Table 3.

Clinical outcome trials in support of safety and tolerability with combination treatment

Reference	Study design	Population and number of patients	Principal findings
Dahlof et al 1991	This was a double-blind, multicenter, randomized study to compare antihypertensive treatment with placebo. Initial drug therapy consisted of a once-daily diuretic (25 mg HCT and 2.5 mg of amiloride), a beta-blocker (50 mg of atenolol, 100 mg of metoprolol succinate ER, or 5 mg of pindolol), or matching placebo after a 1- to 6-month washout period. Active treatment drugs could be combined if BP exceeded 160/95 mmHg after 2 months. For the placebo group, antihypertensive therapy could be added if the BP exceeded 230/120 mmHg. The primary outcome was MI, stroke, and other CV death.	Patients had a SBP between 180 and 230 mmHg and a DBP of 90 mmHg or higher, OR a DBP of 105–129 mmHg. 1627 patients aged 70–84 years	Average follow-up time was 25 months. At 12 months, the placebo-corrected changes in BP were greatest when the beta-blocker was combined with a diuretic. Less than 1/3 of the active treatment patients were on monotherapy. Treatment reduced total mortality by 43% (p = 0.0079) and strokes by 47% (p = 0.0081). The rate of all MIs was not reduced over this short duration of follow-up.
Hansson et al 1999	This was a double-blind, multicenter, randomized study to compare older antihypertensive agents with newer agents. 1st group) Conventional treatment group, which consisted of once-daily diuretic, beta-blocker, or both: 50 mg of atenolol, 100 mg metoprolol succinate ER, 5 mg of pindolol, or the combination of 25 mg HCT and 2.5 mg of amiloride, which could be combined with the beta-blocker monotherapy if the target BP of 160/95 was not achieved. 2nd group) To achieve treatment goals, ACEI was supplemented with HCT. 3rd group) The calcium antagonists felodipine or isradipine were augmented with any of the above beta-blockers to achieve the target BP. The primary combined endpoint was fatal stroke, fatal MI, and other fatal CV diseases.	Patients had a SBP of 180 mmHg or higher, DBP was 105 mmHg or higher, or both. Patients with isolated systolic hypertension were also included. A total of 6614 patients aged 70–84 years - 2213 patients received conventional treatment - 2205 received ACEI - 2196 received a calcium antagonists 33,249 patient-years were accumulated	After 24 months, there was no difference in reduction of BP among the 3 treatment groups. After 60.3 months, there was no difference among the 3 groups for the primary endpoint of CV death. Major morbidity events were similar among the groups. The primary endpoint did not differ significantly among the 719 diabetic elderly patients. Combination therapy was used for 46% of patients.

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HCT, hydrochlorothiazide; ER, extended release; CV, cardiovascular; MI, myocardial infarction.