From the Hypertension and Cardiovascular Rehabilitation Unit, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
Isolated systolic hypertension is defined as an increased systolic blood pressure (≥ 140 mm Hg) and a normal diastolic blood pressure (< 90 mm Hg).1 The condition is ascribed to stiffening of the arterial vasculature and becomes more prevalent with increasing age.2 In some patients, diastolic blood pressure may be as low as 70 mm Hg or less, which causes concern and is regarded as an additional cardiovascular risk factor in current guidelines.1 In other patients, diastolic blood pressure may reach these low values during antihypertensive therapy before systolic blood pressure is normalized. It is unclear whether antihypertensive treatment should be intensified in these patients to reduce systolic blood pressure to the target level of < 140 mm Hg.
In a post-hoc analysis of the Systolic Hypertension in the Elderly Program (SHEP),3 Somes and colleagues4 observed a J curve for incident cardiovascular events during active antihypertensive therapy but not during administration of placebo in older patients with isolated systolic hypertension. The relative risk for an aggregate of cardiovascular events became significant for diastolic blood pressure < 70 mm Hg, and the risk was about 2-fold for diastolic blood pressure < 55 mm Hg. As a result, the researchers concluded that increasing anti-hypertensive therapy when diastolic blood pressure had reached 70 mm Hg could be detrimental. It has been thought that the increased risk of cardiovascular and coronary artery disease (CAD) is at least partly attributed to coronary perfusion occurring during diastole, when blood pressure is low.5 This risk may be exacerbated by antihypertensive therapy, when diastolic blood pressure may reach very low values after treatment has been increased in an attempt to normalize systolic blood pressure.
The SHEP investigators did not categorize the subjects according to their CAD status at baseline. Therefore, we evaluated the association between on-treatment diastolic blood pressure and cardiovascular events in older patients in the Systolic Hypertension in Europe (Syst-Eur) trial and also accounted for CAD status at baseline.6
Patients and methods
Patients aged 60 years and older with a systolic blood pressure of 160 to 219 mm Hg and diastolic blood pressure < 95 mm Hg were randomly assigned to active-medication or matched placebo groups during the placebo run-in phase of the study.7 Active treatment was initiated with the dihydropyridine calcium channel blocker, nitrendipine, which could be combined with or replaced by enalapril (Vasotec) or hydrochlorothiazide (Microzide, Oretic). At the end of the double-blind first phase of the trial, which had a median duration of 2 years, all patients received active study drugs for another 5 years (phase 2).8
In a post hoc analysis, we assessed the relationship between the incidence of cardiovascular events and on-treatment diastolic blood pressure among 2,225 subjects over 5,219 patient-years of follow-up during placebo treatment (phase 1) and in 2,358 subjects over 14,511 patient-years of follow-up during active treatment (phases 1 and 2) by using multivariable Cox regression analysis.6
Table. Patient characteristics at baseline in the placebo group and in the active-
The characteristics of the patients at baseline are shown in the Table. The rate of cardiovascular events was 3.90 events per 100 patient-years in the placebo group and 2.94 events per 100 patient-years in the active-treatment group. The aggregate of cardiovascular events was defined as closely as possible to the definition in the SHEP trial4 and included cardiovascular death, myocardial infarction (MI), stroke, heart failure, coronary revascularization, aortic aneurysm, and transient ischemic attack. Without stratification for CAD at baseline, and with adjustments for age, sex, smoking status, and previous antihypertensive treatment at baseline, as well as body weight and stroke, MI, or diabetes status at baseline and during follow-up, we found no significant association between the risk of cardiovascular events and on-treatment diastolic blood pressure during active treatment or placebo administration.
The Figure shows the relationship between on-treatment diastolic blood pressure and the risk of cardiovascular events in the active-treatment group according to the patient’s history of CAD at baseline, which was present in 14.5%. Patients with CAD (n = 336) were at higher risk than those without CAD (n = 2,022); the incidence of cardiovascular events was 5.67 events per 100 patient-years in subjects with CAD compared with 2.56 events per 100 patient-years in subjects without CAD.
Figure. The hazard ratios for cardiovascular events in relation to on-treatment
diastolic blood pressure in subjects with and without coronary artery disease (CAD) at
baseline in the active-treatment group, adjusted for age, sex, smoking status, and
previous antihypertensive treatment at baseline, as well as body weight and stroke,
myocardial infarction, or diabetes status at baseline and during follow-up. The hazard
ratio provides the risk associated with a 5 mm Hg lower diastolic blood pressure.
(Reprinted with permission from Fagard RH, Staessen JA, Lutgarde T, et al. On-
treatment diastolic blood pressure and prognosis in systolic hypertension. . 2007;167:1884-1891.)
As shown in the Figure, low on-treatment diastolic blood pressure was not associated with increased risk in subjects without CAD at baseline, whereas the risk increased when diastolic blood pressure was lower than approximately 75 mm Hg in subjects with CAD at baseline (< .02), with a hazard rate of about 1.1 at 70 mm Hg. Therefore, we could not confirm the overall results of the SHEP trial, which showed an association between lower achieved diastolic blood pressure and an increased risk of cardiovascular disease in actively treated subjects.4 We did observe, however, that the increased risk was present in subjects with evidence of CAD at baseline, but not in subjects without a history of CAD.
There are several differences between the Syst-Eur trial and the SHEP trial, apart from the fact that the SHEP investigators did not stratify for CAD at baseline in their analyses. Diastolic blood pressure had to be < 95 mm Hg for inclusion in the Syst-Eur trial and < 90 mm Hg for inclusion in the SHEP trial. On-treatment diastolic blood pressure was rarely < 55 mm Hg in the Syst-Eur trial, but the SHEP investigators could analyze the relationship between the incidence of cardiovascular events and on-treatment diastolic blood pressure down to a diastolic blood pressure of 25 mm Hg.
Antihypertensive therapy was based on nitrendipine, a dihydropyridine calcium channel blocker, in the Syst-Eur trial and on the diuretic chlorthalidone (Thalitone) in the SHEP study. A larger prevalence of CAD at baseline in the participants in the SHEP trial may have played a role in the divergent findings, but there was no evidence that this was the case.
Finally, we used different statistical techniques for our primary analysis, but when we used the same statistical methodology as in the SHEP trial, we confirmed the finding of our primary analysis that there was no significant association between the incidence of cardiovascular events and on-treatment diastolic blood pressure in the overall analysis of all patients who were receiving active treatment.
The findings of our post-hoc analysis of the Syst-Eur trial support the hypothesis that antihypertensive treatment can be intensified for the prevention of cardiovascular events when systolic blood pressure is not under control in older patients with isolated systolic hypertension. A prudent approach is warranted, however, in patients with isolated systolic hypertension and concomitant CAD, and diastolic blood pressure should probably not be decreased to < 70 mm Hg in these patients.6