Table 2:

Brief Overview of Select Observational, Randomized Controlled Trial and Meta-Analysis Studies Addressed in the Viewpoint^*

Observational Cohort Analysis

Adults Screened for Participation in the Multiple Risk Factor Intervention Trial (MRFIT) [6]

Overview: Non-concurrent prospective analysis of the association between blood pressure (BP) and mortality from coronary heart disease (CHD) and stroke during an average follow-up of 11.6 years in a cohort of 347,978 men with no history of hospitalization for myocardial infarction who were screened for possible participation in MRFIT.

Primary outcomes: mortality from CHD or stroke, including subarachnoid hemorrhage, intracranial hemorrhage, non-hemorrhagic strokes, and transient ischemic attacks (TIAs).

Demographics: men aged 35-57 years (average 46 years) at baseline; 312,998 White, 22,471 Black, 8,511 Hispanic, 4,257 Asian participants.

Randomized Controlled Trials

Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT2) [9]

Overview: 2,839 participants with spontaneous intracranial hemorrhage (ICH) within 6 hours of onset who had elevated BP (150 to 220 mmHg) were randomized to open-treatment (blinded end point) with either intensive BP lowering (goal <140 mmHg) within 1 hour or guideline-recommended treatment (goal <180 mmHg) using BP lowering agents according to the physician’s choice.

Primary outcome: death or major disability (modified Rankin Scale [mRS] score of 3-6) at 90 days.

Secondary outcome: A pre-specified mRS ordinal analysis.

Demographics: mean age 63.5 years, men 62.9%, and Chinese enrollees 67.7%.

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-2) [10]

Overview: 1,000 participants with ICH (volume <60cm3) and a Glasgow Coma Score of 5 or more were randomized to open-label treatment with a systolic blood pressure (SBP) goal of either 110-139 mmHg (intensive therapy) or 140-179 mmHg (standard therapy) within 4.5 hours of symptom onset to test the superiority of intensive BP lowering over standard BP lowering. Participants had a SBP measurement after symptom onset and before study treatment of 180 mmHg or greater. Intravenous nicardipine was the main intervention for intensive BP lowering.

Primary outcome: death or disability (defined as mRS of 4-6) at 3 months.

Demographics: mean age 61.9 years, men 60.8%, and Asian enrollees 56.2%.

China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) [12]

Overview: 4,071 participants enrolled in a single-blind (blinded end points) RCT to evaluate immediate BP lowering in acute ischemic stroke (AIS) within 48 hours of stroke onset by achieving BP lowering of 10% to 25% within 24 hours, <140/90 mmHg within 7 days, and maintenance of the BP level during hospitalization compared to discontinuation of all antihypertensives (control) during hospitalization. Several antihypertensive agents, including intravenous enalapril (1st), a calcium channel blocker (2nd), and a diuretic (3rd) could be used individually or in combination to achieve the BP target.

Primary outcome: death and major disability (mRS score 3 or higher) at 14 days or at hospital discharge.

Demographics: mean age 62.0 years, men 64%, and Chinese enrollees 100%.

Systolic Hypertension in the Elderly Program (SHEP) [14]

Overview: 4,736 participants with isolated systolic hypertension were enrolled if SBP was 160 to 219 mmHg and diastolic BP <90 mmHg and randomized to receive double-blinded treatment with either chlorthalidone (step 1)/atenolol (step 2) to reach the BP lowering goal (reduction of at least 20 mm Hg from baseline and to below 160 mm Hg) or placebo.

Primary outcome: nonfatal and fatal (total) stroke.

Demographics: mean age 71.6 years, men 43.2%, and black enrollees 13.9%.

Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [21]

Overview: 6,105 hypertensive and non-hypertensive participants with a history of stroke or TIA were randomized to double-blind therapy with perindopril, alone or combined with indapamide, or placebo with a BP reduction goal of 8-9/4-5 mmHg in the active treatment arm.

Primary outcome: fatal or nonfatal stroke.

Demographics: mean age 64 years, women 30%, and Asian enrollees 39%.

Systolic Blood Pressure Intervention Trial (SPRINT) [23]

Overview: 9,361 non-diabetic participants without a history of stroke who had a SBP 130 mmHg or greater were enrolled and randomized to open-label intensive antihypertensive therapy with a SBP goal of <120 mmHg or standard treatment with a SBP goal of <140 mmHg. BP lowering agents were chosen according to the most robust medical evidence, and specific agents were encouraged but not mandated.

Primary outcome: myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death of cardiovascular causes.

Demographics: mean age 67.9 years, women ~36% and black enrollees ~30%.

Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) [24]

Overview: 33,357 participants 55 years of age or older with hypertension and at least 1 other CHD risk factor were randomized to double-blind therapy with chlorthalidone, amlodipine or lisinopril to determine the best 1st step BP lowering therapy.

Primary outcome: fatal CHD or non-fatal MI.

Secondary outcomes: all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization or angina with hospitalization) and combined CVD (CHD, stroke, treated angina without hospitalization, heart failure and peripheral arterial disease).

Demographics: mean age 67 years, women 47%, and enrollees who were black (35%) and Hispanic (19%).

Meta-analyses

Prospective Studies Collaboration [8]

Overview: A meta-analysis that included 61 prospective observational studies of BP and mortality covering 12.7 million person-years at risk with 56,000 vascular deaths (12,000 stroke, 34,000 ischemic heart disease [IHD], 10,000 other vascular) and 66,000 other vascular deaths in adults aged 40-89 years. Time-dependent correction for regression dilution bias related to mortality during each decade of age of death was used to estimate the usual BP at the start of each decade.

Meta-analysis of 6 Randomized Controlled Trials (ATACH2, Gong et al., INTERACT2, ADAPT, INTERACT and Koch et al.) by Shi L et al [11]

Overview: A meta-analysis of six BP lowering trials that included 4,412 participants with acute ICH to assess hematoma growth and neurological improvement at 24 hours, hypotension at 72 hours, death or dependency at 90 days, mortality at 90 days, and serious adverse events at 90 days by comparing intensive and more conservative BP lowering.

Meta-analysis of 147 Randomized Controlled Trials of Blood Pressure Lowering Drugs in Prevention of Coronary Heart Disease and Stroke by Law MR et al [15]

Overview: 108 trials addressing differences in BP between drug and placebo or control; 46 compared drugs; and 7 fell into both groups. The observed results were interpreted in relation to expected results based on the Prospective Studies Collaboration meta-analysis of cohort studies that included 958,000 participants. There were 3 exclusive study groups: no history of vascular disease; a history of CHD; or a history of stroke.

Meta-analysis and Systematic Review of 123 Studies of Blood Pressure Lowering in 613,815 Participants by Ettehad D et al [16]

Overview: Inclusion was restricted to trials with at least 1,000 patient-years of follow-up in each study arm. Baseline comorbidities and use of antihypertensive therapy for indications other than hypertension were not exclusions. Summary level data was presented for baseline characteristics and key outcomes (major CVD events, CHD, stroke, heart failure, and all-cause mortality).

^*If stroke or stroke-related disability or death is not included in the primary outcome, secondary outcomes that include stroke are listed