Pii: s0140-6736(98)05012-0

Articles
Effect of angiotensin-converting-enzyme inhibition compared with
conventional therapy on cardiovascular morbidity and mortality in
hypertension: the Captopril Prevention Project (CAPPP)
randomised trial
Lennart Hansson, Lars H Lindholm, Leo Niskanen, Jan Lanke, Thomas Hedner, Anders Niklason, Kimmo Luomanmäki, Björn Dahlöf, Ulf de Faire, Claes Mörlin, Bengt E Karlberg, P O Wester, Jan-Erik Björck, for the Captopril Prevention with captopril than with conventional treatment (76 v s 9 5 events; relative risk 0·77 [0·57–1·04], p=0·092), the rate of B a c k g r o u n d Angiotensin-converting-enzyme (ACE) inhibitors
fatal and non-fatal myocardial infarction was similar (162 v s have been used for more than a decade to treat high blood 161), but fatal and non-fatal stroke was more common with pressure, despite the lack of data from randomised captopril (189 vs 148; 1·25 [1·01–1·55]. p=0·044).
intervention trials to show that such treatment affects I n t e r p r e t a t i o n Captopril and conventional treatment did not
cardiovascular morbidity and mortality. The Captopril differ in efficacy in preventing cardiovascular morbidity and Prevention Project (CAPPP) is a randomised intervention mortality. The difference in stroke risk is probably due to the trial to compare the effects of ACE inhibition and lower levels of blood pressure obtained initially in previously conventional therapy on cardiovascular morbidity and treated patients randomised to conventional therapy.
mortality in patients with hypertension.
Lancet 1999; 353: 6 1 1 – 1 6
M e t h o d s CAPPP was a prospective, randomised, open trial
with blinded endpoint evaluation. 10 985 patients were enrolled at 536 health centres in Sweden and Finland.
Patients aged 25–66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were Angiotensin-converting-enzyme (ACE) inhibitors areused widely in the treatment of high blood pressure.
randomly assigned captopril or conventional antihypertensive Guidelines for the management of hypertension issued by treatment (diuretics, ␤-blockers). Analysis was by intention- WHO and the International Society of Hypertension, to-treat. The primary endpoint was a composite of fatal and class ACE inhibitors as suitable for first-line treatment, along with diuretics and ␤-blockers. Guidelines issued by the Joint National Committee in the USA used to state F i n d i n g s Of 5492 patients assigned captopril and 5493
the same thing, but more recent versions of these assigned conventional therapy, 14 and 13, respectively, guidelines have not recommended ACE inhibitors as first- were lost to follow-up. Primary endpoint events occurred in line treatment. This change reflects the fact that no data 363 patients in the captopril group (11·1 per 1000 patient- from prospective and randomised trials in hypertensive years) and 335 in the conventional-treatment group patients have shown that ACE inhibitor treatmentprotects against cardiovascular morbidity and mortality.
( 1 0 · 2 per 1000 patient-years; relative risk 1·05 [95% CI There has been concern about the safety of newer 0·90–1·22], p=0·52). Cardiovascular mortality was lower antihypertensive agents and whether they give the same benefits as diuretics and ␤-blockers; such concern has Department of Public Health and Social Sciences, University of
focused on calcium antagonists but not ACE inhibitors.
Uppsala, Uppsala, Sweden (Prof L Hansson MD); Department of
The Captopril Prevention Project (CAPPP) was designed Public Health and Clinical Medicine (Prof L H Lindholm MD) and
as a prospective intervention trial to compare the Department of Medicine (Prof P O Wester MD), Umeå University
potential benefits to cardiovascular morbidity and Hospital, Umeå, Sweden; Department of Medicine, Kuopio
mortality of a regimen based on the ACE inhibitor University Hospital, Kuopio, Finland (Prof L Niskanen MD);
Department of Statistics, Lund University, Lund, Sweden
captopril with a conventional antihypertensive regimen of (Prof J Lanke PhD); Department of Clinical Pharmacology,
diuretics or ␤-blockers. For ethical reasons, a long-term Sahlgrenska University Hospital, Gothenburg, Sweden
comparison with placebo was not done.
(Prof T Hedner MD); Bristol-Myers Squibb, Stockholm, Sweden
The scientific background and rationale of the CAPPP (A Niklason MB, C Mörlin MD, J-E Björck MB); Department of
study have been reported elsewhere.5 Observations on Medicine, Helsinki University Central Hospital, Helsinki, Finland
intermediary endpoints, which were available when the (Prof K Luomanmäki MD)); GU Clinical Research Institute,
study was planned in the late 1980s, suggested that an Gothenburg, Sweden (B Dahlöf MD); Department of Cardiovascular
antihypertensive regimen based on an ACE inhibitor Research, Karolinska Hospital, Stockholm, Sweden
might offer benefits equal to or greater than those of (Prof U de Faire MD); and Department of Medicine, University
Hospital, Linköping, Sweden (Prof B E Karlberg MD)
conventional antihypertensive treatment with diuretics, ␤-blockers, or both.6 ACE inhibitors help to reverse left- Correspondence to: Prof Lennart Hansson, Division of Clinical
ventricular hypertrophy,7,8 itself a powerful indicator of Hypertension Research, Department of Public Health and SocialSciences, University of Uppsala, Box 609, S-751 25 Uppsala, patients with left-ventricular dysfunction,11,12 THE LANCET • Vol 353 • February 20, 1999 Figure 1: Trial profile
favourable metabolic effects,13 and help to maintainquality of life.14 More recently, benefits of ACE inhibitionhave been shown in patients with diabetic nephropathy15and in diabetic patients in general.16 ACE inhibitors also Figure 2: Blood pressure during study
maintain renal function in patients with primary Open Blinded Endpoint), which is similar to routine clinical hypertension,17,18 which strengthens the hypothesis that a practice. Men and women aged 25–66 years who had treated or therapeutic regimen based on ACE inhibitors in the untreated primary hypertension were included in the trial if their treatment of primary hypertension could reduce the risk diastolic blood pressure was 100 mm Hg or higher on two of cardiovascular morbidity and mortality.
separate occasions. Exclusion criteria were secondaryhypertension, serum creatinine concentration of more than 150 ␮mol/L, and disorders that required treatment with ␤-blockers. Eligible patients were randomly assigned captopril treatment or conventional antihypertensive treatment with The CAPPP trial, at 536 health centres in Sweden and Finland, diuretics, ␤-blockers, or both. The initial dose of captopril was used the design of the PROBE study19 (Prospective Randomised 50 mg daily given in one or two doses. In the group receivingconventional treatment, atenolol and metoprolol were the most Characteristic
Captopril
Conventional
commonly used ␤-blockers, and hydrochlorothiazide and treatment
treatment
bendrofluazide the most common diuretics. The initial dose of (n=5492)
(n=5493)
atenolol and metoprolol was 50–100 mg once daily.
Demographic
M/F
Characteristic
Previously untreated (n=5245)
Diabetes (n=572)
Clinical
Demographic
Clinical
Medical history
Medical history
Data are number of patients or *mean (SD).
Data are number of patients or *mean (SD).
Table 2: Baseline characteristics of previously untreated
Table 1: Baseline characteristics
patients and of patients with diabetes at baseline
THE LANCET • Vol 353 • February 20, 1999 Event (n)
Captopril group
Conventional group
Table 3: Patients with events during follow-up by treatment
group
WHO criteria, and required at least two abnormal fastingglucose values or, if not unequivocal, confirmation by an oralglucose-tolerance test. The CAPPP study was approved by ethics Figure 3: Patients remaining free from primary endpoint
Hydrochlorothiazide was given as 25 mg once daily, andbendrofluazide as 2·5 mg once daily. The randomisation sequence was generated by computer and conveyed to the Analysis was by intention to treat. The CAPPP study was investigators by means of sealed numbered envelopes, one for each designed to have an 80% power of detecting a 20% reduction in patient, with instructions to use the envelopes in numerical order.
the rate of primary endpoints in a two-sided test at 5% Blood pressure was measured with the patient supine by significance. 640 primary events were required in the two groups means of conventional mercury sphygmomanometers. The cuffs combined. For each patient, only the first occurrence of primary contained a rubber bladder with dimensions of 12ϫ35 cm.
endpoint was included in the analysis. Cox regression analysis Larger cuffs were used if necessary. We calculated the mean of used time since randomisation as a non-parametrically modelled two measurements of blood pressure made to the nearest 2 mm time variable. The model was adjusted for age at randomisation, Hg. The goal of treatment was a supine diastolic blood pressure sex, diabetes, and systolic blood pressure at randomisation. The of 90 mm Hg or less. To reach this goal, the treatment dose study group included both previously untreated patients and could be increased to 100 mg once or twice daily in the captopril patients receiving antihypertensive treatment before group, and if necessary a diuretic was added. In the group that randomisation, and we did not include a washout period.
received conventional treatment, an optimum dose of ␤-blocker We therefore had to account for baseline differences in the or diuretic was used. The investigators were free to choose model. We included baseline systolic blood pressure, a factor suitable conventional treatment, and the diuretic and the ‘previously untreated’, and the product of these factors in the ␤-blocker could be combined. A calcium antagonist could be model. In the on-treatment analysis a patient was classified as on added to the treatment regimen in both treatment groups.
treatment for as long as he or she took the intended medication The primary endpoint was the combination of fatal and non- and no other medication. All calculations used Stata software fatal myocardial infarction and stroke, and other cardiovascular deaths. Primary events and most secondary events were assessedby an independent endpoint committee from which the treatment allocation was concealed. Secondary endpoints were 11 018 patients were enrolled in the study, but 33 were new or deteriorated ischaemic heart disease and congestive heart excluded because of their age. Of the remaining 10 985 failure, atrial fibrillation, diabetes mellitus, transient ischaemic patients, 5492 were randomly assigned captopril attacks, and death from all causes. A diagnosis of acute treatment and 5493 were randomly assigned conventional myocardial infarction required that at least two of the following treatment (figure 1). Follow-up lasted for a mean of 6·1 criteria were met: central chest pain for more than 15 min;transient increase in serum concentrations of enzymes indicating years: a total of 67 239 patient-years were recorded. Only myocardial damage; and electrocardiographic changes typical of 27 (0·25%) patients were lost to follow-up.
myocardial infarction. A diagnosis of fatal myocardial infarction Baseline characteristics (table 1) and effects on blood required the same criteria as a non-fatal acute myocardial infarct, pressure have been described elsewhere.20 Blood pressure or a statement of that diagnosis in hospital or necropsy reports.
at baseline was higher in the captopril group than in the Diagnosis of stroke required typical symptoms or signs of group that received conventional therapy, both among remaining neurological deficit, with sudden onset and previously untreated patients (166·6/103·6 vs 163·3/101·2 persistence for more than 24 h. Diagnosis of transient ischaemic mm Hg, p<0·0001 in both cases) and among those attacks required symptoms and signs of neurological deficit with already on antihypertensive treatment (157·4/96·2 vs sudden onset but with a duration of less than 24 h. Diagnosis of 156·2/95·4 mm Hg; p=0·025 and p=0·001, respectively, fatal stroke required the same criteria as a non-fatal stroke, or astatement of that diagnosis in hospital records or necropsy figure 2). Diabetes mellitus at baseline was more reports. Diagnosis of diabetes was made according to common in the captopril group than in the group treatment (table 2).
The primary endpoint(fatal myocardial infarction, strokeand other cardiovasculardeaths) did not differbetween the two treatmentgroups (relative risk 1·05; p=0·52, figures 3, 4).
Numbers of the individual Figure 4: Relative risk of captopril vs conventional therapy
*Adjusted for age, sex, diabetes, systolic blood pressure, and previous treatment.
THE LANCET • Vol 353 • February 20, 1999 We corrected our data for imbalance in blood pressure at Relative risk (95% CI)*
baseline, sex, and the prevalence of diabetes in the analyses. Centralised randomisation by fax21 would have been preferable, but this procedure was not standard Myocardial infarction, fatal and non-fatal 10 years ago, when this study was planned.
The proportion of patients lost to follow-up (0·25%) is not as low as that of the STOP-Hypertension trial (0),22 *Adjusted for age, sex, diabetes, systolic blood pressure, and previous treatment.
but much lower than that of the MRC study in older Table 4: On-treatment analysis: relative risk of captopril vs
patients (25%).23 The small number of patients lost to conventional therapy
follow-up could not have affected the results of our study,since the loss was evenly distributed between the two Cardiovascular mortality, defined as fatal stroke and treatment groups (14 vs 13). Complete information on myocardial infarction, sudden death, and other primary events was available for the remaining patients.
cardiovascular death, was slightly lower in the captopril The two treatment regimens had virtually the same group than in the conventional group (0·77; p=0·092).
effect on blood pressure, although blood pressure Fatal and non-fatal strokes were more common in the measurements were slightly but significantly higher in the captopril group (1·25; p=0·044). The rates of fatal and captopril group throughout the study (figure 2). Almost non-fatal myocardial infarction were similar in the two all of the previously treated patients had been taking diuretics, ␤-blockers, or both, and were accustomed to Analyses of secondary outcomes (figure 4) showed that that kind of therapy, whereas captopril was in most total mortality did not differ between the two treatment instances a new therapy. Target blood pressure (diastolic groups (0·93; p=0·49), and the incidence of diabetes was blood pressure 90 mm Hg) was more rapidly achieved in lower in the captopril group than in the conventional the conventionally treated group than in the captopril group (0·86; p=0·039). The rates of all cardiac events—fatal group during the first 6–12 months of the study and non-fatal myocardial infarction, other cardiovascular (figure 2), although this effect was not noted for deaths and sudden deaths, ischaemic heart disease, previously untreated patients. Our study would have been congestive heart failure, atrial fibrillation—did not differ improved if we had included only previously untreated between the two treatment groups (0·94; p=0·30).
patients, but recruitment of a large enough sample would On-treatment analysis was also done. No new differences between groups were shown, although the Almost equal numbers of patients began captopril results that were significant by intention-to-treat were treatment once daily (48%) and twice daily (52%), but more significant in the on-treatment analyses (table 4).
patients were switched between these two regimens There was no difference between groups in blood during the trial. Moreover, patients were not randomly pressure related to cardiovascular mortality or morbidity, assigned once-daily or twice-daily treatment. These or in comparisons between once-daily and twice-daily factors preclude meaningful analysis of outcomes in Separate subgroup analyses were done for patients with The treatment regimens did not differ in terms of diabetes at baseline and for previously untreated patients prevention of the primary endpoint, but the risk of stroke (figure 5, 6). In both of these groups, captopril was as was lower with conventional than with captopril therapy.
effective in preventing cardiovascular events as in the This finding could be the result of non-adjustment for high blood pressure measurements at baseline and throughout the study in the captopril group, or a more Our conventional randomisation procedure, using sealed frequent history of stroke and transient ischaemic attacks envelopes, resulted in an imbalance between groups at in that group than in the group assigned conventional baseline in terms of the blood pressure measurements.
treatment. A difference of 2 mm Hg could account for a 15% difference in risk ofstroke and transientischaemic attack.24 diabetic patients bloodpressure measurements atbaseline were identical inthe two treatment groupsand the incidence of stroke Figure 5: Relative risk in previously untreated patients (n=5245)
*Adjusted for age, sex, diabetes, and systolic blood pressure.
fatal strokes did notdiffer significantly in the conventional): if therereally was an increased riskof stroke in the captoprilgroup, there should havebeen a proportionalincrease in both fatal and Figure 6: Relative risk in patients with diabetes mellitus at baseline (n=572)
*Adjusted for age, sex, systolic blood pressure, and previous treatment.
THE LANCET • Vol 353 • February 20, 1999 term follow-up data from the Glasgow Blood Pressure between regimens might not be apparent. By contrast, Clinic showed that the reduction in fatal stroke among those previously untreated, both regimens would associated with ACE inhibitors was at least as good as be new to the patients and the difference in compliance that associated with non-ACE inhibitors.25 discussion of this issue can be expected when the results of the STOP-Hypertension-2 study become available,26 in The overall results of the CAPPP study suggest than an which hypertensive patients were randomly assigned one antihypertensive regimen based on ACE inhibitors is as of the three therapeutic options: conventional treatment effective as conventional treatment with diuretics, (diuretics, ␤-blockers), calcium antagonists, or ACE ␤-blockers, or both in prevention of cardiovascular inhibitors, with cardiovascular mortality as the primary morbidity and mortality, possibly less effective in the prevention of stroke, and most probably more effective in There were fewer major cardiovascular events in the the prevention of diabetes. This finding is of particular captopril group, in line with our expectation of the effect importance because recent studies have emphasised that of captopril on intermediate endpoints.5,15–18 Significantly both therapies have the same total treatment cost.33–35 fewer patients developed diabetes in the captopril group than in the conventional group. This effect may be Steering committee—L Hansson, J-E Björck, B Dahlöf, U de Faire, attributed to the positive effect of captopril on insulin T Hedner, B E Karlberg, J Lanke, L H Lindholm, K Luomanmäki, sensitivity during long-term antihypertensive treatment,13 C Mörlin, L Niskanen, P O Wester.
Endpoint committee—G Härtel, P Siltanen, K Swedberg, A Terent.
although studies of other ACE inhibitors have not Endpoint secretary—A Holmner.
Safety committee—L Erhardt, M Kupari, T Thulin, P-O Bendahl diabetes in the captopril group should have positive (statistician).
Data management—B Slaug.
implications for long-term cardiovascular prognosis.
Patients with diabetes at baseline had a significantly Sweden—P-O Andersson, J Asplund, A Dahlqvist, B Fagerberg, G Frithz, lower rate of the primary endpoint and of fatal B-G Hansson, A Hägg, S A Jonsen, T Kahan, B Carlberg, B EKristensson, J Kuylenstierna, H Larsson, B Lindström, I Mattiasson, cardiovascular events in the captopril group than in the B-H Möller, O R Nilsson, H Stakeberg, A Svensson, K Tolagen, conventional group. There was a 66% lower rate of fatal and non-fatal myocardial infarctions in the captopril Finland—A Lehtonen, M Lilja, M Nikkilä, J Partanen.
group than in the conventional group. The frequency of InvestigatorsSweden—H Aagaard, G Abrahamsson, T Ahlberg, H Åhlander, N Ahlén, all cardiac events and total mortality was also significantly G Ahlepil, E Ahlzén, L-G Ahnell, K Aljaderi, G Almqvist, M Alvin, lower in the captopril group than in the conventional B Andersson, G Andersson, H Andersson, I Andersson, M André, group. These findings are similar to those of the subgroup A Anglemo, S Anker, C Appelgren, K Arnman, G Asplund, B Atmer,C Aurelius, G Bartfay, E Basilier, L Berg, M Berg, M Bergfeldt, analysis of the ABCD (Appropriate Blood Pressure A Berglund, B Bergman, B-M Bergman, B Bergstad, R Bergström, Control in Diabetes) study,16 and they strengthen the J-E Billner, L Björkman, I Björkvald, S Blanking, U Blomqvist, impression that an antihypertensive regimen based on L Bodegård, S Bojesen, I Boman, O Borgholst, M Boström, G Bredmose-Hansen, M Brian, J Brun, B Bystritski, S Byström, ACE inhibitors is particularly appropriate for the E Bög-Hansen, S-M Carlsson, M Cech, B Christensen, O Christensen, treatment of diabetic patients with hypertension.
A Dahl, G Dahlberg, G Dahlén, C Dahlin, A Dahlman, M Dalemar, On the other hand, the UK Prospective Diabetes Study L Duca, T Dyrborn, R Dziamski, Å Edlund, C Edström, M Edward, (UKPDS 39)30 showed no advantage for captopril over A Egilsson, T Ehn, M Ehnebom, M Ekberg, K Ekenbratt, S Ekesrydh,T Ekman, H Ekström, A Elfstrand, T Elfstrand, M Elm, K-G Enander, atenolol in lowering of the risk of macrovascular and M Enander, J Engborg, C Engstrand, G Engström, U-B Ericsson, microvascular diabetic complications. This finding V Eriksen, S Eriksson, U Eriksson, C Eskilson, C Fabian, L Falk, suggests that lowering of blood pressure per se may be G Filipsson, B-C Flensner, C Floom, I Fogelberg-Abrah, R Forrest, P-G Franke, B Franzén, C Frederiksen, S Fredlund, G Frenkner, more important than the choice of antihypertensive J Frithiof, K Fröstrom, B Furunes, B Gebre-Georgies, A Gidlöf, agent, although captopril was better tolerated than D Gilstring, A Gonn, U Grandell, P Grangaard, R Grenholm, atenolol by most patients.31 The effective lowering of V D Gräslund, L Grönquist, C-L Gustafsson, P Gustafsson, P Hansson,P Hajslund-Hansen, H Hallberg, C Hallendal, L Hallin, G Hansen, blood pressure in the UKPDS 39 trial was highly B Hansson, B Hansson, T Havland, M Hedlund, I-L Hegestrand, beneficial in diabetic patients, which confirms S Hellerstedt, P Hellke, P Hellman, M Hellqvist, T Hermansson, observations in the HOT study21 in which the excess risk C Hersvall, K Hertell, O Herterich, M Hessel, C Heyman, H Hirsch, associated with diabetes was negligible in patients in L Hjelmaeus, I Hjärne, S Hofvendahl, B Hofverberg, S Hollenberg,U Hollertz, R Hollsten, G Holmberg, F Holmer, A Holmgren, A-L Hult, whom diastolic blood pressure was lowered to 80 mm Hg A Hult, A Hägerfors, C Höglund, T Höglund, J Höjer, B-G Idh, S Ingelög, H Isaksson, M Ivermark, G Jansson, R Jansson, J Jarl, Captopril was more effective in lowering the risk of B-O Johansson, B Johansson, E Johansson, G Johansson, H Johansson, L-Å Johansson, N-E Johansson, Y Johansson, Å Johansson, B Johnson, cardiovascular events, particularly fatal events, in the L Jonsson, K Juul, C Jägerström, C Jägrén, H J Jörgensen, C Karkow, previously untreated group than in the study population E Karlsson, T Kjellström, G Klemetz, L Klockhoff, R Klötz, P Koritz, as a whole. One factor that may help to explain the H Kristoferson, P Kronmann, B Kuylenstierna, H Landström, I Lantz, A-K Larsson, G Larsson, K Larrson, M Larsson, R Larsson, R Larsson, variation in findings between previously treated and Å Larsson, L Leander, K Leetmaa, B Lenngren, M Lind, I Lindahl, previously untreated patients is a difference in R Lindbergh, H O Lindbergsson, U Lindblad, B Lindborg, P Linde, compliance between captopril and the conventional L Lindén, T Lindén, B Linder, B Linder, H Lindfors, I Lindgren,A Lindh, B-Å Lindhe, A-C Lindman, E Ljungberg, L Ljungdahl, regimen. We did not investigate this factor, but Monane P Lorenzon, V Lukic, U Lundahl, N Lundström, C Lydén, J Löfgren, and colleagues32 showed that therapy with an ACE T Löfgren, L Lönneborg, B Lönner, F Lönqvist, B Magnusson, inhibitor had 1·9 times better compliance than therapy P-O Magnusson, K Malmlöf, B Malmros, K Marcus, K Marits, with diuretics in a large group of hypertensive patients.
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THE LANCET • Vol 353 • February 20, 1999

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