Response: HOPE Not HYPE But Mechanisms Can Be Discussed
Dr Moutsatsos argues that the BP reduction seen in our substudy on ambulatory BP (ABP) is similar to many hypertension trials. Some of the arguments presented and some of the comparisons made are not correct.
We studied a small subsample that differed from the general HOPE population, most importantly in a higher office BP (OBP) at baseline (151/81 versus 139/79 mm Hg). A greater fall in both OBP (which we found) and ABP during ramipril treatment was thus to be expected in our substudy.
Dr Moutsatsos refers to the magnitude of BP reduction in some trials. Although it is not mentioned, he is referring to reduction of OBP. In doing so, he is comparing our findings of ABP reduction (probably not representative of HOPE overall) with the reduction of OBP in the trials, thus comparing apples and pears since the magnitude of the reduction of ABP in these trials is not known.
HOPE differs in comparison to these BP studies in important aspects. In HOPE, patients were included independent of their OBP levels (up to 160 mm Hg), whereas the hypertension trials included patients with a high OBP.
A bigger difference in OBP vs ABP might be expected in the trials (because patients were selected on OBP). During treatment, a combination of regression toward the mean of OBP as well as greater falls of BP probably affect OBP and ABP differently in the hypertension trials compared with HOPE.
The dosing of ramipril in HOPE (od at bedtime), as well as the time from drug intake to measurement of OBP, differs from the hypertension trials in which treatment was given at daytime. This may have affected the 24-hour BP profile differently in HOPE compared with these trials. We found a significant decrease of night-day ratio of SBP in the ramipril group after 1 year. This effect is less likely influenced by a higher OBP, and it is reasonable to expect that a similar decrease of night-day ratio occurred in the whole HOPE population. Little is known about how BP-lowering during nighttime is related to outcome. Some epidemiological data support the belief that night-day ratio of BP, independently of 24-hour BP levels, is a risk factor for cardiovascular endpoints.1,2
Thirdly, the high-risk category patients in HOPE differ from those in the hypertension trials. A small lowering of a “high normal” BP may be more worthwhile in these patients.
The HOPE study has clearly shown that adding treatment with the ACE inhibitor ramipril, on top of other treatments in high risk patients, improves outcome. Treatment was probably associated with a more pronounced relative lowering of night BP than of OBP. The mechanisms of the positive effects seen in HOPE may be several: a reduction of BP, a decreased night-day ratio of BP, or non–BP-related effects of ramipril. The bedtime dosing of ramipril may be important.
Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster J. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. JAMA. 1999; 282: 539–546.
Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, Matsubara M, Hashimoto J, Hoshi H, Araki T, Tsuji I, Satoh H, Hisamichi S, Imai Y. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study. J Hypertens. 2002; 20: 2183–2189.