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Figure 1.
Effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (CAs) vs placebo and more intensive vs less intensive blood pressure (BP)–lowering regimens (A) and of BP-lowering regimens based on different drug classes (B) on the risks of stroke, coronary heart disease, and heart failure. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes mellitus. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; D/BB, diuretic or β-blocker; RR, relative risk. Asterisk indicates that the overall mean BP difference (systolic/diastolic) during follow-up in the actively treated/first-listed group compared with the control/second-listed group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up BP levels in first-listed treatment groups than in second-listed groups.

Effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (CAs) vs placebo and more intensive vs less intensive blood pressure (BP)–lowering regimens (A) and of BP-lowering regimens based on different drug classes (B) on the risks of stroke, coronary heart disease, and heart failure. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes mellitus. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; D/BB, diuretic or β-blocker; RR, relative risk. Asterisk indicates that the overall mean BP difference (systolic/diastolic) during follow-up in the actively treated/first-listed group compared with the control/second-listed group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up BP levels in first-listed treatment groups than in second-listed groups.

Figure 2.
Effects of angiotensin receptor blocker (ARB)–based regimens vs control regimens on the risks of major cardiovascular outcomes and death in individuals with and without diabetes mellitus. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; RR, relative risk. Asterisk indicates that the overall mean blood pressure difference (systolic/diastolic) during follow-up in the ARB group vs the control group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up blood pressure levels in the ARB group than in controls.

Effects of angiotensin receptor blocker (ARB)–based regimens vs control regimens on the risks of major cardiovascular outcomes and death in individuals with and without diabetes mellitus. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; RR, relative risk. Asterisk indicates that the overall mean blood pressure difference (systolic/diastolic) during follow-up in the ARB group vs the control group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up blood pressure levels in the ARB group than in controls.

Figure 3.
Effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (CAs) vs placebo and more intensive vs less intensive bulood pressure (BP)–lowering regimens (A) and of BP-lowering regimens based on different drug classes (B) on the risks of major cardiovascular events, cardiovascular deaths, and total mortality. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes mellitus. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; D/BB, diuretic or β-blocker; RR, relative risk. Asterisk indicates that the overall mean BP difference (systolic/diastolic) during follow-up in the actively treated/first-listed group vs the control/second-listed group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up BP levels in first-listed treatment groups than in second-listed groups.

Effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (CAs) vs placebo and more intensive vs less intensive bulood pressure (BP)–lowering regimens (A) and of BP-lowering regimens based on different drug classes (B) on the risks of major cardiovascular events, cardiovascular deaths, and total mortality. The P value by χ2 test of homogeneity (P homog) gives an indication of the constancy of effect in patients with and without diabetes mellitus. A P homog < .05 is taken to indicate that there is a difference in the effectiveness of the treatment regimen between patients with and without diabetes that is fairly unlikely to have occurred by chance alone. CI indicates confidence interval; D/BB, diuretic or β-blocker; RR, relative risk. Asterisk indicates that the overall mean BP difference (systolic/diastolic) during follow-up in the actively treated/first-listed group vs the control/second-listed group, calculated by weighting the difference observed in each contributing trial by the number of individuals in the trial. Negative values indicate lower mean follow-up BP levels in first-listed treatment groups than in second-listed groups.

Table 1. 
Characteristics of Included Trials
Characteristics of Included Trials
Table 2. 
Baseline Characteristics and Follow-up Blood Pressure Differences in Subgroups of Patients With and Without Diabetes Mellitus
Baseline Characteristics and Follow-up Blood Pressure Differences in Subgroups of Patients With and Without Diabetes Mellitus
1.
Wild  SRoglic  GGreen  ASicree  RKing  H Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;271047- 1053
PubMedArticle
2.
UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317703- 713
PubMedArticle
3.
Hansson  LZanchetti  ACarruthers  S  et al.  Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;3511755- 1762
PubMedArticle
4.
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators, Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355253- 258
PubMedArticle
5.
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. JAMA 2002;2882981- 2997
PubMedArticle
6.
Chobanian  ABakris  GBlack  H  et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;2892560- 2572
PubMedArticle
7.
European Society of Hypertension-European Society of Cardiology Guidelines Committee, 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;211011- 1053
PubMedArticle
8.
World Health Organization, 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;211983- 1992
PubMedArticle
9.
Williams  BPoulter  NBrown  M  et al.  Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004;18139- 185
PubMedArticle
10.
Brenner  BCooper  MDe Zeeuw  D  et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345861- 869
PubMedArticle
11.
Lewis  EHunsicker  LClarke  W  et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345851- 860
PubMedArticle
12.
Bertoni  AKrop  JAnderson  GBrancati  F Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care 2002;25471- 475
PubMedArticle
13.
Thomas  RPalumbo  PMelton  J  et al.  Trends in the mortality burden associated with diabetes mellitus: a population-based study in Rochester, Minn, 1970-1994. Arch Intern Med 2003;163445- 451
PubMedArticle
14.
World Health Organisation-International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration, Protocol for prospective collaborative overviews of major randomized trials of blood-pressure-lowering treatments. J Hypertens 1998;16127- 137
PubMed
15.
Lithell  HHansson  LSkogg  I  et al.  The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomised double-blind intervention trial. J Hypertens 2003;21875- 886
PubMedArticle
16.
Dahlof  BDevereux  RKjeldsen  S  et al.  Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359995- 1003
PubMedArticle
17.
National Intervention Cooperative Study in Elderly Hypertensives Study Group, Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. Hypertension 1999;341129- 1133
PubMedArticle
18.
MacMahon  SSharpe  NGamble  G  et al.  Randomised, placebo-controlled trial of the angiotensin converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive vascular disease. J Am Coll Cardiol 2000;36438- 443
PubMedArticle
19.
Pitt  BByington  RFurberg  C  et al.  Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000;1021503- 1510
PubMedArticle
20.
PROGRESS Collaborative Group, Randomised trial of a perindopril-based blood pressure lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;3581033- 1041
PubMedArticle
21.
Teo  KBurton  JBuller  C  et al.  Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;1021748- 1754
PubMedArticle
22.
Staessen  JFagard  RThijs  L  et al.  Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension in Europe. Lancet 1997;350757- 764
PubMedArticle
23.
UK Prospective Diabetes Study Group, Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317713- 720
PubMedArticle
24.
Zanchetti  AAgabiti-Rosei  EDal Palu  CLeonetti  GMagnani  BPessina  A The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomised treatment with either verapamil or chlorthalidone on intima-media thickness. J Hypertens 1998;161667- 1676
PubMedArticle
25.
HOPE (Heart Outcomes Prevention Evaluation) Study Investigators, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342145- 153
PubMedArticle
26.
Pitt  BO'Neill  BFeldman  R  et al.  The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001;871058- 1063
PubMedArticle
27.
Dens  JDesmet  WCoussement  P  et al.  Usefulness of nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). Am J Cardiol 2001;8728- 33
PubMedArticle
28.
Wright  JBakris  GGreen  T  et al.  Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;2882421- 2431
PubMedArticle
29.
Estacio  RJeffers  BHiatt  WBiggerstaff  SGifford  NSchrier  R The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998;338645- 652
PubMedArticle
30.
Schrier  REstacio  REsler  AMehler  P Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;611086- 1097
PubMedArticle
31.
Wing  LReid  CRyan  P  et al.  A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348583- 592
PubMedArticle
32.
Hansson  LLindholm  LNiskanen  L  et al.  Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353611- 616
PubMedArticle
33.
Hansson  LLindholm  LEkbom  T  et al.  Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;3541751- 1756
PubMedArticle
34.
Black  HElliot  WGrandits  G  et al.  Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial. JAMA 2003;2892073- 2082
PubMedArticle
35.
Zanchetti  ABond  MHennig  M  et al.  Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis. Circulation 2002;1062422- 2427
PubMedArticle
36.
Brown  MPalmer  CCastaigne  A  et al.  Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356366- 372
PubMedArticle
37.
Hansson  LHedner  TLund-Johansen  P  et al.  Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000;356359- 365
PubMedArticle
38.
Malacco  EGnemmi  ARomagnoli  ACoppini  ASHELL Study Group, Systolic hypertension in the elderly: long-term lacidipine treatment. J Cardiovasc Pharmacol 1994;23 ((suppl 5)) S62- S66
PubMedArticle
39.
Yui  YSumiyoshi  TKodama  K  et al.  Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res 2004;27181- 191
PubMedArticle
40.
Berl  THunsicker  LGLewis  JB  et al. Collaborative Study Group, Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138542- 549
PubMedArticle
41.
Lindholm  LIbsen  HDahlof  B  et al.  Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;3591004- 1010
PubMedArticle
42.
Blood Pressure Lowering Treatment Trialists' Collaboration, Effects of ACE inhibitors, calcium antagonists and other blood pressure lowering drugs: results of prospectively-designed overviews of randomised trials. Lancet 2000;3561955- 1964
PubMedArticle
43.
Blood Pressure Lowering Treatment Trialists' Collaboration, Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;3621527- 1535
PubMedArticle
44.
Zanchetti  ARuilope  L Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials? J Hypertens 2002;202099- 2110
PubMedArticle
45.
Prospective Studies Collaboration, Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;3461647- 1653
PubMedArticle
46.
Asia Pacific Cohort Studies Collaboration, The effects of diabetes mellitus on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care 2003;26360- 366
PubMedArticle
47.
Collins  RMacMahon  S Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet 2001;357373- 380
PubMedArticle
Original Investigation
June 27, 2005

Effects of Different Blood Pressure–Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes MellitusResults of Prospectively Designed Overviews of Randomized Trials

Blood Pressure Lowering Treatment Trialists’ Collaboration
Arch Intern Med. 2005;165(12):1410-1419. doi:10.1001/archinte.165.12.1410
Abstract

Background  Blood pressure (BP) level is a major determinant of cardiovascular morbidity and mortality in individuals with diabetes mellitus. Several guidelines recommend lower BP goals and specific drug classes for these patients. The overviews reported herein were performed to formally compare the effects on cardiovascular events and death of different BP-lowering regimens in individuals with and without diabetes.

Methods  Twenty-seven randomized trials (N = 158 709 participants) that included 33 395 individuals with diabetes and 125 314 without diabetes contributed to these analyses. For each outcome and each comparison summary, estimates of effect and 95% confidence intervals were calculated for patients with and without diabetes using a random-effects model. The constancy of the effects of each treatment regimen in participants with and without diabetes was examined using χ2 tests of homogeneity.

Results  Total major cardiovascular events were reduced to a comparable extent in individuals with and without diabetes by regimens based on angiotensin-converting enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, and diuretics/β-blockers (P > .19 for all by χ2 test of homogeneity). There was limited evidence that lower BP goals produced larger reductions in total major cardiovascular events in individuals with vs without diabetes (P = .03 by χ2 test of homogeneity).

Conclusions  These overviews showed that the short- to-medium-term effects on major cardiovascular events of the BP-lowering regimens studied were broadly comparable for patients with and without diabetes. Different effects of regimens on intermediate renal outcomes not evaluated in these overviews may still provide a rationale for using specific drug classes in patients with diabetes.

Diabetes mellitus is a major health problem that affects more than 135 million people worldwide.1 There is clear evidence that blood pressure (BP)–lowering agents protect against cardiovascular complications in this patient group,25 and guidelines now recommend intensive BP-lowering treatment for many individuals with diabetes.69 Widely publicized studies4,10,11 of drug regimens that antagonize the renin-angiotensin system have reported particular benefits of these drug classes on renal outcomes in patients with diabetes. However, patients with diabetes are more likely to experience macrovascular complications than serious renal impairment,12,13 and it has been unclear whether there are corresponding differences in the effects of regimens on macrovascular disease.

The Blood Pressure Lowering Treatment Trialists’ Collaboration was established in 1995 with the goal of performing a series of prospective overviews of randomized trials that investigated the effects of different BP-lowering regimens on serious cardiovascular disease events.14 The Collaboration, composed of the principal investigators of large-scale randomized trials of BP-lowering regimens, defined the criteria for these overviews in advance, including trial eligibility, primary and secondary outcomes, treatment comparisons, and subgroup analyses. The objectives of the diabetes subgroup analyses reported herein are to quantify the benefits associated with different treatment regimens in patients with and without diabetes and to determine whether there are important differences in the effects of different BP-lowering regimens between these 2 patient groups.

METHODS
TRIAL ELIGIBILITY CRITERIA AND SEARCH STRATEGY

Trials are eligible for inclusion in the Collaboration’s overviews if they meet 1 of the following criteria: (1) randomization of patients between a BP-lowering agent and a control (placebo or a less intensive BP-lowering regimen) or (2) randomization of patients between regimens based on different classes of BP-lowering drug. Trials are also required to have a minimum of 1000 patient-years of planned follow-up in each randomized group and must not have presented or published their main results before finalization of the overview protocol in July 1995. Trials with factorial assignment of patients to other interventions, such as aspirin therapy and cholesterol lowering, are eligible, but trials in which any such additional randomized interventions are assigned jointly with the BP-lowering treatment are not eligible because the effects of the BP-lowering treatments would be confounded by the effects of the other treatments. Potentially eligible trials, investigator and industry initiated, are identified on an ongoing basis using a variety of methods, including computer-aided literature searches, scrutiny of the reference lists of trial reports and review articles, scrutiny of abstracts and meeting proceedings, and inquiry among colleagues, collaborators, and industry. For the analyses reported herein, all eligible trials for which data had been received and checked by the end of 2003 and that contributed to the second main cycle of analyses were included.

TREATMENT COMPARISONS

In the broad group of trials comparing an active agent and a control, separate overviews were conducted for (1) angiotensin-converting enzyme (ACE) inhibitor–based regimens vs placebo, (2) calcium antagonist–based regimens vs placebo, and (3) more intensive vs less intensive BP-lowering regimens. In the broad group of trials comparing different active agents, separate overviews were conducted for (1) ACE inhibitor–based regimens vs conventional therapy (diuretic- or β-blocker–based regimens), (2) calcium antagonist–based regimens vs conventional therapy, and (3) ACE inhibitor–based regimens vs calcium antagonist–based regimens. Comparisons of an angiotensin receptor blocker (ARB)–based regimen with other regimens were treated as separate series of overviews. Four ARB trials were available for these analyses. One trial15 was a placebo-controlled study in which active treatment was initiated in the placebo group early in the study (starting with diuretic-based regimens but with the addition of agents other than ACE inhibitors and ARBs as required). Two trials10,11 used a placebo while simultaneously attempting to achieve BP reductions in both randomized groups (using BP-lowering agents other than ACE inhibitors and the specific trial intervention treatments). One trial16 was designed as a head-to-head comparison of active agents. Because all these trials included control treatment with agents other than ARBs, we analyzed them as 1 group.

PRIMARY OUTCOMES

The 6 primary outcomes were defined according to the International Classification of Disease, Ninth Revision (ICD-9), and were prespecified in the Blood Pressure Lowering Treatment Trialists’ Collaboration protocol: (1) nonfatal stroke or death from cerebrovascular disease (ICD-9 codes 430-438); (2) nonfatal myocardial infarction or deaths from coronary heart disease (CHD), including sudden deaths (ICD-9 codes 410-414); (3) heart failure causing death or requiring hospitalization (ICD-9 code 428); (4) total major cardiovascular events (stroke, CHD events, heart failure, and other cardiovascular death); (5) total cardiovascular deaths (ICD codes 396-459); and (6) total mortality. Patients were categorized as having diabetes or not according to the definition used at randomization in each contributing trial.

DATA COLLECTION AND STATISTICAL ANALYSIS

Individual patient data and summary tabular data were sought directly from each trial investigator. The data requested included participant characteristics recorded at screening or randomization, selected measurements made during follow-up, and details of the occurrence of all the primary outcomes during follow-up. The BP reduction in each trial arm was calculated as the difference between mean BP during follow-up and mean BP at baseline. Mean levels of baseline characteristics and mean differences in BP reductions between randomized groups were calculated separately for participants with and without diabetes, with estimates from each individual study weighted in proportion to the number of individuals in that study. Meta-analyses of the effects of randomized treatments used the “metan” routine in STATA (release 8.0; StataCorp, College Station, Tex). For each trial and each outcome, estimates of relative risk and its variance were calculated for individuals with and without diabetes according to the principle of intention to treat.14 Each participant could contribute only the first event in any category to the calculation for each outcome but might contribute an event to analyses of several outcomes. Pooled estimates of effect and 95% confidence intervals were calculated using a random-effects model and inverse variance weighting (weighting by the precision of each trial). The constancy of the results for patients with and without diabetes was tested using χ2 tests of homogeneity. A P < .05 for the test of homogeneity was taken to indicate that the difference between the effects in the 2 patient groups was unlikely to have occurred by chance.

RESULTS
CHARACTERISTICS OF TRIALS AND PATIENTS

Twenty-nine studies2,3,5,10,15,1740 that collectively included 162 341 individuals were eligible for inclusion. Twenty-seven trials2,3,5,10,15,1725,2737,39,40 that included 158 709 individuals provided data for these analyses (Table 1). The remaining 2 trials26,38 did not provide separate data for patients with and without diabetes. In the 27 included trials, there were 33 395 individuals with diabetes and 125 314 without diabetes (Table 1). Five trials2,10,29,30,40 (5326 participants) were conducted exclusively in patients with diabetes, 1 trial28 (n = 1094) was conducted exclusively in individuals without diabetes, and the remainder (21 trials with 152 289 participants) included a mean of 21% (range, 4%-38%) of individuals with diabetes.

COMPARATIVE EFFECTS OF TREATMENT IN PATIENTS WITH AND WITHOUT DIABETES

Twenty-two of the 27 included trials provided complete information about all 6 outcomes. Five trials15,27,32,36,37 did not provide data for heart failure exactly as defined in the protocol (hospitalized or fatal cases) and were excluded from the analyses of that outcome. Mean follow-up BP differences for each treatment comparison are given in Table 2.

Effects on Stroke, CHD, and Heart Failure

For the outcome stroke, there was no evidence of differences in the effects of the treatment regimens between patients with and without diabetes (Figure 1) except in the comparison that included ARB-based regimens (Figure 2). In this comparison, ARBs provided lesser protection to patients with diabetes compared with patients without diabetes (P = .05 by χ2 test of homogeneity). For the outcomes CHD and heart failure, there were no differences observed between patients with and without diabetes for any comparison (Figure 1), again except for the comparison that included ARBs (Figure 2). The ARBs this time provided significantly greater protection to patients with diabetes compared with those without diabetes for the outcome heart failure (P = .002 by χ2 test of homogeneity).

Effects on Total Major Cardiovascular Events, Cardiovascular Deaths, and Total Mortality

For none of these outcomes did the head-to-head comparisons between different drug classes provide any evidence of differences in the effects of ACE inhibitors, calcium antagonists, or diuretics/β-blockers (Figure 3B). However, there was some limited evidence that patients with diabetes achieved greater reductions in the risk of total major cardiovascular events (P = .03 by χ2 test of homogeneity) and cardiovascular deaths (P = .02 by χ2 test of homogeneity) with regimens targeting lower BP goals than those without diabetes (Figure 3A). There was also some evidence of a difference between the 2 patient groups in protection against cardiovascular death (P = .05 by χ2 test of homogeneity) and total mortality (P = .03 by χ2 test of homogeneity) favoring patients with diabetes in the comparison of ACE inhibitor–based regimens vs placebo (Figure 3A).

COMMENT

The overview results previously reported by this Collaboration42,43 have demonstrated broad comparability in the effects on major cardiovascular events of most classes of BP-lowering drugs and have implied a central role for BP reduction in producing the benefits observed. In general, the results reported herein seem to extend these findings to patients with diabetes and provide some evidence to support lower BP goals for this patient group.69,44 The data also suggest that clinicians may reasonably choose from a wide range of BP-lowering agents in their efforts to reduce the short- to medium-term risks of macrovascular complications in patients with diabetes. The overviews do not, however, fully characterize the effects of different BP-lowering regimens during the longer term, and neither do they incorporate estimates of effects on other outcomes of particular interest, such as renal function. Consequently, important benefits from the selective use of certain agents, such as those that antagonize the renin-angiotensin system, cannot be excluded.

Although there was broad comparability in the effects on total major cardiovascular events of the different regimens studied for patients with and without diabetes, there was some evidence of heterogeneity for selected comparisons and outcomes. This was most marked for ARBs, which seemed to afford greater protection against heart failure in patients with diabetes compared with those without diabetes. For this comparison there was a corresponding, although nonsignificant, trend for CHD but a finding in the opposite direction for stroke. Whether the greater observed effect on heart failure is attributable to BP reduction, BP-independent effects of regimens based on ARBs, or simply chance (only 1 trial41 contributed data for patients without diabetes) is unclear. Additional beneficial effects of regimens that antagonize the renin-angiotensin system have been postulated for patients with diabetes,10,40 but none of the other comparisons involving ACE inhibitor–based regimens showed corresponding greater protection against heart failure, CHD, or stroke for this patient group. For the outcome cardiovascular death, there was greater beneficial effect (of borderline statistical significance) for regimens based on ACE inhibitors compared with placebo and for more intensive vs less intensive regimens in patients with diabetes compared with those without. For the latter comparison, this might be explained by differences in the follow-up BP levels between randomized groups, but such differences would not account for the greater benefit of ACE inhibitors compared with placebo. In contrast, for the outcome total mortality, the observed greater benefits in patients with diabetes than in those without diabetes of more intensive vs less intensive BP-lowering regimens might be anticipated on the basis of a greater proportion of deaths being of cardiovascular cause in patients with diabetes, although this does not seem to explain the finding for ACE inhibitor–based regimens compared with placebo. Previously observed greater protective effects of diuretic-/β-blocker–based regimens compared with calcium antagonist–based regimens for the outcome of heart failure43 were observed for patients with and without diabetes (Figure 1B).

There was reasonable comparability in the age and baseline BP levels of patients with and without diabetes, and the baseline differences that did exist for these characteristics seem unlikely to have produced the heterogeneity in treatment effects observed.45,46 Whether differences in the proportion with other characteristics, such as established cardiovascular disease or renal impairment, might have affected the conclusions drawn cannot be established from these overviews. Chance is a likely explanation for at least some instances of heterogeneity because many comparisons were made and much of the heterogeneity was of only borderline statistical significance.47 Differences in the mean follow-up BP levels between randomized groups in patients with and without diabetes are another important consideration in the interpretation of these results because follow-up BP differences were not adjusted for in the analyses. Furthermore, the ability of these analyses to detect differences between regimens would have been diminished by incomplete adherence to randomized treatments and by the extensive use of add-on therapies. Blood pressure–independent effects of regimens may still be important for some outcomes, but these data suggest that for the prevention of major cardiovascular events, BP-independent effects unique to patients with diabetes do not provide a strong rationale for the selection of particular BP-lowering regimens for these patients.

These analyses included more than 17 000 major cardiovascular events and provided fairly precise estimates of the effects of the most widely used BP-lowering regimens on major vascular events separately for patients with and without diabetes. There are, however, several aspects of these analyses that limit their interpretation. First, these overviews have not defined the effects of the regimens on renal outcomes, the risk of new diabetes, or the progression of existing diabetes. These outcomes are a planned focus of future overviews using individual participant data from all contributing studies. It is possible that there may be important differences between regimens for these outcomes and that although any such differences do not seem to affect macrovascular events and death in the 3 to 6 years covered by these analyses (ie, a mean time to an event of only 1.5-3.0 years), effects on these outcomes may have longer-term implications yet to be uncovered. Second, the combined comparator group of diuretics and β-blockers might have concealed differences that would have been apparent if separate comparator groups of diuretics alone and β-blockers alone were used. Although repeating the relevant analyses first using only the trials in which the primary comparator was a diuretic and second using only the trials in which the primary comparator was a β-blocker identified no differences between the effects of the regimens in individuals with and without diabetes, note that the power for these analyses was more limited. Third, some studies selected patients on the basis of either the presence2,10,11,29,30 or the absence28 of diabetes. Repeating the overview analyses with these trials excluded resulted in estimates of effect suggesting greater benefits from more intensive therapy for individuals with diabetes compared with those without diabetes for the outcomes CHD and total mortality. There was also an apparently greater effect of ARBs on total mortality for patients with diabetes compared with those without diabetes. However, for each of these results there was only 1 trial that contributed to the estimates for patients without diabetes, and the reliability of these findings is uncertain.

In conclusion, small differences in the effects of regimens on macrovascular events cannot be excluded even by overviews of this magnitude, but it does seem that clinicians can be reassured that any of the major classes of BP-lowering agents are likely to produce substantial reductions in the short- to medium-term risks of the leading causes of death and disability in patients with diabetes. These findings should facilitate the management of BP in patients with diabetes because many individuals will require 2 or more agents to reach recommended targets. These data should also have important implications for the treatment of patients with diabetes in resource-poor settings, where the cost of BP-lowering agents may be a key consideration.

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Correspondence: Fiona Turnbull, MBChB, FAFPHM, Blood Pressure Lowering Treatment Trialists’ Collaboration, The George Institute for International Health, University of Sydney, Missenden Rd, PO Box M201, Sydney, New South Wales 2050, Australia (fturnbull@thegeorgeinstitute.org).

Accepted for Publication: January 21, 2005.

Financial Disclosure: Writing committee members have received honoraria and/or research funding from AstraZeneca, Servier, and Pfizer (Drs Turnbull, Neal, and MacMahon); Sanofi-Synthelabo (Drs Turnbull and Neal); and Bristol-Myers Squibb, Merck, Boehringer-Ingelheim, Bayer AG, GlaxoWellcome, and Solvay (Drs Neal and MacMahon). Dr Chalmers has received research grants from Servier for the PROGRESS and ADVANCE studies, administered through the University of Sydney, Sydney, Australia.

Funding/Support: The design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript were supported by grants and awards from the National Health and Medical Research Council of Australia, Canberra. Dr Neal is the recipient of a fellowship from the National Heart Foundation of Australia. Recent meetings of collaborators have been sponsored by AstraZeneca (Mölndal, Sweden), Bayer AG (Wuppertal, Germany), Boehringer-Ingelheim (Ingelheim am Rhein, Germany), Merck (Whitehouse Station, NJ), Pfizer (New York, NY), Servier (Neuilly-sur-Seine, France), and Solvay (Marietta, Ga).

Acknowledgment: We thank Craig Anderson, PhD; Hisatomi Arima, PhD; Ann Belmans, MSc; Simona Bruno, MD; Jan Buch, MD; Diane Catellier, William Elliott, MD, PhD; Lars Elvelin, BDS; Dag Elmfeldt, MD, PhD; Angelo Ferraro, Greg Grandits, MS; Eileen Handberg, PhD; Linda Hemphill, Patricia Kearney, MBBChBAO; Jan Lanke, PhD; Helen Merianos, Beverley Mullane, Chris Palmer, PhD; Vlado Perkovic, PhD; Janice Pogue, MSc; Neil Poulter, FRCP; Sara Pressel, MS; Denise Ramjit, Chris Reid, PhD; Irene Stratton, MSc; Lutgarde Thijs, MSc; Jiguang Wang, MD, PhD; Ingrid Warnold, PhD; Kate Wilson, DPhil; and Kristyn Willson, BSc(Hons), for their comments and contributions to this study.

Box Section Ref ID

Members of the Blood Pressure Lowering Treatment Trialists’ Collaboration

Larry Agodoa, MD; Colin Baigent, BM, BCh; Henry Black, MD; Jean-Pierre Boissel, MD; Barry Brenner, MD; Morris Brown, FMed Sci; Chris Bulpitt, MD; Robert Byington, MD, PhD; John Chalmers, MD, PhD; Rory Collins, FMedSci; Jeff Cutler, MD; Bjorn Dahlof, MD; Barry Davis, MD, PhD; Joseph Dens, MD, PhD; Ray Estacio, MD; Robert Fagard, MD, PhD; Kim Fox, MD; Lennart Hansson, MD (deceased); Rury Holman, FRCP; Lawrence Hunsicker, MD; Yutaka Imai, MD; John Kostis, MD; Kizuku Kuramoto, MD; Edmund Lewis, MD; Lars Lindholm, MD, PhD; Jacobus Lubsen, PhD; Stephen MacMahon, PhD; Ettore Malacco, MD; Giuseppe Mancia, MD, PhD; Bruce Neal, MRCP, PhD; Carl Pepine, MD, MACC; Marc Pfeffer, MD, PhD; Bertram Pitt, MD; Philip Poole-Wilson, FMedSci; Giuseppe Remuzzi, MD; Anthony Rodgers, MBChB, PhD; Piero Ruggenenti, MD; Robert Schrier, MD; Peter Sever, FRCP; Peter Sleight, MD; Jan Staessen, MD, PhD; Koon Teo, MD, PhD; Paul Whelton, MD; Lindon Wing, FRACP; Yoshiki Yui, MD, PhD; Salim Yusuf, MD, DPhil; and Alberto Zanchetti, MD, PhD. Executive Committee: Stephen MacMahon, PhD; Colin Baigent, BM, BCh; Jeff Cutler, MD; Robert Fagard, MD, PhD; Bruce Neal, MRCP, PhD; Paul Whelton, MD; and Salim Yusuf, MD, DPhil. Coordinating Centre: Charles Algert, MPH; John Chalmers, MD, PhD; Stephen MacMahon, PhD; Bruce Neal, MRCP, PhD; Fiona Turnbull, MB, ChB; and Mark Woodward, PhD. Writing Committee: Fiona Turnbull, MBChB, FAFPHM; Bruce Neal, MRCP, PhD; Charles Algert, MPH; John Chalmers, MD, PhD; Neil Chapman, MRCP; Jeff Cutler, MD; Mark Woodward, PhD; and Stephen MacMahon, PhD.

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