PROGRESS: Prevention of Recurrent Stroke

STATE OF THE ART REVIEW SERIES REVIEW PAPER PROGRESS: Prevention of Recurrent Stroke Hisatomi Arima, MD, PhD; John Chalmers, MD, PhD From The George Institute for Global Health, University of Sydney and the Royal Prince Alfred Hospital, Sydney, Australia The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized placebo-controlled trial which clearly demonstrated that perindopril-based blood pressure (BP) lowering treatment is one of the most effective and generalizable strategies for secondary prevention of stroke. Beneficial effects of BP lowering were observed on recurrent stroke, other cardiovascular events, disability, dependency, and cognitive function across a variety of subgroups defined by age, sex, geographical region, body mass index, diabetes, atrial fibrillation, chronic kidney disease, and baseline BP levels. Once patients with stroke have stabilized, all patients should receive BP-lowering therapy irrespective of their BP levels. On the basis of recommendations from current international guidelines, BP should be lowered to <140 90 mm Hg in all patients with cerebrovascular disease and to <130 80 mm Hg if therapy is well tolerated. J Clin Hypertens (Greenwich). 011;13;693 70. Ó011 Wiley Periodicals, Inc. Annually, 15 million people experience strokes globally. 1 Of these, 5 million die and another 5 million are left permanently disabled, placing a burden on family and community. 1 Among those who survive a stroke or a transient ischemic attack (TIA), the risk of further stroke is very high.,3 Stroke survivors also face increased risks of other manifestations of atherosclerosis and degenerative vascular disease, such as coronary heart disease, 3,4 peripheral vascular disease, and cognitive decline. 5,6 While the incidence rate of stroke is declining in many developed countries, the absolute number of stroke continues to increase globally due to progressive aging of populations. 1,7 Elevated blood pressure (BP) is the most important modifiable risk factor for stroke 8 and there is now strong evidence from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) and other randomized controlled trials that BP-lowering treatment is one of the most effective interventions for both primary and secondary prevention of stroke. 9,10 Furthermore, BP-lowering treatment provides the only proven strategy for the secondary prevention of intracerebral hemorrhage. This article will review the results obtained from the PROGRESS trial focusing on BP-lowering treatment for secondary prevention of stroke. RANDOMIZED TRIALS BEFORE PROGRESS Randomized trials have clearly demonstrated that BPlowering treatment reduces the risk of initial stroke. 10 In contrast, before the results of PROGRESS were published in 001, there was little convincing Author for Correspondence: John Chalmers, MD, PhD, The George Institute for Global Health, PO Box M01, Missenden Road, NSW 050, Australia E-mail: jchalmers@georgeinstitute.org.au Manuscript received: May 1, 011; Revised: July 1, 011; Accepted: July 1, 011 DOI: 10.1111/j.1751-7176.011.00530.x evidence that BP-lowering treatment would reduce the incidence of recurrent stroke in patients with cerebrovascular disease. Some evidence was provided in the mid-1990s by a preliminary report from a randomized trial of diuretics among 5665 individuals with a history of cerebrovascular disease (the Post- Stroke Antihypertensive Study [PATS]) 11 and by a systematic review of subsets of stroke survivors in randomized trials of BP-lowering treatment performed by the Individual Data Analysis of Antihypertensive Intervention Trials (INDANA) Project Collaborators. 1 PATS suggested that BP-lowering treatment with the diuretic indapamide reduced the risk of recurrent stroke by 7% (95% confidence interval [CI], 11% 40%). 11 The systematic review by IN- DANA Project Collaborators suggested that BP-lowering treatment would reduce the risk of recurrent stroke by 8% (95% CI, 15% 39%) in mainly hypertensive patients with prior cerebrovascular disease. 1 However, these data were insufficient to determine the benefits of BP lowering in normotensive patients with cerebrovascular disease. MAIN RESULTS OF PROGRESS Issues raised from early trials were resolved at the start of the new century by the completion of the PRO- GRESS trial. 9 The PROGRESS trial was a randomized placebo-controlled trial that clearly established the benefits of perindopril-based BP lowering in a heterogeneous group of patients with cerebrovascular disease. A total of 6105 patients with prior stroke or TIA was randomly assigned to either active treatment (an angiotensin-converting enzyme [ACE] inhibitor, perindopril [4 mg daily], for all participants plus a diuretic, indapamide [ to.5 mg daily], for those with neither an indication for, nor a contraindication to, a diuretic) or matching placebo(s). Over a mean follow-up of 4 years, the overall relative risk of recurrent stroke was reduced by 8% (95% CI, 17% 38%) in the Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 No 9 September 011 693

A B Proportion With Stroke, % Proportion With Major Coronary Event, % 0 10 0 6 4 0 Relative risk reduction 8% P<.0001 0 1 3 4 Follow-Up, y Relative risk reduction 6% P=.0 0 1 3 4 Follow-Up, y FIGURE 1. Cumulative incidence of stroke (A) and major coronary events (B) among participants assigned active treatment and those assigned to placebo. Reproduced with permission from Elsevier and Oxford University Press. 9,13 active treatment group compared with the placebo group (Figure 1A and Figure ). PROGRESS trial also demonstrated that the benefits of treatment were comparable for patients that were and were not hypertensive at baseline, using a cut off of 160 90 mm Hg in accord with the evidence available in 1994 when the trial was initiated. This resolved the issue in normotensive patients with cerebrovascular disease that previous trials had left unanswered. Beneficial effects of BP lowering were also observed for key secondary outcomes. treatment reduced the risk of major coronary events by 6% (95% CI, 6% 4%), that of congestive heart failure by 6% (95% CI, 5% 4%), and that of major vascular events by 6% (95% CI, 16% 34%) (Figure 1B and Figure ). 9,13 Beneficial effects of BP lowering was also observed for the risks of long-term disability (relative risk reduction [RRR], 4%; 95% CI, 11% 35%) and dependency (RRR, 16%; 95% CI, 1% 9%), although these benefits were due largely to a reduction in recurrent stroke (Figure ). 14 There were no significant differences between randomized groups in total deaths and deaths from vascular causes (Figure ). 9 In the PROGRESS trial, combination therapy with perindopril plus indapamide produced consistently larger reductions in the risk of stroke (43%; 95% CI, 30% 54%) compared with single-drug therapy with perindopril (5%; 95% CI, )19% to 3%, nonsignificant reduction) and it is likely that the large differences in treatment effect represent the benefits of greater BP reduction with combination therapy with perindopril plus indapamide compared with singledrug therapy with perindopril (1 5 mm Hg vs 5 3 mm Hg). 9 An economic evaluation of the PROGRESS trial has demonstrated that the incremental cost per qualityadjusted life-year (QALY) for BP-lowering treatment is 697 British pounds ( ) for the duration of the study (4 years). 15 The lifetime incremental cost per QALY is 10,133, suggesting that BP-lowering treatment is a cost-effective strategy for secondary prevention of stroke. EFFECTS OF BP LOWERING ON STROKE SUBTYPES PROGRESS has also investigated the effects of BP lowering on the risks of different types of stroke (Figure 3). There were broadly beneficial effects of perindopril-based BP lowering on different types of stroke: RRR 4% (95% CI, 10% 35%) for total ischemic stroke and 50% (95% CI, 6% 67%) for intracerebral hemorrhage. 9,16 In regard to ischemic stroke subtypes, active treatment reduced the risk of lacunar infarction by 3% (95% CI, )7% to 44%), that of cardioembolic infarction by 3% (95% CI, )38% to 57%), and that of large artery infarction by 39% (95% CI, 5% 61%). 16 Comparable effects of BP lowering were also observed for intracerebral hemorrhage related to amyloid angiopathy (RRR, 77%; 95% CI, 19% 93%) and that related to hypertension (RRR, 46%; 95% CI, 4% 69%). 17 These findings suggest that BP lowering is likely to be a generalizable strategy for secondary prevention of stroke across a variety of subtypes. EFFECTS OF BP LOWERING ON COGNITIVE FUNCTION Another important outcome reported from the PRO- GRESS trial was cognitive function, because high BP and stroke are associated with increased risks of dementia and cognitive decline. 5,6,18,19 Perindoprilbased BP-lowering treatment reduced the risk of dementia by 1% (95% CI, )8% to 8%) and that of cognitive decline by 19% (95% CI, 4% 3%) (Figure 4). 0 The risks of the composite outcomes of dementia with recurrent stroke and cognitive decline with recurrent stroke were reduced by 34% (95% CI, 3% 55%) and 45% (95% CI, 1% 61%), respectively, while there were no clear effects on either dementia or cognitive decline in the absence of recurrent stroke. Combination therapy with perindopril plus indapamide produced significant reductions in the risks of dementia (3%; 95% CI, 0% 41%) and cognitive decline (%; 95% CI, % 38%), while single-drug therapy with perindopril had no clear effects 694 The Journal of Clinical Hypertension Vol 13 No 9 September 011 Official Journal of the American Society of Hypertension, Inc.

Number of Events (n=3051) (n=3054) Risk Reduction (95% CI) Stroke 307 40 8% (17 to 38%) Major coronary events Heart failure Major vascular events 115 113 458 154 151 604 6% (6 to 4%) 6% (5 to 4%) 6% (16 to 34%) Total disability Disability with recurrent stroke Other disability 571 105 466 67 16 510 4% (11 to 35%) 36% (18 to 50%) 11% (-5 to 5%) Total dependency Dependency with recurrent stroke Other dependency 36 91 71 47 16 301 16% (1 to 9%) 7%(4 to 45%) 8% (-1 to 4%) Vascular death Total death 181 306 198 319 9% (-1 to 5%) 4% (-1 to 18%) 0.5 0.5 1 Relative Risk, 95% CI FIGURE. Effects of blood pressure lowering on serious clinical outcomes. Solid boxes represent estimates of relative risk of outcomes (hazard ratio for stroke, major coronary events, heart failure, major vascular events, vascular death and total death, and odds ratio for disability and dependency). Unfilled boxes represent subtypes of disability and dependency; areas of the boxes are proportional to the inverse variance of the estimates. Vertical lines represent 95% confidence intervals (CIs). Adapted from previously published figures with permission from Elsevier, Oxford University Press and Wolters Kluwer Health. 9,13,14 Number of Events (n=3051) (n=3054) Risk Reduction (95% CI) Total ischemic stroke 46 319 4% (10 to 35%) Lacunar infarction Cardioembolic infarction Large artery infarction 64 0 3 83 6 5 3% (-7 to 44%) 3% (-38 to 57%) 39% (5 to 61%) Unknown ischemic stroke Total ICH Probable CAA-related ICH 150 37 3 184 74 13 19% (0 to 35%) 50% (6 to 67%) 77% (19 to 93%) Probable HT-related ICH Unclassified ICH Stroke of unknown type 18 16 4 33 8 51 46% (4 to 69%) 43% (-5 to 69%) 18% (-4 to 45%) Total stroke 307 40 8% (17 5o 38%) 0.5 0.5 1 Hazard Ratio, 95% CI FIGURE 3. Effects of blood pressure lowering on different types of stroke. CI indicates confidence interval; ICH, intracerebral hemorrhage; CAA, cerebral amyloid angiopathy; HT, hypertension. Solid boxes represent estimates of hazard ratio of total ischemic stroke, ICH, stroke of unknown type, and total stroke. Unfilled boxes represent subtypes of ischemic stroke and ICH. Adapted from previously published figures with permission from Wolters Kluwer Health. 6,17 on dementia ()8%; 95% CI, )48% to 1%) or cognitive decline (15%; 95% CI, )8% to 34%, respectively). Again, these differences are likely to represent the benefits of greater BP reduction with combination therapy compared with single-drug therapy (1 5 mm Hg vs 5 3 mm Hg). BP lowering also attenuated the progression of white matter hyperintensities on magnetic resonance imaging, 1 which is strongly associated with incidence of dementia and cognitive decline. These findings suggest that BP-lowering treatment is likely to Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 No 9 September 011 695

Number of Events Risk Reduction (n=3051) (n=3054) (95% CI) Dementia Effects in all participants Total dementia 193 17 1% (-8 to 8%) Dementia with recurrent stroke 43 65 34% (3 to 55%) Other dementia 150 15 1% (-4 to %) Effects in subgroups Combination therapy 106 136 3% (0 to 41%) Single drug therapy 87 81-8% (-48 to 1%) Cognitive decline Effects in all participants Total cognitive decline 76 334 19% (4 to 3%) Cognitive decline with recurrent stroke 48 86 45% (1 to 61%) Other cognitive decline 8 48 9% (-10 to 4%) Effects in subgroups Combination therapy 144 181 % ( to 38%) Single drug therapy 13 153 15% (-8 to 34%) 0.5 0.5 1 Odds Ratio, 95% CI FIGURE 4. Effects of blood pressure lowering on dementia and cognitive decline. Combination therapy indicates perindopril plus indapamide, while single-drug therapy indicates perindopril alone. Solid boxes represent estimates of odds ratio of dementia and cognitive decline. Unfilled boxes represent effects on subtypes of dementia and cognitive decline or effects in subgroups. CI indicates confidence interval. Adapted from previously published figures with permission from the American Medical Association. 0 be an effective strategy for attenuation of decline in cognitive function, particularly that associated with recurrent stroke, among patients with prior cerebrovascular disease. EFFECTS OF BP LOWERING IN CLINICALLY IMPORTANT SUBGROUPS A number of subsidiary analyses of the PROGRESS trial demonstrated beneficial effects of perindoprilbased BP lowering across clinically important subgroups (Figure 5). There was clear evidence of reductions in stroke risks in each patient group defined by demographic factors such as age, sex, and geographical region. 3,4 Comparable treatment effects on the risks of recurrent stroke were also observed for all major clinical subgroups defined by body mass index (BMI), 5 diabetes, 6 atrial fibrillation, 7 and chronic kidney disease. 8 A subsidiary analysis also demonstrated that BP lowering was likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension (RRR, 8%; 95% CI, )9% to 60%) as for those with isolated systolic hypertension (RRR, 7%; 95% CI, 10% 41%) and systolic-diastolic hypertension (RRR, 3%; 95% CI, 17% 45%). 9 These results suggest that BP lowering is one of the most effective and generalizable strategies for secondary prevention of stroke. THRESHOLD FOR BP LOWERING AND OPTIMAL TARGET BP IN SECONDARY PREVENTION OF STROKE Large-scale observational studies have demonstrated clear associations between BP and initial stroke. 30,31 A systematic review of observational studies performed by the Prospective Studies Collaboration demonstrated that lower BP levels are continuously associated with lower risks of fatal stroke down to very low BP levels (as low as 115 75 mm Hg). 30 A continuous relationship of BP with the outcome fatal and nonfatal stroke was also observed down to levels as low as 115 75 mm Hg in a systematic review performed by the Asia Pacific Cohort Studies Collaboration. 31 More limited evidence from studies in patients with a history of cerebrovascular disease has also suggested that lower BP levels are associated with lower risks of stroke recurrence. A large-scale observational study demonstrated that the relationship between BP levels and recurrent stroke was strong and continuous down to levels of 130 80 mm Hg. 3 In addition, an observational analysis of PROGRESS showed that the lowest risk of recurrent stroke was observed amongst individuals who achieved a followup BP of approximately 115 75 mm Hg (Figure 6). 33 Similar relationships were observed for both ischemic stroke and intracerebral hemorrhage (Figure 6) 33 and 696 The Journal of Clinical Hypertension Vol 13 No 9 September 011 Official Journal of the American Society of Hypertension, Inc.

Age <65 years 65 years Sex Male Female Region Asia Europe + ANZ BMI <3.1 kg/m 3.1 to 5.3 kg/m 5.4 to 7.8 kg/m 7.9 kg/m Diabetes Diabetes No diabetes Atrial fibrillation Atrial fibrillation No atrial fibrillation Estimated GFR <60 ml/min 60 ml/min Number of Events 107 00 85 118 189 91 7 76 68 48 59 33 74 11 194 187 33 99 11 18 38 99 100 106 115 65 355 44 376 15 66 Risk Reduction (95% CI) 43% (8 to 55%) 18% (1 to 33%) 7% (14 to 39%) 33% (11 to 50%) 39% ( to 5%) % (5 to 35%) 0% (-7 to 40%) 6% (-1 to 46%) 3% (7 to 49%) 41% (0 to 57%) 38% (8 to 58%) 8% (16 to 39%) 34% (-13 to 61%) 8% (16 to 39%) 35% (17 to 50%) 7% (1 to 39%) P Homogeneity 0.0 0.6 0.1 0.07 0.5 08 0.8 0.7 0.5 0.5 1 Hazard Ratio, 95% CI FIGURE 5. Effects of blood pressure lowering on stroke among major clinical subgroups. CI indicates confidence interval; ANZ, Australia and New Zealand; BMI, body mass index; GFR, glomerular filtration rate. Solid boxes represent estimates of hazard ratio of stroke. Adapted from previously published figures with permission from Wolters Kluwer Health, Taylor & Francis A B and American Society of Nephrology. 3 8 Ischemic Stroke 8 0.3 Intracerebral Hemorrhage 0.16 Annual Rate, % 4 0.08 0.04 0.0 1 0.01 100 10 140 160 180 Systolic Blood Pressure, mm Hg 100 10 140 160 180 Systolic Blood Pressure, mm Hg FIGURE 6. Annual rates of ischemic stroke and intracerebral hemorrhage according to achieved follow-up systolic blood pressure levels. Annual incidence rates and P values were controlled for age, sex, smoking, diabetes, study treatment, and combination therapy. Solid boxes represent estimates of annual incidence rates of stroke. Centers of the boxes are placed at the estimates of annual incidence rates and at median values of systolic blood pressure. Areas of the boxes are proportional to the number of events. Vertical lines represent 95% confidence intervals. P trend =.0005 for ischemic stroke, <.0001 for intracerebral hemorrhage. Reproduced with permission from Wolters Kluwer Health. 33 both in patients with and without chronic kidney disease. 34 Each 10-mm Hg reduction in systolic BP (SBP) was associated with a 8% lower risk of stroke recurrence. 3 These observational data suggest that lower BP levels are continuously associated with lower risks of both initial and recurrent stroke, down to very low BP levels (115 mm Hg systolic). Although intensive BP lowering towards this level may be beneficial in primary and secondary prevention of stroke, such optimal targets are unlikely to be established without additional positive findings from randomized controlled trials. Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 No 9 September 011 697

In this respect, a subsidiary analysis of the PRO- GRESS trial investigated the effects of randomized treatment on recurrent stroke by baseline BP levels (Figure 7). 33 BP lowering with combination therapy of perindopril plus indapamide produced similar risk reductions in each of subgroups defined by baseline SBP of <10 mm Hg, 10 to 139 mm Hg, 140 to 159 mm Hg, and 160 mm Hg (P homogeneity=0.5) and those defined by baseline diastolic BP of <80 mm Hg, 80 to 89 mm Hg, 90 to 99 mm Hg, and 100 mm Hg (P homogeneity=0.). The effects of single-drug therapy with perindopril alone were also comparable across these subgroups (P homogeneity=0. and 0.8 for systolic and diastolic BP, respectively), but consistently greater benefits were observed with combination compared with single-drug therapy. Recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial demonstrated that intensive therapy targeting a SBP of <10 mm Hg was associated with 41% (95% CI, 11% 61%) lower risks of initial stroke among 4733 patients with type diabetes, 35 supporting the concept of such treatment for primary prevention of stroke. Further definitive evidence of intensive BP lowering for secondary prevention of stroke will be provided by ongoing trials such as the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial and Recurrent Stroke Prevention Clinical Outcome Study (RESPECTS). Meanwhile, it is clear that BP-lowering treatment should be considered routinely for patients with a history of stroke or TIA, irrespective of their BP. Furthermore, in keeping with the current international guidelines, 36,37 we would recommend that BP should be lowered to <140 90 mm Hg in all patients with stroke or TIA and to <130 80 mm Hg if therapy is well tolerated. PATIENTS WITH LARGE ARTERY STENOSIS A contentious area of BP-lowering treatment for secondary prevention of stroke is the risk and benefits in patients with severe large-artery occlusive disease. Among patients with severe large-artery occlusive disease, cerebral perfusion may depend on BP and BPlowering treatment may lead to ischemic stroke via hemodynamic mechanisms. An observational study of the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial investigated the association between BP and ischemic stroke among 567 patients with cerebrovascular disease due to angiographically verified 50% to 99% stenosis of a large artery. 38 Among patients with moderate large-artery stenosis (50% to 69%), SBP was associated with increased risk of ischemic stroke. Among patients with severe large artery stenosis (70% to 99%), in contrast, SBP was not significantly associated with the risk of ischemic stroke. Furthermore, a meta-analysis of the European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET) investigated the association of SBP and stroke among patients with cerebrovascular disease and severe, symptomatic stenosis (70%) in both carotid arteries and found that lower SBP was associated with increased risks of stroke. 39 These results suggest that intensive BP lowering may be harmful among patients with severe, symptomatic stenosis in both sides of large arteries, although such patients represent only a few percent of patients with cerebrovascular disease. Number of Events Risk Reduction P (95% CI) Homogeneity Systolic blood pressure 160 mm Hg 57 106 47% (7 to 6%) 0.5 140 to 159 mm Hg 10 to 139 mm Hg <10 mm Hg 54 37 87 58 4 41% (16 to 58%) 41% (11 to 61%) 36% (-49 to 88%) Diastolic blood pressure 100 mm Hg 16 40 64 %(35 to 80%) 0. 90 to 99 mm Hg 89 to 90 mm Hg <80 mm Hg 53 5 49 84 85 46 41% (17 to 58%) 39% (14 to 57%) 38%(1to61%) 0.5 0.5 1 Hazard Ratio, 95% CI FIGURE 7. Effects of blood pressure lowering with combination therapy of perindopril plus indapamide on stroke by baseline blood pressure. Solid boxes represent estimates of hazard ratio of stroke. CI indicates confidence interval. Adapted from previously published figures with permission from Wolters Kluwer Health. 33 698 The Journal of Clinical Hypertension Vol 13 No 9 September 011 Official Journal of the American Society of Hypertension, Inc.

RANDOMIZED TRIALS AFTER PROGRESS Several randomized controlled trials completed after PROGRESS have reported the effects of BP lowering on recurrent stroke. The first head-to-head comparison of different classes of BP-lowering drugs was conducted by the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) trial. 40 The main results of the MOSES trial were published in 00 and suggested that an angiotensin receptor blocker (ARB), eprosartan, was superior to a calcium antagonist, nitrendipine, in reducing recurrent stroke despite similar achieved follow-up BP levels between randomized groups. However, the strength of this evidence is somewhat limited because of the small number of events observed and a nonstandard approach for statistical analysis. A subgroup analysis of the Study on Cognition and Prognosis in the Elderly (SCOPE) demonstrated that an ARB, candesartan, reduced the risks of recurrent stroke by 38% (95% CI, 1% 85%) among 193 patients with prior stroke, while there was no clear BP reduction (+0.4 )1.5 mm Hg). 41 The Felodipine Event Reduction (FEVER) study also demonstrated a trend towards reduction in recurrent stroke in a subset of 368 patients with a history of stroke or TIA (RRR, 18%; 95% CI, )1% to 40%), associated with a modest reduction in BP (4.0 1.8 mm Hg), obtained with a calcium antagonist felodipine. 4 While many trials completed after PROGRESS have broadly confirmed our findings, the results of the Prevention Regimen For Effectively Avoiding Second Strokes (PRo- FESS) study, 43 which was published in 008, were less positive. The PRoFESS trial investigated the effects of the ARB telmisartan in addition to standard care for secondary prevention of stroke among 0,3 patients with recent ischemic stroke. treatment lowered BP by 4 mm Hg and reduced the risk of recurrent stroke by 5% (95% CI, )4% to 14%). Although telmisartan did not confirm significant benefit, factors that might have contributed to the negative outcome include the small difference in BP between randomized groups, the good background care, and the frequent use of ACE inhibitors (37%) that had already achieved a moderate degree of BP control at baseline (144 84 mm Hg). Our updated meta-analysis of 16 randomized controlled trials including PROGRESS and PRoFESS, with a total of 40,9 patients, demonstrates that BP-lowering treatment clearly reduced the risk of recurrent stroke (RRR, 18%; 95% CI, 9% 6%) (Figure 8). A meta-regression analysis also suggests that each 10- mm Hg reduction in SBP is associated with 33% (95% CI, 9% 51%) reduction in the risks of recurrent stroke (Figure 9). This is consistent with findings from observational studies, in which there was a 8% lower risk of stroke associated with each 10-mm Hg reduction in SBP. 3 Thus, the totality of the evidence, including the findings from PRoFESS, confirms that BP-lowering treatment reduces the risk of stroke recurrence among patients with cerebrovascular disease. 1 st Listed nd Listed Year Event N Event N 1 st Listed nd Listed Relative Risk (95% CI) vs control Carter 1970 10 50 HSCSG 1974 37 33 Dutch TIA 1993 5 73 TEST 1995 81 37 PATS 1995 159 841 INDANA 1997 EWPHE 5 35 Coope 11 HDFP 15 136 SHEP 8 59 STOP 1 31 HOPE 000 43 500 PROGRESS 001 307 3051 SCOPE 003 6 97 FEVER 005 66 1136 PRoFESS 008 880 10146 Subtotal Test for homogeneity: chi-square=3.03, df=14 (P=.06) Test for overall effect: Z=3.70 (P<.001) 1 4 6 75 17 9 1 16 7 4 51 40 15 87 934 49 19 741 348 84 8 6 138 40 35 513 3054 97 13 10186 0.47 (0.5-0.89) 0.83 (0.55-1.4) 0.85 (0.60-1.1) 1.01 (0.77-1.33) 0.73 (0.60-0.89) 0.44 (0.17-1.18) 1.09 (0.1-9.70) 0.95 (0.49-1.85) 0.78 (0.31-1.97) 0.8 (0.03-. 39) 0.87 (0.59-1.7) 0.73 (0.64-0.84) 0.40 (0.16-0.99) 0.8 (0.60-1.1) 0.95 (0.87-1.03) 0.81 (0.73-0.91) ARB vs CCB MOSES 005 80 681 89 671 089(067118).. -. Total Test for homogeneity: chi-square=3.09, df=15 (P=.08) Test for overall effect: Z=3.87 (P<.001) 0.8 (0.74-0.91) 0.5 0.5 1.0.0 Relative Risk, 95% CI FIGURE 8. Meta-analysis of 16 randomized controlled trials of blood pressure lowering for secondary prevention of stroke. 9,11,1,40 43,46 Solid boxes represent estimates of trials. Diamonds represent estimates and 95% confidence intervals (CIs) for overall effects. Overall estimates of effect and 95% CI were calculated using random-effects models and inverse variance weighting. See text for trial name expansions. Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 No 9 September 011 699

Relative Risk, 95% CI 1 05. 0.5 Reduction in risk for each 10-mm Hg reduction 33% (95% CI% 9 to 51%), P=.04 HOPE PROGRESS PATS DutchTIA PRoFESS DIFFERENT CLASSES OF BP-LOWERING DRUGS IN PREVENTION OF STROKE BP-Lowering Treatment Trialists Collaboration (BPLTTC) conducted a systematic review comparing regimens based on different drug classes. 10 There was a trend towards a greater risk reduction with regimens based on diuretics or b-blockers compared with regimens based on ACE inhibitors (9%; 95% CI, 0% 18%), and trends towards greater reductions with regimens based on calcium antagonists compared with those based on diuretics or blockers (7%; 95% CI, )1% to 14%) or with those based on ACE inhibitors (1%; 95% CI, 1% 5%). However, weighted mean BP differences between randomized groups were directly associated with differences in risks of stroke. With regard to the role of b- blockers, there has been much debate driven by suggestions that b-blockers are less effective in preventing cardiovascular disease, particularly in older patients. 44,45 For the primary prevention of stroke, BP reduction appears to be generally more important than choice of BP-lowering regimen for reducing the risk of stroke. There are insufficient data to determine whether one class of drugs is superior to another in the secondary prevention of stroke. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the risk of recurrent stroke by approximately 5% among a subgroup of 1013 patients with history of cerebrovascular disease. 46 PROGRESS has clearly demonstrated the beneficial effects of combination therapy with the ACE inhibitor perindopril plus the diuretic indapamide in the secondary prevention of stroke. 9 Clinicians wishing to practice in accord with the tenets of evidence-based medicine should use combination therapy with ACE inhibitors plus thiazide-like diuretics, such as indapamide, which was shown to be effective in PRO- GRESS, 9 unless there are contraindications. FEVER TEST MOSES SCOPE -15-10 -5 0 5 Reduction in Systolic Blood Pressure, mm Hg FIGURE 9. Meta-regression analysis of 9 randomized controlled trials of blood pressure lowering 9,11,40 43,46 to investigate association of reduction in systolic blood pressure with risk reduction for recurrent stroke. Nine randomized controlled trials for secondary prevention of stroke published after 1990 with information on reduction in systolic blood pressure were included. The area of each circle is proportional to inverse variance of log relative risk. The fitted line represents summary meta-regressions for recurrent stroke. CI indicates confidence interval. Calcium antagonists also require consideration for secondary prevention of stroke. The systematic review of BPLTTC showed trends towards greater efficacy of calcium antagonists compared with other drug classes for primary prevention of stroke although these trends may have reflected greater BP reduction with calcium antagonists. 10 The FEVER trial has also demonstrated modest reduction in recurrent stroke associated with the calcium antagonist felodipine. 4 Therefore, it would seem reasonable to use a calcium antagonist in patients who are not suitable for treatment with an ACE inhibitor. In regard to ARBs, the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study demonstrated that the ARB losartan prevented more first-ever strokes than a b-blocker atenolol (RRR, 6%; 95% CI, 1% 37%). 47 The MOSES trial suggested that the ARB eprosartan was superior to the calcium antagonist nitrendipine in reducing recurrent stroke. 40 The SCOPE trial also demonstrated beneficial effects of the ARB candesartan on recurrent stroke. 41 However, the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trial did not show significant reduction in first-ever stroke among 596 patients with high cardiovascular risk. 48 The PRoFESS trial also failed to demonstrate the beneficial effects of the ARB telmisartan in secondary prevention of stroke. 43 Therefore, there is still considerable uncertainty surrounding the role of ARBs in secondary prevention of stroke. CONCLUSIONS The PROGRESS trial has clearly demonstrated beneficial effects of perindopril-based BP-lowering treatment on recurrent stroke, other cardiovascular events, disability, dependency, and cognitive function in a heterogeneous group of patients with prior stroke or TIA. As BP-lowering treatment produced similar risk reductions across a wide range of baseline BP levels, all patients who have had a completed stroke or TIA should receive BP-lowering therapy irrespective of their BP levels. On the basis of the totality of evidence presently available, and in keeping with the current international guidelines, 36,37 we would recommend that BP should be lowered to <140 90 mm Hg in all patients with stroke or TIA and to <130 80 mm Hg if therapy is well tolerated. SOURCE OF FUNDING The PROGRESS Study was funded by grants from Servier, the Health Research Council of New Zealand, and the National Health and Medical Research Council (NHMRC) of Australia. Disclosures: HA holds ARC Future Fellowship from the Australian Research Council. JC has received lecture fees and research grants from Servier, administered through the University of Sydney as Co-Principal Investigator for PROGRESS and ADVANCE. The authors received no honoraria for their contribution to this issue. 700 The Journal of Clinical Hypertension Vol 13 No 9 September 011 Official Journal of the American Society of Hypertension, Inc.

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