MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension

The Journal of Family Practice. 2012 August;61(8):S5-S14

August 1, 2012|Family Medicine

Other early notable clinical trials that evaluated treatment options for hypertension in the general public include the Hypertension Detection and Follow-up Program (HDFP),³ the Hypertension Optimal Treatment (HOT) study,¹⁶ and the United Kingdom Prospective Diabetes Study/Hypertension in Diabetes (UKPDS/HDS).^17,18 The key outcomes of these trials are shown in TABLE 1.^{3,4,11,12,16,20,22,25,39,40}

TABLE 1

Findings from the early clinical trials in hypertension

Clinical Trial	Intervention	Primary Outcome	Result
HDFP^3,39	Patients randomized to systemic antihypertensive treatment or community medical therapy (referral)	5-year mortality	5-year mortality reduced by 17% in treatment group (P < 0.01); after 12 years, BP still higher in treatment than in stepped-care treatment group
HOT¹⁶	Patients all began on felodipine, with an ACEI or a BB added as necessary If BP goal was still not reached, HCTZ could be added Patients in each group also randomized to low-dose aspirin or placebo Subjects were randomly assigned to reach 1 of 3 DBP goals: ≤90 mm Hg; ≤85 mm Hg; or ≤80 mm Hg	Major CV events with 3 target DBPs reached during therapy and with low-dose aspirin therapy	Lowest incidence of major CV events achieved at mean BP of 138.5/82.6 mm Hg; lowest risk of CV mortality achieved at mean BP of 138.8/86.5 mm Hg Low-dose aspirin reduced major CV events by 15% and all MI by 36%, although nonfatal major bleeding was twice as common with low-dose aspirin than with placebo
UKPDS/HDS^17,18	Patients with T2DM randomized to atenolol or captopril, with additional antihypertensive agents (other than ACEIs or BBs) allowed	Effect of tight BP control on diabetes-related complications, morbidity, and mortality	Tight BP control (<150/85 mm Hg) with either atenolol or captopril significantly reduced the risk of all endpoints, including risk of diabetes-related death or complication, stroke, MI, and heart failure
EWPHPE⁴	Patients ≥60 years of age randomized to HCTZ + triamterene + methyldopa or placebo	CV and MI mortality; nonfatal CV events	Significant reduction in CV and MI mortality (P < .05) but not nonfatal CV events in treatment group vs placebo Found U-shaped relationship between mortality and SBP in treated group vs mortality and DBP in placebo group
MRC-2¹²	Patients 65-74 years of age randomized to atenolol + HCTZ or amiloride	Reduction in mortality and morbidity due to stroke and CHD and reduction in mortality due to all causes	Only the HCTZ group demonstrated a significant reduction in stroke, coronary events, and all CV events (P=.4, P=.0009, and P=.0005, respectively)
STOP-2²²	Patients 70-84 years of age randomized to atenolol + HCTZ or amiloride; or to metoprolol or prinodolol	Incidence of fatal stroke, MI, or other CVD mortality	Similar reductions in BP, mortality, and major events in all treatment groups
SCOPE²⁵	Patients 70-89 years of age randomized to candesartan or placebo (open-label antihypertensive therapy added as needed and extensively used in control group)	Major CV events; secondary measures included CV death, nonfatal and fatal stroke and MI, cognitive function	Greater BP decreases in candesartan group but no significant risk reduction in major CV events between the 2 groups Significant reduction in nonfatal stroke (P=.04) and all stroke (P=.06) in the treatment group No other significant differences between the groups, although a post-hoc analysis found less cognitive decline among those with only mild cognitive impairment at baseline in the candesartan-treated group (P=.04)⁴⁰
SHEP¹¹	Patients ≥60 years of age randomized to chlorthalidone with or without atenolol or reserpine, with nifedipine as third-line therapy, or to placebo	Stroke; nonfatal MI, coronary death, major CV events, death due to all causes	Significant reduction in 5-year incidence of total stroke in active treatment group (P=.0003) and significant reduction in all secondary endpoints
Syst-Eur¹⁹	Patients >60 years of age randomized to nitrendipine with possible addition of enalapril, HCTZ, or both, or to placebo	Fatal and nonfatal stroke, fatal and nonfatal cardiac events including sudden death, all-cause mortality	Significant reductions in all endpoints except all-cause mortality in treatment group; study halted early because of the 42% total stroke reduction in treatment arm (P < .003)
Syst-China²⁰	Patients ≥60 years of age randomized to nitrendipine with captopril or HCTZ, or both if needed; or matching placebo	Nonfatal stroke; all-cause, CV, and stroke mortality; and all fatal and nonfatal CV events	Significant reductions in all endpoints
ACEI, angiotensin-converting enzyme inhibitor; BB, beta-blocker; BP, blood pressure; CV, cardiovascular; CHD, coronary heart disease; CVD, CV disease; DBP, diastolic BP; EWPHE, European Working Party on High Blood Pressure in the Elderly study; HDFP, Hypertension Detection and Follow-up Program; HCTZ, hydrochlorothiazide; HOT, Hypertension Optimal Treatment study; MI, myocardial infarction; MRC-2, Medical Research Council trial of treatment of hypertension in older adults; SBP, systolic BP; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; STOP-2, Swedish Trial in Old Patients with Hypertension-2; Syst-Eur, Systolic Hypertension in Europe trial; Syst-China, Systolic Hypertension in China trial; T2DM, type 2 diabetes mellitus; UKPDS/HDS, United Kingdom Prospective Diabetes Study/Hypertension in Diabetes.

References