Journal of Human Hypertension (2000) 14, 435–440 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Practice vs ambulatory blood pressure measurement under treatment with ramipril (PLUR Study): a randomised, prospective long-term study to evaluate the benefits of ABPM in patients on antihypertensive treatment J Schrader, S Lu¨ ders, C Zu¨ chner, M Herbold and G Schrandt St. Josefs-Hospital, Ritterstr. 17, D-49661 Cloppenburg, Germany The usefulness of ambulatory blood pressure monitor- reason for discontinuation in 55 of these patients (20 ing (ABPM) vs casual blood pressure measurement in from group 1 and 35 from group 2) was that they the physicians practice (PM) for the routine manage- reached the main endpoint (total mortality/morbidity and ment of patients with hypertension concerning total cardio- and cerebrovascular events) of the study. The -in fa (0.037 ؍ mortality and morbidity has been compared in a pro- difference was statistically significant (P spective, randomised, open multicentre study with a 5- vour of group 1. Cardio- and cerebrovascular events in (14 ؍ year follow-up. The study was performed in general also occurred in a lower number of patients (n The difference .(24 ؍ practitioners offices in Germany from 1991 to 1997. A group 1, as compared to group 2 (n A difference in .(0.097 ؍ total of 1298 patients with essential hypertension were however was not significant (P included. Cardio- and cerebrovascular events, total a direct drug-saving effect could not be observed mortality/morbidity and drug-saving effects in hyperten- between the two groups but 22% of the initially screened sives treated according to two different methods of patients were detected with the ABPM to have white blood pressure measurement were the primary and sec- coat hypertension and thus these patients did not ondary endpoints of the study. A total of 239 patients receive antihypertensive treatment. and 208 from group 2 Journal of Human Hypertension (2000) 14, 435–440 ,(651 ؍ from group 1 (ABPM, n prematurely discontinued the study. The (647 ؍ PM, n) Keywords: ambulatory blood pressure monitoring; ramipril; PLUR; office blood pressure; reverse white coat hypertension Introduction number of blood pressure values measured during patients normal daily activity, which results in an In recent years, ambulatory blood pressure (ABPM) improved evaluation of the patients blood pressure has been increasingly used in hospitals and in the under stresses of everyday life.4,5 physician’s office for diagnosis, clinical trials, and Furthermore the potency and duration of action in particular for monitoring treatment of hyperten- of an antihypertensive agent can be recorded more sion in selected patients. This method is considered effectively over the entire dosage interval.6 Thereby, to be a better predictor of cardiovascular risk in the 1,2 unnecessary intensified antihypertensive treatment individual patient. Moreover this procedure helps can be avoided in patients who have higher casual to better target patients who will benefit from anti- in-office measured blood pressure than with ABPM. hypertensive drug treatment, and at the same time Alternatively, it offers the possibility to intensify avoiding unnecessary antihypertensive treatment in 3 antihypertensive therapy in those patients who have patients with white coat hypertension. ABPM also higher ABPM values as compared to blood pressure offers advantages for monitoring antihypertensive levels measured in the physicians practice. treatment. The possible superiority of ABPM in To date little information exists in the literature patients undergoing treatment is based on a large concerning the prognostic benefits of ABPM. A number of studies have indicated that ABPM as compared to casual office blood pressure measure- Correspondence: Prof Dr Joachim Schrader, St.-Josefs-Hospital, Ritterstr. 17, D-49661 Cloppenburg, Germany ment shows a better correlation to hypertensive tar- E-mail: slclpȰt-online.de get organ damage and to cardiovascular events.7–13 Received 13 September 1999; revised 29 February 2000; accepted Nevertheless, there is a lack of prospective, long- 30 March 2000 term studies, which demonstrate the value of ABPM Practice vs ABPM under treatment with ramipril J Schrader et al 436 as compared to blood pressure measured occasion- and/or diastolic Ͼ85 mm Hg or average 24 h blood ally in the physician’s office. The important ques- pressure systolic Ͼ130 and/or diastolic Ͼ80 mm Hg, tion, whether consistent use of ABPM will result in according to the guidelines of the German Hyperten- an improved prognosis of hypertensives and to a sion League16 these patients were included in group reduction in the use of antihypertensive medication 1 of the study, and those with lower blood pressure as compared to in-office casual blood pressure values than mentioned above were defined as ‘white measurement, still remains unanswered. coat hypertensives’ and were not included. Therefore the following prospective, randomised, Scheduled visits in both groups were after 2–4 multicentre study was performed to answer the weeks, 3, 6, 9, 12 months and 2, 3, 4, 5 years after question, whether hypertensives managed on the inclusion. ABPM in group 1 was performed once a basis of ABPM have a better prognosis and require a year or when change of treatment seemed to be lesser number of antihypertensive drugs than those necessary according to office blood pressure (Ͼ140 treated according to casual office blood pressure and/or Ͼ90 mm Hg) or clinical reasons. Office blood measurement. pressure was documented at each visit in both groups. Materials and methods In group 1 office blood pressure was documented, but during the entire study period all required This prospective, open, randomised, multicentre changes in antihypertensive medication were car- study was approved by the Ethics Committee of the ried out on the basis of ABPM; ie, the antihyperten- University of Go¨ttingen, Germany. The study was sive treatment was to be intensified if the average conducted according to the Declaration of Helsinki.14 day blood pressure exceeded 135 and/or 85 mm Hg, There were 50 general practitioners who participated or the average 24-h blood pressure was above 130 in this trial, and an independent Clinical Event Com- and/or 80 mm Hg. In group 2, the decision to adjust mittee was used for evaluation of events. A total of the dosage of the antihypertensive medication was 1500 patients were planned to be included in the exclusively taken according to the blood pressure study. According to the definition of the Deutsche values measured in the physician’s practice. The Hochdruckliga (German High Blood Pressure League) treatment was to be intensified if office blood press- the patient must present hypertension requiring treat- ure values were above 140 and/or 90 mm Hg (mean ment (after 5 min sitting), clinic blood pressure (Riva- of three measurements). In patients of this group Rocci method) Ͼ140 and/or Ͼ90 mm Hg in three ABPM was not performed. The patients were measurements on two different days. Patients had to included in this study from 1991 to 1993, and moni- be between 35 and 65 years old. tored for an average period of 4–7 years (maximum Exclusion criteria were contraindication for rami- 6 years, minimum 4 years). The study was termin- pril treatment, manifest cardiac insufficiency ated in July 1997. (NYHY III–IV), higher-grade aortic or mitral sten- To ensure a comparable antihypertensive treat- osis, pregnant or lactating women, women of child- ment in both groups, the ACE inhibitor ramipril was bearing potential, patients with a progressive, poten- used as baseline drug starting with 1.25 mg o.d. in tially fatal disease (life expectancy Ͻ1 year), both the groups. The dosage was titrated up to 5 mg patients with alcohol or drug abuse, known hyper- o.d. if necessary for normalising blood pressure dur- sensitivity against angiotensin-converting enzyme ing the first 4–6 weeks. In the event of undesirable (ACE)-inhibitor, history of Quincke’s oedema, reactions or the need for a combination treatment patients who received other investigational sub- according to the guidelines of the German Hyperten- stances within 30 days or five half-lives of this drug sion League, a calcium antagonist (felodipine 5 mg (the longer will apply) before entry to this protocol, o.d. or nifedipine ret 10 mg t.d.), or a diuretic patients who have been included in a previous (hydrochlorothiazide 12.5 mg o.d.), or a beta-blocker ongoing study, legally incapable patients or patients (metoprolol 100 mg o.d.) could be administered unable to give consent. alternatively or added to ramipril on physicians Patients receiving antihypertensive medication preference. had a washout period of 4 weeks (when blood press- ure increased to Ͼ165/95 mm Hg patients could be randomised before the end of these 4 weeks). The Definition of events patients were then randomised into two groups: Cardiovascular events were defined as all (fatal and group 1 ‘ABPM’ and group 2 casual office blood non-fatal) myocardial infarctions, all (fatal and non- pressure measurement (‘PM’). The patients belong- fatal) strokes, and all other cardiovascular deaths. ing to group 2 were directly included into the study, The diagnosis of these events required electrocardio- and in the patients of group 1 an ABPM was perfor- grams or hospital records or necropsy reports. med in addition by using Space Labs equipment consisting of validated oscillometric 90207 moni- 15 tors. The ambulatory readings were programmed Drug score at 15-min intervals from 6 am to 10 pm and at 30- min intervals from 10 pm to 6 am according to the For comparison of antihypertensive therapy all recommendations of the German Hypertension medication was estimated by a drug-score which League.16 If a hypertensive blood pressure profile was based on the daily recommended dosage of each was also documented during ABPM (average day drug (ϭ 1 pt, half of recommended dosage ϭ 0.5 pts, blood pressure from 6 am to 10 pm) systolic Ͼ135 double-dosage ϭ 2 pts).