ORIGINAL INVESTIGATION On-Treatment Diastolic Blood Pressure and Prognosis in Systolic Hypertension Robert H. Fagard, MD; Jan A. Staessen, MD; Lutgarde Thijs, MSc; Hilde Celis, MD; Christopher J. Bulpitt, MD; Peter W. de Leeuw, MD; Gastone Leonetti, MD; Jaakko Tuomilehto, MD; Yair Yodfat, MD Background: It has been suggested that low diastolic mortality, but not cardiovascular mortality, increased with blood pressure (BP) while receiving antihypertensive treat- low diastolic BP with active treatment (PϽ.005) and with ment (hereinafter called on-treatment BP) is harmful in placebo (PϽ.05); for example, hazard ratios for lower older patients with systolic hypertension. We examined diastolic BP, that is, 65 to 60 mm Hg, were, respectively, the association between on-treatment diastolic BP, mor- 1.15 (95% confidence interval, 1.00-1.31) and 1.28 (95% tality, and cardiovascular events in the prospective pla- confidence interval, 1.03-1.59). Low diastolic BP with ac- cebo-controlled Systolic Hypertension in Europe Trial. tive treatment was associated with increased risk of car- diovascular events, but only in patients with coronary Methods: Elderly patients with systolic hypertension heart disease at baseline (PϽ.02; hazard ratio for BP 65-60 were randomized into the double-blind first phase of the mm Hg, 1.17; 95% confidence interval, 0.98-1.38). trial, after which all patients received active study drugs (phase 2). We assessed the relationship between out- Conclusions: These findings support the hypothesis that come and on-treatment diastolic BP by use of multivar- antihypertensive treatment can be intensified to pre- iate Cox regression analysis during receipt of placebo vent cardiovascular events when systolic BP is not un- (phase 1) and during active treatment (phases 1 and 2). der control in older patients with systolic hypertension, at least until diastolic BP reaches 55 mm Hg. However, a Results: Rates of noncardiovascular mortality, cardio- prudent approach is warranted in patients with concomi- vascular mortality, and cardiovascular events were 11.1, tant coronary heart disease, in whom diastolic BP should 12.0, and 29.4, respectively, per 1000 patient-years with probably not be lowered to less than 70 mm Hg. active treatment (n=2358) and 11.9, 12.6, and 39.0, re- spectively, with placebo (n=2225). Noncardiovascular Arch Intern Med. 2007;167(17):1884-1891 HE EXISTENCE OF A J-CURVE tension and isolated systolic hypertension. relationship between mor- Therefore, the results may not apply to pa- tality or cardiovascular event tients with systolic hypertension who may and diastolic blood pres- be particularly vulnerable to low on- Author Affiliations: sure (BP) during antihyper- treatment diastolic BP, as shown in a post Hypertension and tensive treatment (hereinafter called on- hoc analysis of the Systolic Hypertension Cardiovascular Rehabilitation T Unit, University of Leuven, treatment BP) remains a matter of debate in the Elderly Program (SHEP), in which 1 Leuven, Belgium (Drs Fagard, in patients with hypertension. Apart from a J-curve was observed for incident car- Staessen, and Celis and intervention trials, in which patients are diovascular events during active treat- Ms Thijs); Imperial College, randomized to different target BP levels,2 ment but not during administration of pla- Hammersmith Hospital, placebo- or nontreatment-controlled trials cebo.15 The SHEP investigators concluded London, United Kingdom are probably the best way to evaluate the that it could be harmful to intensify anti- (Dr Bulpitt); University of J-curve. A large meta-analysis of indi- hypertensive therapy when diastolic BP has Maastricht, Maastricht, the 3-10 Netherlands (Dr de Leeuw); vidual patient data from 7 trials showed reached 70 mm Hg. In addition, the SHEP Istituto Auxologico Italiano, a higher incidence of cardiovascular death analysis did not stratify for coronary heart Ospedale San Luca, Milan, Italy with lower on-treatment diastolic BP, but disease (CHD) at baseline, whereas the risk (Dr Leonetti); National Public this relationship was also observed for non- of low on-treatment diastolic BP could be Health Institute and the cardiovascular death and similar relation- particularly high in patients with CHD.1,16 University of Helsinki, Helsinki, ships existed in the control patients; thus, Because of the far-reaching conse- Finland, and South the worse prognosis of lower diastolic BP quences of the conclusions from the SHEP Ostrobothnia Central Hospital, could not be solely ascribed to antihyper- trial, we analyzed the relationship be- Seina¨joki, Finland tensive treatment. A more recent meta- tween on-treatment diastolic BP, mortal- (Dr Tuomilehto); and 11 4-10,12-14 Department of Family analysis involving 10 trials con- ity, and cardiovascular events in older Medicine, Hadassah Medical cluded that lowering diastolic BP to less patients with systolic hypertension ran- School, Hebrew University of than 70 mm Hg did not cause harm. How- domized into the Systolic Hypertension in Jerusalem, Jerusalem, Israel ever, these meta-analyses did not differ- Europe (Syst-Eur) Trial12,17 and also ac- (Dr Yodfat). entiate between systolic-diastolic hyper- counted for CHD at baseline. (REPRINTED) ARCH INTERN MED/ VOL 167 (NO. 17), SEP 24, 2007 WWW.ARCHINTERNMED.COM 1884 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 METHODS Table 1. Patient Characteristics at Baseline in the Placebo and Active Treatment Groupsa TRIAL DESIGN Active 12 The protocol of the Syst-Eur Trial was approved by the ethics Placebo Treatment committees of the University of Leuven, Leuven, Belgium, and Group Group participating centers; all subjects in the 198 centers gave in- Characteristic (n = 2225) (n = 2358) formed consent. Eligible patients had to be 60 years or older. Dur- Age, y 70.1 ± 6.6 70.2 ± 6.7 ing the run-in period with placebo, patients were seen at 3 base- Female sex 66.5 67.4 line visits 1 month apart. Data about medical history were collected, Body mass indexb 27.0 ± 4.0 27.0 ± 4.2 including history of CHD, which comprised myocardial infarc- Blood pressure, mm Hg tion and angina pectoris, based on supporting documents and ex- Systolic 173.9 ± 10.1 173.7 ± 9.8 aminations available to the local investigators. At each visit, BP Diastolic 85.5 ± 5.9 85.5 ± 5.8 was measured twice with a standard sphygmomanometer with Pulse rate, beats/min 73.0 ± 8.1 73.2 ± 7.9 the patient sitting. Patients were admitted to the double-blind phase Previous antihypertensive therapy 46.7 46.3 of the trial when they had an average run-in period systolic BP Previous cardiovascular complicationsc 30.3 29.4 of 160 to 219 mm Hg with diastolic BP less than 95 mm Hg. History of coronary heart diseasec 14.7 14.2 Patients were randomized to active medication or matched Diabetes 10.1 10.5 placebo groups. Active treatment consisted of nitrendipine (10- Current smoking 7.0 7.3 40 mg/d), which could be combined with or replaced by enala- Serum creatinine, mg/dL 1.0 ± 0.2 1.0 ± 0.2 pril maleate (5-20 mg/d) or hydrochlorothiazide (12.5-25 mg/d) Serum cholesterol, mg/dL 236 ± 46 231 ± 46 or both drugs, to reduce the sitting systolic BP by 20 mm Hg or more and to less than 150 mm Hg. At each 3-month visit, BP was SI conversion factors: To convert creatinine to millimoles per liter, multiply measured twice with the patient sitting and the 2 BP measure- by 88.4; cholesterol to millimoles per liter, multiply by 0.0259. a Data are given as mean ± SD or percentage. ments were averaged. When phase 1 of the Syst-Eur Trial was b Calculated as weight in kilograms divided by height in meters squared. stopped on February 14, 1997, after a median follow-up of 2.0 c Includes coronary heart disease (myocardial infarction and angina pectoris), years (range, 1 month to 8.1 years),12 patients in the control group heart failure, left ventricular hypertrophy, stroke, central nervous system. were switched to the active study treatment regimen and patients involvement, renal involvement, retinopathy grade 3, and aortic aneurysm. in the active treatment group continued receiving active treatment (phase 2).17 Visits were scheduled every 6 months in the study cen- ters and the same information was collected as during the double- ables with potential influence on BP and outcome, that is, age, blind phase of the trial. The extended follow-up ended on Decem- sex, smoking status, and previous antihypertensive treatment at ber 31, 2001. In the present analyses, follow-up data in the baseline, and weight, stroke, myocardial infarction, and diabetes placebo group are from phase 1 of the trial and follow-up data in mellitus both at baseline and as time-dependent covariates dur- the active treatment group are from phases 1 and 2. For patients ing follow-up. The analyses were performed with and without sys- who withdrew from the study or who could not be followed up tolic BP as a continuous time-dependent covariate. We plotted as planned, investigators collected data about vital status, occur- the adjusted hazard ratio (HR) vs on-treatment diastolic BP. The rence of diseases, and use of antihypertensive medication via yearly (adjusted HR−1)ϫ100 is the percent increase in risk associated telephone contact with patients, family members, or general 12,17 with the 5–mm Hg lower on-treatment diastolic BP. In the sec- practitioners. ond analysis, we calculated HRs in 5–mm Hg decrements of on- treatment diastolic BP, as in the SHEP study.15 For each cutoff OUTCOMES value, outcome was compared between patients with diastolic BP below that level and patients with diastolic BP at or above that Outcome measures were as follows: (1) fatal and nonfatal cere- level.