stroke
Compared with placebo, ACE inhibitors showed a 28% reduction in the risk of stroke for a systolic blood pressure (SBP) reduction of 5 mm Hg, and CCBs showed a 38% reduction in the risk of stroke for a greater reduction in blood pressure of 8 mm Hg (Table 3). More intensive therapy showed only a 4 mm Hg greater reduction in blood pressure vs less intensive therapy, but a risk reduction for stroke of 23%. All these comparisons indicated that in the presence of a modest blood pressure difference, there is a further reduction in the risk of stroke.
Table 3. Drug Treatment Effects for Stroke
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
Comparison of ACE inhibitor vs diuretic/beta-blocker showed a 2 mm Hg difference in blood pressure in favor of diuretic/beta-blocker, and a trend toward lesser reduction in the risk for stroke with the ACE inhibitor. CCB vs diuretic/beta-blocker showed no blood pressure difference but a slight trend in favor of CCB, and ACE inhibitor vs CCB showed a 1 mm Hg difference in blood pressure in favor of CCB with 12% greater reduction in the risk for stroke. However, the confidence intervals for all the active comparisons were wide (Table 2) and the results showed only borderline statistical significance.
CHD
ACE inhibitors showed a highly significant 20% reduction in the risk of CHD vs placebo; CCBs showed a 22% reduction vs placebo, but of only borderline statistical significance; and intensive therapy showed a nonstatistical trend toward benefit vs less intensive therapy (Table 4).
Table 4. Drug Treatment Effects for CHD
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
Comparisons of different active regimens showed no difference in risk reduction for CHD.
Heart Failure
ACE inhibitors showed an 18% reduction in the risk of heart failure vs placebo, but this difference was of only borderline significance (Table 5). CCBs showed a trend toward an excess of risk for heart failure vs placebo, although this difference was not statistically significant. A trend was seen in favor of more intensive therapy for heart failure risk. These results appear to confirm that ACE inhibitors reduce the risk of heart failure.
Table 5. Drug Treatment Effects for Heart Failure
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
ACE inhibitor vs diuretic/beta-blocker showed a trend toward benefit for diuretic/beta-blocker in heart failure risk reduction. By contrast, a highly significant clear excess of heart failure (34%) was seen with CCB vs diuretic/beta-blocker, and there was an 18% lower risk of heart failure for ACE inhibitors vs CCB (highly significant).
Major Cardiovascular Events (Fatal and Nonfatal Outcomes)
Clear benefit vs placebo for major cardiovascular events was seen with ACE inhibitors, CCBs, and more intensive blood pressure-lowering therapy (Table 6). Comparison of different active regimens showed no evidence of any differences between ACE inhibitors, CCBs, or diuretics/beta-blockers.
Table 6. Drug Treatment Effects for Major Cardiovascular Events
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
ARB vs Other
A total of 16,791 patients with a total of 2478 events were analyzed for the effects of the newest drug treatment regimen, angiotensin II receptor blockers (ARBs). The mean blood pressure difference was -3/-2 mm Hg in the ARB patients vs other. Overall, benefit of ARBs was seen with regard to stroke (21% risk reduction), heart failure (17%), and major cardiovascular events (10%), but there was no clear effect on CHD (Table 7).
Table 7. Drug Treatment Effects for ARBARB vs Other
Is it the Blood Pressure, or Is it The Drug?
To determine the extent to which these effects could be explained by the size of the blood pressure reduction achieved, the difference in SBP between randomized groups during follow-up was plotted against the relative risk of outcome event for each of the comparisons. For both stroke and CHD, the result was a clear linear association between the size of the blood pressure reduction achieved and the relative risk of stroke and of CHD -- in other words, the larger the blood pressure reduction, the greater the risk reduction for stroke and CHD. On the other hand, for heart failure, there was no relation between reduction in SBP and risk of heart failure.
Conclusions of the BPLTTC Second Cycle
Evidence from these analyses points to the following:
AASK: African American Study of Kidney Disease and Hypertension
ABCD (H): Appropriate Blood Pressure Control in Diabetes trial (hypertensive subgroup)
ABCD (N): Appropriate Blood Pressure Control in Diabetes trial (non-hypertensive subgroup)
ALLHAT: Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial
ANBP2: Second Australian National Blood Pressure Study
BPLTTC: Blood Pressure Lowering Treatment Trialists' Collaboration
CAPPP: Captopril Prevention Project
CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular Endpoints Trial
ELSA: European Lacidipine Study on Atherosclerosis
HOPE: Heart Outcomes Prevention Evaluation
HOT: Hypertension Optimal Treatment study
IDNT: Irbesartan Diabetic Nephropathy Trial
INSIGHT: International Nifedipine-GITS Study: Intervention as a Goal in Hypertension Treatment
JMIC-B: Japan Multicenter Investigation for Cardiovascular Diseases / Bayer
LIFE: Losartan Intervention for Endpoint Reduction in Hypertension study
NICOLE: Nisoldipine In Coronary Artery Disease in Leuven
NICS-EH: National Intervention Cooperative Study in Elderly Hypertensives
NORDIL: Nordic Diltiazem study
PART-2: Prevention of Atherosclerosis with Ramipril Therapy
PREVENT: Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial
PROGRESS: Perindopril Protection Against Recurrent Stroke Study
QUIET: Quinapril Ischemic Event Trial
RENAAL: Randomized Evaluation of Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan
SCAT: Simvastatin and Enalapril Coronary Atherosclerosis Trial
SCOPE: Study on Cognition and Prognosis in the Elderly
SHELL: Systolic Hypertension in the Elderly Long-term Lacidipine Trial
STOP II: Swedish Trial in Old Patents with Hypertension 2 Ongoing trial
Syst-Eur: Systolic Hypertension-Europe trial
UKPDS: United Kingdom Prospective Diabetes Study
VHAS: Verapamil Hypertension Atherosclerosis Study
References
Presenter: Stephen MacMahon, PhD, Institute for International Health, University of Sydney (Sydney, Australia, UK)
The second cycle of analyses of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) has confirmed that ACE inhibitors, calcium channel blockers (CCBs), and diuretics/beta-blockers have similar effects on total cardiovascular events. However, CCBs appear to be less effective for prevention of heart failure, although the analysis also suggests that they may be effective in preventing stroke. Angiotensin-receptor blockers (ARBs) have been confirmed as effective in reducing total cardiovascular events. The analysis also confirmed that the size of the blood pressure reduction achieved is important in reducing the risk for stroke and coronary heart disease (CHD) but not in reducing the occurrence of heart failure.
The BPLTTC -- established in 1995 (at a European Society of Hypertension meeting) by the principal investigators of all the ongoing large scale trials of blood pressure lowering -- aims to determine the effects of various blood pressure-lowering regimens on major cardiovascular outcomes and death. Unlike many other meta-analyses and systematic overviews, this is a prospectively planned series of overviews (meta-analyses), with prespecified hypotheses, inclusion criteria, and outcomes. The BPLTTC is supported by the National Health & Medical Research Council of Australia and the World Health Organization-International Society of Hypertension Liaison Committee.
With > 160,000 patients enrolled in the program, the BPLTTC is the largest single analysis of any intervention in cardiovascular disease.
Completed in 2000, the first cycle of analyses included the 15 trials (N = 74,696) listed below. (See Trial Glossary for expansion of acronyms.)
| 1. ABCD (H) 2. CAPPP 3. HOPE 4. HOT 5. INSIGHT 6. NICS-EH 7. NORDIL 8. PART-2 |
9. PREVENT 10. QUIET 11. SCAT 12. STOP-2 13. Syst-Eur 14. UKPDS-HDS 15. VHAS |
For the second cycle, the following 14 trials were added (N = 87,669).
| 1. AASK 2. ABCD (N) 3. ALLHAT 4. ANBP2 5. CONVINCE 6. ELSA 7. IDNT 8. JMIC-B |
9. LIFE 10. NICOLE 11. PROGRESS 12. RENAAL 13. SCOPE 14. SHELL |
The second-cycle analysis aimed to compare the effects of the following treatments on mortality and major morbidity:
Newer blood pressure-lowering agents vs placebo (primarily in nonhypertensive subjects)
More intensive vs less intensive blood pressure-lowering regimens (mostly in hypertensive or diabetic subjects)
Newer blood pressure-lowering regimens vs older regimens (primarily in hypertensives and diabetics).
Three types of treatment comparisons were made:
1. Active vs control (Table 1)
Table 1. Active vs Control
| Randomized Treatment | Trials (N) | Patients (N) |
| ACEI vs placebo | 5 | 18,229 |
| CCB vs placebo | 4 | 7482 |
| More vs less intensive | 5 | 21,982 |
ACEI, ACE inhibitor; CCB, calcium channel blocker
2. Active vs active (head to head comparisons of drugs; Table 2).
Table 2. Active vs Active
| Randomized Treatment | Trials (N) | Patients (N) |
| ACEI vs D/BB | 6 | 47,449 |
| CCB vs D/BB | 9 | 68,467 |
| ACEI vs CCB | 6 | 25,767 |
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
3. ARB vs other regimen. (The ARBs were analyzed separately since the design of several of these trials differed from that of any of the other trials.)
The prespecified primary outcomes of the analysis were stroke (fatal and nonfatal), CHD-related death and nonfatal myocardial infarction (MI), heart failure (fatal and hospitalized), total cardiovascular events, cardiovascular mortality, and total mortality. Data on cardiovascular mortality and total mortality were not presented, but were consistent with the other results, according to Dr MacMahon. All analyses presented were intention-to-treat. Relative risks and 95% confidence interval were calculated using a fixed-effects model, and each study was weighted by inverse of variance.
Drug Treatment Effects for Primary Outcomes Stroke
Compared with placebo, ACE inhibitors showed a 28% reduction in the risk of stroke for a systolic blood pressure (SBP) reduction of 5 mm Hg, and CCBs showed a 38% reduction in the risk of stroke for a greater reduction in blood pressure of 8 mm Hg (Table 3). More intensive therapy showed only a 4 mm Hg greater reduction in blood pressure vs less intensive therapy, but a risk reduction for stroke of 23%. All these comparisons indicated that in the presence of a modest blood pressure difference, there is a further reduction in the risk of stroke.
Table 3. Drug Treatment Effects for Stroke
| Randomized Treatment |
BP (mm Hg) |
RR (95% CI) |
| Active regimen vs control: | ||
| ACEI vs placebo | -5/-2 | 0.72 (0.64,0.81) |
| CCB vs placebo | -8/-5 | 0.62 (0.47,0.82) |
| More vs less intensive | -4/-3 | 0.77 (0.63.0.95) |
| Different active regimens: | ||
| ACEI vs D/BB | 2/0 | 1.09 (1.00,1.18) |
| CCB vs D/BB | 0/0 | 0.93 (0.86,1.01) |
| ACEI vs CCB | 1/1 | 1.12 (1.01.1.25) |
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
Comparison of ACE inhibitor vs diuretic/beta-blocker showed a 2 mm Hg difference in blood pressure in favor of diuretic/beta-blocker, and a trend toward lesser reduction in the risk for stroke with the ACE inhibitor. CCB vs diuretic/beta-blocker showed no blood pressure difference but a slight trend in favor of CCB, and ACE inhibitor vs CCB showed a 1 mm Hg difference in blood pressure in favor of CCB with 12% greater reduction in the risk for stroke. However, the confidence intervals for all the active comparisons were wide (Table 2) and the results showed only borderline statistical significance.
CHD
ACE inhibitors showed a highly significant 20% reduction in the risk of CHD vs placebo; CCBs showed a 22% reduction vs placebo, but of only borderline statistical significance; and intensive therapy showed a nonstatistical trend toward benefit vs less intensive therapy (Table 4).
Table 4. Drug Treatment Effects for CHD
| Randomized Treatment |
BP (mm Hg) |
Relative Risk (95% CI) |
| Active regimen vs control | ||
| ACEI vs placebo | -5/-2 | 0.80 (0.73,0.88) |
| CCB vs placebo | -8/-5 | 0.78 (0.62,0.99) |
| More vs less intensive | -4/-3 | 0.86 (0.72,1.03) |
| Different active regimens | ||
| ACEI vs D/BB | 2/0 | 0.98 (0.91,1.05) |
| CCB vs D/BB | 0/0 | 1.01 (0.94,1.08) |
| ACEI vs CCB | 1/1 | 0.96 (0.88,1.05) |
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
Comparisons of different active regimens showed no difference in risk reduction for CHD.
Heart Failure
ACE inhibitors showed an 18% reduction in the risk of heart failure vs placebo, but this difference was of only borderline significance (Table 5). CCBs showed a trend toward an excess of risk for heart failure vs placebo, although this difference was not statistically significant. A trend was seen in favor of more intensive therapy for heart failure risk. These results appear to confirm that ACE inhibitors reduce the risk of heart failure.
Table 5. Drug Treatment Effects for Heart Failure
| Randomized Treatment |
BP (mm Hg) |
Relative Risk (95% CI) |
| Active regimen vs control | ||
| ACEI vs placebo | -5/-2 | 0.82 (0.69,0.98) |
| CCB vs placebo | -8/-5 | 1.21 (0.93,1.58) |
| More vs less intensive | -4/-3 | 0.84 (0.59.1.18) |
| Different active regimens | ||
| ACEI vs D/BB | 2/0 | 1.07 (0.96,1.19) |
| CCB vs D/BB | 0/0 | 1.34 (1.22,1.47) |
| ACEI vs CCB | 1/1 | 0.82 (0.73,0.92) |
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
ACE inhibitor vs diuretic/beta-blocker showed a trend toward benefit for diuretic/beta-blocker in heart failure risk reduction. By contrast, a highly significant clear excess of heart failure (34%) was seen with CCB vs diuretic/beta-blocker, and there was an 18% lower risk of heart failure for ACE inhibitors vs CCB (highly significant).
Major Cardiovascular Events (Fatal and Nonfatal Outcomes)
Clear benefit vs placebo for major cardiovascular events was seen with ACE inhibitors, CCBs, and more intensive blood pressure-lowering therapy (Table 6). Comparison of different active regimens showed no evidence of any differences between ACE inhibitors, CCBs, or diuretics/beta-blockers.
Table 6. Drug Treatment Effects for Major Cardiovascular Events
| Randomized Treatment |
BP (mm Hg) |
Relative Risk (95% CI) |
| Active regimen vs control | ||
| ACEI vs placebo | -5/-2 | 0.78 (0.73,0.83) |
| CCB vs placebo | -8/-5 | 0.80 (0.69,1.92) |
| More vs less | -4/-3 | 0.86 (0.77, 0.96) |
| Different active regimens | ||
| ACEI vs D/BB | 2/0 | 1.02 (0.98,1.07) |
| CCB vs D/BB | 0/0 | 1.04 (0.99,1.08) |
| ACEI vs CCB | 1/1 | 0.97 (0.92,1.03) |
ACEI, ACE inhibitor; CCB, calcium channel blocker; D/BB, diuretic/beta-blocker
ARB vs Other
A total of 16,791 patients with a total of 2478 events were analyzed for the effects of the newest drug treatment regimen, angiotensin II receptor blockers (ARBs). The mean blood pressure difference was -3/-2 mm Hg in the ARB patients vs other. Overall, benefit of ARBs was seen with regard to stroke (21% risk reduction), heart failure (17%), and major cardiovascular events (10%), but there was no clear effect on CHD (Table 7).
Table 7. Drug Treatment Effects for ARBARB vs Other
| Outcome | Relative Risk (95% CI) |
| Stroke | 0.79 (0.69,0.90) |
| CHD | 0.96 (0.85,1.09) |
| Heart failure | 0.83 (0.72,0.97) |
| Major cardiovascular events | 0.90 (0.83,0.96) |
To determine the extent to which these effects could be explained by the size of the blood pressure reduction achieved, the difference in SBP between randomized groups during follow-up was plotted against the relative risk of outcome event for each of the comparisons. For both stroke and CHD, the result was a clear linear association between the size of the blood pressure reduction achieved and the relative risk of stroke and of CHD -- in other words, the larger the blood pressure reduction, the greater the risk reduction for stroke and CHD. On the other hand, for heart failure, there was no relation between reduction in SBP and risk of heart failure.
Conclusions of the BPLTTC Second Cycle
Evidence from these analyses points to the following:
Similar net effects on total cardiovascular events are seen with ACE inhibitors, CCBs, and diuretics/beta-blockers.
ARBs also effective in reducing total cardiovascular events.
CCBs are less effective for the prevention of heart failure, but may be more effective for stroke prevention (emphasis provided by the Trialists).
More intensive blood pressure lowering produced larger reductions in stroke and total cardiovascular events.
The size of the blood pressure reduction is closely associated with size of the reduction in risk (except in the case of heart failure).
The size of the blood pressure reduction appears to be a more important determinant of outcome than the choice of drug.
AASK: African American Study of Kidney Disease and Hypertension
ABCD (H): Appropriate Blood Pressure Control in Diabetes trial (hypertensive subgroup)
ABCD (N): Appropriate Blood Pressure Control in Diabetes trial (non-hypertensive subgroup)
ALLHAT: Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial
ANBP2: Second Australian National Blood Pressure Study
BPLTTC: Blood Pressure Lowering Treatment Trialists' Collaboration
CAPPP: Captopril Prevention Project
CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular Endpoints Trial
ELSA: European Lacidipine Study on Atherosclerosis
HOPE: Heart Outcomes Prevention Evaluation
HOT: Hypertension Optimal Treatment study
IDNT: Irbesartan Diabetic Nephropathy Trial
INSIGHT: International Nifedipine-GITS Study: Intervention as a Goal in Hypertension Treatment
JMIC-B: Japan Multicenter Investigation for Cardiovascular Diseases / Bayer
LIFE: Losartan Intervention for Endpoint Reduction in Hypertension study
NICOLE: Nisoldipine In Coronary Artery Disease in Leuven
NICS-EH: National Intervention Cooperative Study in Elderly Hypertensives
NORDIL: Nordic Diltiazem study
PART-2: Prevention of Atherosclerosis with Ramipril Therapy
PREVENT: Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial
PROGRESS: Perindopril Protection Against Recurrent Stroke Study
QUIET: Quinapril Ischemic Event Trial
RENAAL: Randomized Evaluation of Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan
SCAT: Simvastatin and Enalapril Coronary Atherosclerosis Trial
SCOPE: Study on Cognition and Prognosis in the Elderly
SHELL: Systolic Hypertension in the Elderly Long-term Lacidipine Trial
STOP II: Swedish Trial in Old Patents with Hypertension 2 Ongoing trial
Syst-Eur: Systolic Hypertension-Europe trial
UKPDS: United Kingdom Prospective Diabetes Study
VHAS: Verapamil Hypertension Atherosclerosis Study
References
MacMahon S. Blood Pressure Lowering Treatment Trialists' Collaboration - Second cycle of analyses. Program and abstracts of the 13th European Meeting on Hypertension; June 13-17, 2003; Milan, Italy.
Neal B, MacMahon S, Chapman N, for the Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet. 2000;355:1955-1964.
