Degree of blood pressure reduction and recurrent stroke: the PROGRESS trial.

OBJECTIVE: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke. DESIGN: Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke. RESULTS: During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥ 20, 10-19, 0-9 and <0 mm Hg, respectively (p=0.0006 for trend). CONCLUSIONS: The present analysis provided no evidence of an increase in recurrent stroke associated with larger reductions in SBP produced by treatment among patients with cerebrovascular disease.

Effects of blood pressure lowering on intracranial and extracranial bleeding in patients on antithrombotic therapy: the PROGRESS trial.

BACKGROUND AND PURPOSE: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy. METHODS: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding. RESULTS: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg). CONCLUSIONS: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.

Effects of blood pressure lowering on major vascular events among patients with isolated diastolic hypertension: the perindopril protection against recurrent stroke study (PROGRESS) trial.

BACKGROUND AND PURPOSE: Despite clear evidence that blood pressure (BP) lowering is effective for prevention of cardiovascular events among patients with isolated systolic hypertension and systolic-diastolic hypertension, there is ongoing uncertainty about its effects in those with isolated diastolic hypertension. The objective of the present analysis is to determine whether BP lowering provides benefits to patients with isolated diastolic hypertension. METHODS: Patients with cerebrovascular disease and hypertension at baseline (n=4283) were randomly assigned to either active treatment (perindopril in all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcome was total major vascular events. RESULTS: There were 1923 patients with isolated systolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP < 90 mm Hg), 315 with isolated diastolic hypertension (systolic BP <140 mm Hg and diastolic BP ≥ 90 mm Hg), and 2045 with systolic-diastolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP ≥ 90 mm Hg) at baseline. Active treatment reduced the relative risk of major vascular events by 27% (95% CI, 10% to 41%) among patients with isolated systolic hypertension, by 28% (-29% to 60%) among those with isolated diastolic hypertension, and by 32% (17% to 45%) among those with systolic-diastolic hypertension. There was no evidence of differences in the magnitude of the effects of treatment among different types of hypertension (P homogeneity=0.89). CONCLUSIONS: BP lowering is likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension as for those with isolated systolic hypertension and systolic-diastolic hypertension. Clinical Trial Registration Information- This trial was not registered because patients were enrolled before July 1, 2005.

Perindopril-based blood pressure lowering reduces major vascular events in Asian and Western participants with cerebrovascular disease: the PROGRESS trial.

OBJECTIVE: To assess the benefits of blood pressure (BP) lowering on vascular events separately for Asian and for Western participants with particular emphasis on stroke subtypes and cardiac outcomes. METHODS: This is a subsidiary analysis of Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a randomized, placebo-controlled trial that established the benefits of BP lowering in 6105 patients with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, and indapamide for those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). Outcomes are total and cause-specific vascular outcomes. RESULTS: The annual rates for total major vascular events were 4.2% in Asian and 5.2% in Western participants. Overall stroke rates were greater in Asian compared to Western participants with proportionally more lacunar infarctions and haemorrhagic strokes in Asians and more cardio-embolic infarctions and large artery infarctions in Western participants. Active treatment reduced BP by 10.3/4.6 mmHg in Asian, and by 8.1/3.6 mmHg in Western participants. Among Asian participants there was a 38% [95% confidence interval (CI) 23-49%] reduction in major vascular events compared to a 20% (95% CI 7-31%) reduction in Western participants (P homogeneity = 0.06). Similarly, there were higher relative risk reductions for all other outcomes among Asian participants, but this only reached statistical significance for heart failure and vascular death (P = 0.02 for each). The number needed to treat for major vascular events over 5 years was 15 (95% CI 10-26) in Asian compared to 28 (95% CI 17-94) in Western participants (P homogeneity = 0.09). CONCLUSIONS: BP lowering reduces the risk of major vascular events, with separately significant reductions, in both Asia and the West.

Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial.

BACKGROUND AND PURPOSE: The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)-lowering. METHODS: Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP-lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). RESULTS: Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4). CONCLUSIONS: Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP-lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.

Effects of perindopril-based blood pressure lowering and of patient characteristics on the progression of silent brain infarct: the Perindopril Protection against Recurrent Stroke Study (PROGRESS) CT Substudy in Japan.

Controversy persists as to whether reducing the blood pressure of patients with a history of stroke leads to an increased risk of silent brain infarct (SBI) and dementia. A total of 667 patients were randomized to receive the angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg daily), with or without the diuretic indapamide (2 mg daily) or matching placebo(s). Brain CT scanning was performed annually over the mean follow-up period of 3.9 years. Active treatment reduced the blood pressure (systolic/diastolic) by 5.2/2.6 mmHg over the follow-up period. A total of 119 new SBI were detected and 92% of them were lacunar type small infarcts. The frequency of reaching the primary end-point (recurrent symptomatic stroke or new SBI) was similar in the placebo group (26.5%) and in the active treatment group (25.9%). There was no significant difference in brain atrophy indices between two groups. In the subgroup with a history of large artery infarction, 7 out of 55 patients from the placebo group developed new SBI, while none of the 40 patients from the active treatment group did so (p = 0.020). The baseline diastolic blood pressure was significantly associated with the risk of new SBI (p = 0.004), but the stroke subtype was not. In conclusion, blood pressure-lowering with a perindopril-based regimen did not increase the risk of SBI and brain atrophy in patients with a history of stroke. The baseline diastolic blood pressure was an independent predictor of new SBI, but the index stroke subtype did not influence the risk of SBI.

Effects of an angiotensin-converting enzyme inhibitor-based regimen on pneumonia risk.

Observational studies conducted among Asian populations suggest that the risk of pneumonia is substantially reduced among users of angiotensin-converting enzyme (ACE) inhibitors but not other blood pressure-lowering agents. We conducted analyses of the effects of ACE inhibitor therapy on pneumonia in 6,105 patients with a history of stroke or transient ischemic attack enrolled in a randomized trial conducted in Australasia, Europe, and Asia. Patients were randomly assigned perindopril-based active treatment or placebo. The effects of ACE inhibitors on pneumonia (fatal or nonfatal) were determined from Cox models fitted according to the principle of intention to treat. During a median follow-up of 3.9 years, 261 patients developed pneumonia. Overall, active treatment was associated with a nonsignificant 19% lower risk of pneumonia (95% confidence interval, -3 to 37; p = 0.09) compared with placebo. Active treatment significantly reduced the risk of pneumonia among participants of Asian ethnicity (47%, 14-67%; p = 0.01), with no significant effect among non-Asian participants (5%, -27 to 29%; p = 0.7) (p for homogeneity = 0.04). These findings substantially add to the body of evidence about the effects of these drugs on pneumonia but do not provide the definitive information required to inform clinical decisions about the prevention of pneumonia with ACE inhibitors.

Increase in pulse pressure relates to diabetes mellitus and low HDL cholesterol, but not to hyperlipidemia in hypertensive patients aged 50 years or older.

Higher pulse pressure is associated with higher cardiovascular risk. We investigated the relationship between pulse pressure and known metabolic risk factors in hypertensive patients who had not experienced stroke or myocardial infarction. In a multicenter cross-sectional survey made in 1995, we registered 939 hypertensive patients aged > or = 50 years. Of these, 734 had never experienced stroke or myocardial infarction. We divided these 734 patients into two groups based on the value of their pulse pressures: 396 patients with a pulse pressure > or = 60 mmHg, and 338 patients with a pulse pressure<60 mmHg. The average pulse pressure value was 72 +/- 12 mmHg in the former group, and 49 +/- 8 mmHg in the latter group. The former group exhibited advanced age, a higher women-to-men ratio, lower high-density lipoprotein (HDL) cholesterol, and higher systolic and lower diastolic blood pressure. Diabetes mellitus (DM) and left ventricular hypertrophy were more frequently noticed in the former group than in the latter group. The prevalence of hyperlipidemia, however, was similar in the two groups. The association of pulse pressure with DM and low HDL cholesterol was statistically significant by multiple logistic analysis adjusted for age, sex, and other known cardiovascular risk factors. In conclusion, pulse pressure increases with advancing age. DM made a substantially larger contribution to the increase in pulse pressure than hyperlipidemia.

Effects of alcohol consumption and restriction on home blood pressure in hypertensive patients: serial changes in the morning and evening records.

To study the time course of alcohol effects on blood pressure (BP), we examined morning and late evening home BP for 4 weeks in a regular alcohol consumption period and for 4 weeks in a alcohol restriction period in 30 Japanese men with essential hypertension (52 +/- 2 years, m +/- SE) in a randomized crossover study. Mean daily intake of alcohol were 66.5 +/- 4.7 and 10.2 +/- 1.9 ml, respectively. At the end of the regular alcohol period, morning BP had increased by 4.4 +/- 1.1/2.9 +/- 0.8 mmHg but evening BP had decreased by 7.4 +/- 1.9/5.7 +/- 1.7 mmHg. The depressor effect of alcohol on the evening BP was evident from day 1 to week 4, while the pressor effect on the morning BP was significant from week 2 regardless of the order of the two periods. These results confirm the biphasic effect of alcohol on BP, and suggest that the status of alcohol intake may markedly influence the morning-evening BP difference.