THRESHOLDS FOR DIASTOLIC BLOOD PRESSURE REDUCTION IN OLDER PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSION APPEAR TO BE DIFFERENT DEPENDING ON THE PRESENCE OR ABSENCE OF UNDERLYING CORONARY HEART DISEASE
Whether a J-curve relationship exists between achieved diastolic blood pressure (BP) and cardiovascular (CV) events or total mortality in persons with hypertension is a subject of ongoing debate. It is clear that coronary heart disease (CHD) events are high in patients with diastolic BP >90 mm Hg and lowest in patients with diastolic BPs <80 mm Hg, but do they increase again when diastolic BPs get below 60–70 mm Hg? A recent meta-analysis of 10 prospective randomized trials from the Hypertension Detection and Follow-Up Program Cooperative Group concluded that lowering diastolic BP to <70 mm Hg was not associated with a poor outcome. This analysis, however, did not differentiate between patients with systolic-diastolic hypertension and those with isolated systolic hypertension (ISH). A post hoc analysis of the Systolic Hypertension in the Elderly Program (SHEP) did observe a J curve for CV events in older patients with ISH in whom on-treatment diastolic BP <60 mm Hg was achieved, but it did not stratify for coronary heart disease (CHD) at baseline. The numbers of patients in the lower diastolic BP groups were small and, for example, one subset of patients in the diastolic BP group of 45 to 50 mm Hg did not experience more CHD events than those in the 70 to 80 mm Hg group. The Systolic Hypertension in Europe (Syst-Eur) trial provided an opportunity to examine this question. The current post hoc analysis was designed to determine the relationship between on-treatment diastolic BP and mortality or CV events in older patients with ISH with or without established CHD at baseline.
The Syst-Eur trial was a prospective randomized, placebo-controlled double-blind intervention trial performed in 198 centers in Europe. Eligible patients had to be at least 60 years of age, with an average systolic BP of 160 to 219 mm Hg and diastolic BP <95 mm Hg during the 3-month run-in period. Patients were then randomized to either placebo or active treatment consisting of the calcium channel blocker (CCB) nitrendipine (10–40 mg/d), which could be combined with or replaced by enalapril (5–20 mg/d) and/or hydrochlorothiazide (12.5–25 mg/d), as needed, to reduce sitting systolic BP by at least 20 mm Hg and to <150 mm Hg. After the main phase of the trial (phase 1) was completed in 1997 (median follow-up, 2 years [range, 1 month–8.1 years]), patients in the placebo group were changed to active therapy while those in the original active therapy group continued to receive active treatment for an additional 4 years (phase 2) ending on December 31, 2001.
In the present post hoc analysis of the Syst-Eur trial, follow-up data were analyzed separately for placebo and active treatment; data for placebo treatment are from phase 1 only, and data on active treatment are from both phase 1 and phase 2. Outcomes measured included fatal and nonfatal cerebrovascular events (stroke and transient ischemic attack); fatal and nonfatal CHD events (sudden death, myocardial infarction, and coronary revascularization); an aggregate of all CV events (CV death, myocardial infarction, stroke, heart failure, coronary revascularization, aortic aneurysm, and transient ischemic attack); CV mortality; and non-CV death. To determine the effect of achieved diastolic BP on the risk of outcomes, multivariate Cox regression models were performed after correcting for age, sex, smoking status, previous antihypertensive treatment at baseline, weight, and previous history of stroke, myocardial infarction, and diabetes. Hazard ratios were calculated for each 5-mm Hg decrement of achieved diastolic BP. These analyses were repeated with and without systolic BP as a continuous time-dependent or dichotomous variable.
A total of 4695 patients were randomized in phase 1 of the Syst-Eur trial with no significant differences in baseline characteristics between those randomized to active treatment or placebo. Mean age was 70.2±6.7 years, 66.9% were women, and 14.5% had a previous history of established CHD. Mean systolic BP was 173.8±9.9 mm Hg, and mean diastolic BP was 85.5±5.8 mm Hg. After the completion of phase 1, as originally reported, there was a statistically significant (42%) reduction in the incidence of fatal and nonfatal cerebrovascular events. Significant reductions were also demonstrated for fatal and nonfatal CHD (−30%), heart failure (−29%), and all CV events (−31%).
When data from phase 1 and phase 2 were combined for the present report, there were 14,511 patient-years of follow-up on active treatment and 5219 patient-years of follow-up with placebo. On active treatment, the mean achieved systolic BP was 149.0±10.3 mm Hg and mean achieved diastolic BP was 78.8±6.0 mm Hg. During placebo treatment, the mean achieved systolic BP was 161.8±13.6 mm Hg and mean achieved diastolic BP was 83.6±6.4 mm Hg. Of interest is that only 1.7% of patients with active treatment and 0.44% of patients on placebo treatment had a mean on-treatment diastolic BP level <65 mm Hg.
The results of the regression models presented for diastolic BP as a continuous variable revealed that on-treatment diastolic BP was not associated with an increase in CV mortality with either placebo or active treatment. Non-CV mortality, however, was significantly increased with decreasing diastolic BP. For cerebrovascular events, decreasing on-treatment diastolic BP was associated with increased risk in the placebo group, but not in the active treatment group. For CHD events, there was a significant increase in risk in patients in the active treatment only group among patients with a history of established CHD at baseline; conversely, with placebo there was an increase in the risk of CHD with decreasing diastolic BP only in patients without CHD at baseline. These results did not change appreciably when on-treatment systolic BP was included as a continuous variable in the model or when on-treatment diastolic BP was examined using 5-mm Hg cutoffs as opposed to a continuous variable.
The authors of this post hoc analysis of the Syst-Eur trial conclude that these findings “support the hypothesis that antihypertensive treatment can be intensified for the prevention of CV events when systolic BP is not under control in older patients with ISH, at least until diastolic BP reaches about 55 mm Hg.” They did, however, suggest a more “prudent approach” in patients with ISH and concomitant CHD, in which diastolic BP “should probably not be lowered to <70 mm Hg.”—Fagard RH, Staessen JA, Thijs L, et al. On-treatment diastolic blood pressure and prognosis in systolic hypertension. Arch Intern Med. 2007;167(17):1884–1891.