Postgrad MedJ3 1995; 71: 287-292 i) The Fellowship of Postgraduate Medicine, 1995 Postgrad Med J: first published as 10.1136/pgmj.71.835.287 on 1 May 1995. Downloaded from Effects of captopril and enalapril on renal function in elderly patients with chronic heart failure CA Haffner, MJ Kendall, AD Struthers, A Bridges, DJ Stott Summary Keywords: ACE-inhibitors, renal function, elderly, Objective: To compare the effects on renal enalapril, captopril function of captopril and enalapril in elderly patients with chronic heart failure. Introduction Design: A multi-centre double-blind parallel-group comparison of the two Cardiac failure is a common clinical problem angiotensin-converting enzyme (ACE) and the majority of patients with heart failure inhibitors, captopril (12.5 mg bid) and are more than 65 years old.'-4 Better treatment enalapril (2.5 mg bid). of heart failure in the elderly could therefore Subjects: 80 elderly patients with chronic make a great impact (box 1). heart failure (41 in the captopril group, 39 Over the last decade, angiotension- in the enalapril group). converting enzyme (ACE) inhibitors have Main outcome measures: The blood pres- established themselves in the treatment ofheart sure and pulse rate response to the first failure. Controlled trials5`7 show symptomatic dose of ACE inhibitor was assessed in all improvement and increased exercise tolerance patients. Glomerular filtration rate on chronic treatment (more than three (GFR) was measured radioisotopically by months). The CONSENSUS study compared 99mTcDTPA or 51CrEDTA clearance enalapril with placebo and demonstrated a after three and six months of each treat- reduction in one-year mortality from 52% to ment. Subgroups were assessed for 31 %.1 The SOLVD study showed a 16% effective renal plasma flow (33 patients), reduction in mortality at one year among exercise tolerance (25 patients) and by a enalapril-treated patients with less severe heart symptom-oriented questionnaire (45 failure associated with systolic dysfunction.9 patients). The SAVE study'0 and the AIRE study" Department ofHealth Results: No serious adverse effect on GFR established that the benefits of ACE-inhibitor http://pmj.bmj.com/ Care for the Elderly, was noticed. There was no significant therapy also apply to post-myocardial infarc- Hayward Building, difference between the two treatments in tion patients with left ventricular dysfunction Selly Oak Hospital, the mean baseline GFR or in changes who were at risk of developing heart failure. Selly Oak, West from baseline at three and six months These are important findings for a condition Midlands, UK (captopril mean baseline GFR 49.6 ml with such a poor prognosis. CA Haffner min-' 1.76 m-2, enalapril 54.7 ml min-' Many of the studies cited above included 1.76 m-2; mean change confidence some patients over 65 years ofage but few have Department of (95% on September 30, 2021 by guest. Protected copyright. Medicine, Queen interval) at three months captopril considered ACE-inhibitor therapy specifically Elizabeth Hospital, 12 ml min'1 (+3.0, +21.0), enalapril in elderly people.'2-'7 The age of patients Edgbaston, -2 ml min-' (-13.0; + 9.0); mean change participating in large multicentre trials is lower Birmingham 15, UK at six months, captopril 3.7 ml min' than patients with heart failure in the com- MJ Kendall (-6.7; + 14.2), enalapril - 6.0 ml min- 1 munity. There is some evidence that ACE Department of (-21.0; + 9.4). Significantly more patients inhibitors have a worse side-effect profile in the Pharmacology and given captopril had an improvement in elderly'7 and the fear of hypotension and renal Clinical GFR during the study period (26/31 com- dysfunction in particular may hinder the use of Pharmacology, pared with 20/31 enalapril-treated Ninewells Hospital and patients at three months, p = 0.0096, and Medical School, 23/30 compared with 15/27 at six months, Dundee, DD1 9SY, UK Cardiac failure in the elderly AD Struthers p = 0.021). There were no significant A Bridges changes in effective renal plasma flow. * a common clinical problem becoming more Three patients treated with enalapril common Department of developed symptomatic hypotension * increases in frequency with advancing age - Geriatric Medicine, within three days of starting treatment. most patients are over 65 years old Southern General * high mortality Hospital, Glasgow, Quality of life questionnaires revealed more - overall 5 year mortality 50O0 G51 4TF, UK gastrointestinal symptoms in the - post-myocardial infarction, one year DJ Stott enalapril group (p = 0.039). mortality 40-600o Conclusions: Captopril seems margin- * cannot be described as mild - the prognosis is Correspondence to ally preferable to enalapril in the treat- worse than most cancers Dr MJ Kendall ment of chronic heart failure in elderly Accepted 6 December 1994 patients. Box 1 288 Haffner, Kendall, Struthers, Bridges, Stott ACE-inhibitor therapy in elderly heart failure The first dose of ACE inhibitor was patients. For these reasons we only studied administered the day after a reduction of dose heart failure patients who were over 65 years of of frusemide to 40 mg daily if the dose had age. previously been 80 mg daily. Semi-supine Postgrad Med J: first published as 10.1136/pgmj.71.835.287 on 1 May 1995. Downloaded from Two studies comparing short-acting and blood pressure and pulse rate were measured long-acting ACE inhibitors suggested that the every 30 minutes for six hours following the former cause less renal dysfunction.'8"9 It may first dose. be that a short-acting ACE inhibitor allows Patients were reviewed one week following restoration of some angiotensin II at the end of initiation of therapy when haemodynamic each dose interval and that this protects the measurements, blood tests and the question- glomerular filtration rate (GFR).20 Our aim was naire were repeated. Further complete assess- therefore to compare the effects of low doses of ments, including measurement of GFR and captopril and enalapril on renal function in a effective renal plasma flow, were done at three group of elderly people with chronic cardiac and six months. In addition to the formal failure. assessments, patients were visited monthly to deliver supplies ofmedications and assess com- Subjects and methods pliance (by tablet count). Patients were withdrawn from the study if This was a six-month double-blind, group any of the following were observed: worsening comparative study of captopril (12.5 mg, bid) cardiac function, serious adverse event, death, versus enalapril (2.5 mg bid). Six centres were poor compliance (more than 80% tablets must involved in recruitment. Inclusion and ex- have been consumed for the patient to remain clusion criteria for the study population are in the study), symptomatic hypotension, shown in box 2. development of an exclusion criterion, in- At their first visit, patients were assessed for clusion criteria later found to be inadequate, or their suitability to join the study and after full if they were lost to follow-up. explanation gave their written consent. The The walking test was performed in 25 study was approved by the ethics committees of patients from one centre, by asking them to all centres involved. Baseline assessments walk an individually selected distance and the included: haemodynamic measurements (lying time taken to perform this was measured using and standing blood pressure and pulse); blood a stopwatch. This had previously been tests (urea, creatinine and electrolytes, liver validated by a pilot study in 10 fit and 20 frail function tests, glucose, full blood count); stan- elderly people. dard 12-lead electrocardiogram (ECG); In one centre an interviewer administered a postero-anterior chest X-ray; exercise test; and symptom-oriented questionnaire to assess administration of a symptom-oriented ques- quality of life and minor adverse effects. This tionnaire. had also been validated by a pilot study in 10 fit There followed a run-in period of up to two and 20 frail elderly people. weeks when each patient took a placebo capsule The distribution of all the variables studied twice daily. A second set of baseline assess- were assessed for normality and differences ments was performed within a week of the first between the treatment groups were tested by http://pmj.bmj.com/ visit and this included measurement of GFR. analysis of variance with treatment and centre This was measured using a single injection, as factors or by using permutation tests22 as three blood sample radio isotope clearance appropriate. Formal comparisons between the technique,2' the radio isotope being treatment groups for symptom profiles and 99mTcDTPA at one centre and 51CrEDTA at adverse events were carried out using either the other centres. In addition, iodohippurate chi-square or Fisher's exact test. Confidence measurement ofeffective renal plasma flow was intervals were two-tailed. Differences were on September 30, 2021 by guest. Protected copyright. performed by three centres. accepted as statistically significant at the 5% level of probability. Measurements for GFR were corrected for body surface area using the standard equation. Entry criteria for study population Inclusion criteria Results * age over 65 years on entry * heart failure as defined by two or more ofthe A total of 96 patients from six centres entered following criteria: tachycardia (> 100 the placebo run-in phase of the study; 16 were beats/min), gallop rhythm, raised jugular ineligible, thus 80 patients were randomised to venous pressure, bilateral basal crepitations active treatment. The characteristics of the on auscultation ofthe lungs, peripheral oedema, and/or evidence ofheart failure on patients studied are shown in table 1. There chest X-ray. were no significant differences between the two * required 40-80 mg frusemide daily treatment groups in any of the baseline Exclusion criteria features. A further 24 patients were withdrawn * systolic blood pressure> 190 mmHg or during the study for the reasons shown in table <110mmHg 2.