|Effects of ramipril on
cardiovascular and microvascular outcomes in people with
diabetes mellitus: results of the HOPE study and
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators*
*Study organisation and investigators listed at end of paper
Correspondence to: Dr Hertzel C Gerstein, Canadian Cardiovascular Collaboration Project Office, HGH-McMaster Clinic, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada (e-mail:HOPE@ccc.mcmaster.ca)
Background Diabetes mellitus is a strong risk
factor for cardiovascular and renal disease. We
investigated whether the angiotensin-converting-enzyme
(ACE) inhibitor ramipril can lower these risks in
patients with diabetes. Methods 3577 people with
diabetes included in the Heart Outcomes Prevention
Evaluation study, aged 55 years or older, who had a
previous cardiovascular event or at least one other
cardiovascular risk factor, no clinical proteinuria,
heart failure, or low ejection fraction, and who were not
taking ACE inhibitors, were randomly assigned ramipril
(10 mg/day) or placebo, and vitamin E or placebo,
according to a two-by-two factorial design. The combined
primary outcome was myocardial infarction, stroke, or
cardiovascular death. Overt nephropathy was a main
outcome in a substudy. Findings The study was
stopped 6 months early (after 4·5 years) by the
independent data safety and monitoring board because of a
consistent benefit of ramipril compared with placebo.
Ramipril lowered the risk of the combined primary outcome
by 25% (95% CI 1236, p=0·0004), myocardial infarction
by 22% (636), stroke by 33% (1050), cardiovascular
death by 37% (2151), total mortality by 24% (837),
revascularisation by 17% (230), and overt nephropathy
by 24% (340, p=0·027). After adjustment for the
changes in systolic (2·4 mm Hg) and diastolic (1·0 mm
Hg) blood pressures, ramipril still lowered the risk of
the combined primary outcome by 25% (1236, p=0·0004). Interpretation
Ramipril was beneficial for cardiovascular events and
overt nephropathy in people with diabetes. The
cardiovascular benefit was greater than that attributable
to the decrease in blood pressure. This treatment
represents a vasculoprotective and renoprotective effect
for people with diabetes. Lancet 2000; 355:
People with diabetes mellitus are at high risk of cardiovascular disease. Epidemiological studies show that the risk of cardiovascular mortality is two to three times higher in men with diabetes and three to five times higher in women with diabetes than in people without diabetes.16 The age-adjusted prevalence of coronary heart disease in white adults who have diabetes is about 45%, compared with about 25% in individuals without diabetes,7 and cardiovascular disease accounts for about 70% of all deaths in people with diabetes mellitus.8
The presence of other risk factors increases the risk of cardiovascular disease in people with diabetes mellitus. The absolute annual risk of fatal and non-fatal cardiovascular disease in middle-aged and elderly people with type 2 diabetes is 45%.1,913 Despite decreases in the incidence of heart disease in the general population, the decline is much smaller in people with type 2 diabetes, and may even be rising in women with diabetes.13
Experimental studies, epidemiological studies, and clinical trials suggest that inhibitors of angiotensin-converting enzyme (ACE) may delay or prevent cardiovascular outcomes. For patients with diabetes, such benefit has been seen after acute myocardial infarction,14 in the presence of hypertension,1519 and in the presence of a low ejection fraction or heart failure.20 ACE inhibitors may also prevent overt nephropathy and other microvascular outcomes in patients with type 1 or type 2 diabetes.17,21,22
Although studies suggest that ACE inhibitors may
prevent or delay serious events in some subgroups, their
role in a broader group of people with diabetes who are
at high risk of cardiovascular events remains unknown.
The Heart Outcomes Prevention Evaluation (HOPE) study
investigated whether the addition of the ACE inhibitor
ramipril to the current medical regimen of high-risk
patients with diabetes mellitus can lower the risk of
cardiovascular events. In the microalbuminuria,
cardiovascular, and renal outcomes (MICRO) HOPE substudy,
the effect of this intervention on the risk of overt
nephropathy was investigated. We present here the results
from these two studies for patients with diabetes
The HOPE and MICRO-HOPE study protocol has been published.23,24 Briefly, people with and without diabetes were recruited, who were aged 55 years or older, and who had a history of cardiovascular disease (coronary artery disease, stroke, or peripheral vascular disease) or diabetes plus at least one other cardiovascular risk factor (total cholesterol >5·2 mmol/L, HDL cholesterol <=0·9 mmol/L, hypertension, known microalbuminuria, or current smoking). Key exclusion criteria were dipstick-positive proteinuria or established diabetic nephropathy, other severe renal disease, hyperkalaemia, congestive heart failure, low ejection fraction (<0·4), uncontrolled hypertension, recent myocardial infarction or stroke (<4 weeks), and use of or hypersensitivity to vitamin E or ACE inhibitors.23 The study was done in 19 countries in North and South America and in Europe. The HOPE study protocol was approved by each institution's review board or ethics committee, and all participants provided written, informed consent.
Eligible participants were included who completed a run-in period, during which they received 2·5 mg ramipril daily for 710 days, followed by matching placebo for 1014 days, who were at least 80% compliant, tolerated the drug without side-effects, and maintained a serum creatinine concentration of 200 µmol/L or lower and potassium concentration of 5·5 mmol/L or lower.
The study had a two-by-two factorial design with randomisation of participants to 10 mg ramipril or placebo taken once daily in the evening and 400 IU vitamin E or placebo daily. Follow-up visits were at 1 month and then every 6 months.
The combined primary endpoint was the development of myocardial infarction, stroke, or cardiovascular death. Secondary endpoints were total mortality, admission to hospital for congestive heart failure or unstable angina, cardiovascular revascularisation, or development of overt nephropathy. Other outcomes were any heart failure, worsening angina, and the development of diabetes in people with no history of the disorder. A preplanned analysis in the HOPE and MICRO-HOPE studies was to find out whether ramipril delayed or prevented these outcomes, as well as microalbuminuria or overt nephropathy, in participants with diabetes.22,25 All primary and secondary outcomes were documented on separate forms and centrally assessed by the event committee (who were unaware of the participants' assigned treatments) according to standard definitions.23
Diabetes status and other demographic and clinical variables were established by history and physical examination at each visit. Participants were judged to have type 2 diabetes if they developed diabetes at age 30 years or older or were not taking insulin. We defined a history of hypertension as the taking of drugs to treat hypertension or blood pressure at recruitment higher than 160 mm Hg systolic or 90 mm Hg diastolic. Glycated haemoglobin (HbA1c) and serum creatinine were assayed for participants with a history of diabetes in each study centre's local laboratory. Results for HbA1c were expressed as the percentage higher than the upper limit of normal for the assay used. Any admissions for hypoglycaemia were recorded.
As part of the MICRO-HOPE substudy, urinary albumin excretion was measured at baseline, 1 year, and study end (4·5 years) by measuring the albumin/creatinine ratio in a first morning urine sample. Urine was stored at 70ºC. The albumin/creatinine ratio was measured in four different laboratories during the study (in Canada, UK, Argentina, and Brazil) by different assay systems.22 Microalbuminuria was defined in 1993 as a ratio of 2 mg/mmol or higher in men and women.22
Participants whose albumin/creatinine ratio was higher than 36 mg/mmol after randomisation were asked to provide a 24 h urine sample that was assayed in their local laboratory for total protein or urinary albumin; assays were chosen according to availability at each clinical site. Overt nephropathy was diagnosed if the 24 h urine albumin was 300 mg or more per day, if the 24 h urine total protein excretion was 500 mg or more per day, or if the measured albumin/creatinine ratio was higher than 36 mg/mmol and no 24 h urine result was available (ie, if there was evidence of clinical proteinuria). The measurements of actual daily excretion of albumin or protein for all 24 h urine collections were sent to the project office and all cases of overt nephropathy were centrally assessed.
The HOPE study was designed to recruit up to 4000 participants with diabetes. With the assumption of a constant event rate in participants with diabetes of 5% per year, this sample size would provide 90% power (two-sided alpha=0·05) to detect an 18% relative risk reduction in the rate of myocardial infarction, stroke, or cardiovascular death during the planned mean follow-up period of 5 years. The study was ended 6 months early on the recommendation of the independent data safety and monitoring board. Therefore, we report results for a median follow-up period of 4·5 years.
We report only analyses done by intention to treat.
Analyses were stratified according to randomisation to
vitamin E or placebo by Cox's regression, to account for
the factorial design. Results are reported as the
relative risk reduction (95% CI), defined as 1 minus the
relative hazard. Kaplan-Meier curves were used to
estimate survival and were compared by log-rank test.
Changes in continuous variables (ie, HbA1c,
albumin/creatinine ratio, blood pressure, serum
creatinine) from baseline values, by treatment group,
were analysed by ANOVA, adjusted for the baseline value.
Albumin/creatinine ratios were transformed to account for
non-normality and values were adjusted for the
laboratories in which ratios were measured. Statistical
tests for interaction were done with Cox's regression to
assess the effect on the primary outcome of diabetes
type, diabetes treatment, history of previous
cardiovascular events, and presence of microalbuminuria
or a history of hypertension at randomisation, and a
similar approach was used to assess the effect of the
presence of baseline microalbuminuria on the development
of overt nephropathy. Cox's regression models were also
used to assess the effect of randomisation to ramipril on
the primary outcome after adjustment for the change in
blood pressure during the course of the study.
Of all 9541 participants in the HOPE study, 3654 (39·3%) had diabetes at randomisation. 77 people who participated in another substudy in which they received only 2·5 mg ramipril or placebo were excluded from the analysis. Therefore, 3577 people with diabetes were included. The mean age was 65·4 years, 1322 (37%) were women, and 1996 (56%) had a history of hypertension. Baseline characteristics of participants in the ramipril and placebo groups were similar (table 1).
Of surviving participants at 1 year, 1486 (84%) patients in the ramipril group and 1516 (88%) in the placebo group were still taking study drugs, as were 1045 (65%) and 992 (66%), respectively, at the end of the study. At 4 years, 184 (12%) participants initially assigned ramipril and 220 (15%) initially assigned placebo were taking open-label ACE inhibitors. Non-medical reasons for stopping the study drug are shown in table 2. The only notable side-effect that led to excess discontinuation of study drug was cough, which was 5% more frequent among participants taking ramipril than among those taking placebo. The rate of admission to hospital because of hypoglycaemia did not differ between the ramipril and placebo groups (2 vs 2%), nor did the mean change in serum creatinine concentration.
The rate of the combined primary outcome of myocardial infarction, stroke, or cardiovascular death was significantly lower in the ramipril group than in the placebo group (relative risk reduction 25% [95% CI 1236], p=0·0004). When the outcome components were analysed separately, the rates were also lowered significantly in the ramipril group, as were the secondary outcomes (table 3, figure 1). Ramipril lowered the risk of the primary outcome by 16% (14 to 39, p=0·26) after 1 year, and significantly by 26% (641, p=0·011) after 2 years. This effect was maintained at each subsequent year of follow-up.
Ramipril's benefit was noted irrespective of whether participants had a history of cardiovascular events (p for interaction=0·91), hypertension (p for interaction=0·93), or microalbuminuria (p for interaction=0·34), whether or not participants had type 1 or type 2 diabetes (p for interaction=0·32), and irrespective of current treatment for hyperglycaemia (p for interaction=0·51). The effect of ramipril in different diabetes-related subgroups is shown in figure 2.
Compared with baseline, mean absolute HbA1c values increased by absolute amounts of 1·5% higher than the upper limit of normal in the ramipril group and 3·4% in the placebo group at 1 year (p=0·04). They fell by 0·1% among participants taking ramipril and rose by 2·2% among participants taking placebo at 2 years (p=0·016); the change from baseline in HbA1c was the same for both groups at subsequent visits and at the end of the study (2·2% for ramipril and 2·0% for placebo respectively; p=0·8).
Blood pressure decreased slightly more among participants on ramipril than among those on placebo. By the end of the study, systolic blood pressure had fallen by 1·92 mm Hg and risen by 0·55 mm Hg in participants on ramipril and placebo, respectively (p=0·0002); diastolic blood pressure had fallen by 3·30 mm Hg and 2·30 mm Hg in the ramipril and placebo groups (p=0·008; table 4). After adjustment for changes in blood pressure, ramipril had the same effect on the primary outcome as that before adjustment (relative risk reduction 25% , p=0·0004).
Albumin/creatinine ratio was measured in 3498 (98%) participants at baseline, 2914 (83%) of 3511 at 1 year, and 2671 (86%) of 3106 at the end of the study. During follow-up, 345 (10%) participants developed an albumin/creatinine ratio of more than 36 mg/mmol and were asked to provide a 24 h urine collection to test for overt nephropathy. Results were available for 295 (85·5%) individuals. 117 (7%) participants on ramipril and 149 (8%) on placebo developed overt nephropathy (24% , p=0·027). When a more stringent definition of overt nephropathy was used and the analysis was restricted to people in whom 24 h urine results were available, 100 (6%) participants in the ramipril group and 124 (7%) in the placebo group were affected (22% [2 to 40], p=0·07). Restriction of the definition of overt nephropathy even further to include only people who had a positive 24 h urine collection and who reported a history of laser therapy for retinopathy gave similar results (25% [39 to 59], p=0·36).
225 (20%) participants with and 41 (2%) without baseline microalbuminuria developed overt nephropathy (relative risk 14·0 , p<0·0001). Ramipril lowered the risk of overt nephropathy in participants who did and did not have baseline microalbuminuria (p for interaction 0·51). Moreover, ramipril treatment led to a lower albumin/creatinine ratio than placebo at 1 year and at the end of the study end (figure 3). In participants without baseline microalbuminuria, the risk of new microalbuminuria was non-significantly reduced (relative risk reduction 9% [4 to 20], p=0·17).
The effect of ramipril on a reported history of new
laser therapy for diabetic retinopathy, and on a reported
history of renal dialysis are shown in table 3. Ramipril
reduced the risk of a combined microvascular outcome of
overt nephropathy, dialysis, or laser therapy by 16%
Ramipril significantly lowered the risk of major cardiovascular outcomes by 2530% in a broad range of high-risk middle-aged and elderly people with diabetes mellitus. The benefit was apparent irrespective of whether participants had a history of cardiovascular events, hypertension, or microalbuminuria, were taking insulin or oral antihyperglycaemic agents, or had type 1 or type 2 diabetes mellitus. The study had, however, low power to detect different effects in the subgroups. Since adherence to ramipril was 65% at the last visit, our results may underestimate the benefit that would have been seen with higher adherence.
Ramipril also lowered the risk of overt nephropathy, renal failure, or laser therapy. It had no long-term effect on glycaemic control.
When the major cardiovascular and microvascular events are taken into account, 15 high-risk people with diabetes would have to be treated with ramipril for a median of 4·5 years to prevent one individual from having a myocardial infarction, stroke, cardiovascular death, admission to hospital for heart failure, a revascularisation procedure, development of overt nephropathy, laser therapy for retinopathy, or renal dialysis.
We assessed blood pressure by cuff pressures, which is the normal approach in clinical practice and large randomised trials. We did not monitor ambulatory blood pressure and, therefore, excess overnight hypertension in the placebo group cannot be excluded. The risk reduction for cardiovascular events was, however, greater than would be expected from the observed mean difference in blood pressure between groups, which supports the results of the regression model showing that the effect of ramipril was much greater than can be attributed to its effect on blood pressure. For example, in the UK Prospective Diabetes Study (UKPDS),16 mean differences between groups in systolic and diastolic blood pressures of 10 mm Hg and 5 mm Hg, respectively, lowered the risk of myocardial infarction by 21% and stroke by 44%. Similarly, in participants with diabetes in the Systolic Hypertension in the Elderly (SHEP) study,26 a decrease in systolic and diastolic pressures of 10 mm Hg and 2 mm Hg, respectively (using a diuretic-based approach), reduced the risk of cardiovascular events by up to 34%. By contrast, in the HOPE study the differences in systolic and diastolic blood pressures were only slight at 2·2 mm Hg and 1·4 mm Hg, yet the decreases in risk of myocardial infarction and stroke were similar to those seen in UKPDS.
These considerations suggest that the observed benefits of ramipril may be due largely to a protective effect of ACE inhibitors on the arterial wall.27 Angiotensin II is a powerful direct vasoconstrictor, and promotes vascular smooth-muscle growth, possibly by inducing various proto-oncogenes and growth factors. It may also promote plaque rupture, possibly by stimulating release of endothelin, inhibiting fibrinolyis, and promoting thrombosis.27 Bradykinin is a direct vasodilator and also promotes release of the vasodilating substances nitric oxide and prostacyclin. The effect of ACE inhibitors may, therefore, be mediated by the lowering of angiotensin-II concentrations and the increasing of bradykinin concentrations.
The observed effect of ramipril on cardiovascular outcomes are consistent with the results of other trials of ACE inhibitors in people with diabetes that were designed as trials of lowering blood pressure. For example, the Captopril Prevention Project15 randomised 717 participants with diabetes mellitus who had severe hypertension in an open trial. After 6·1 years of follow-up those taking captopril had a 14% (95% CI 126) lower rate of myocardial infarction, stroke, or cardiovascular death than those taking diuretics and ß-blockers.15 Similarly, the UKPDS study showed that the lowering of blood pressure with captopril or atenolol clearly decreased the risk of cardiovascular and microvascular events, but found no benefit of captopril over atenolol.17 Because 758 participants were randomly assigned captopril or atenolol and the event rate was 34%, the study had high power (about 80%) to detect large differences (eg, 30% differences in relative risk). However, differences in benefit between two active therapies are likely to be smaller than those between active treatments and placebo, and may typically be about 10%. Such differences could, therefore, have been missed. The results of other trials have supported a beneficial cardiovascular effect of ACE inhibitors over calcium-channel blockers, although this was not the primary aim of these studies.18,19,28
For microvascular outcomes, our results are consistent with previous observations in individuals with type 1 and type 2 diabetes that ACE inhibitors lower the risk of diabetic nephropathy29,30 and renal failure,31 and are consistent with previous reports suggesting that ACE inhibition with lisinopril reduces the risk of diabetic retinopathy in normotensive people with type 1 diabetes.21 The findings are limited by the fact that the albumin/creatinine ratio was measured in four different laboratories, and that 24 h urine collections to confirm the presence of overt nephropathy were done in many different laboratories. Nevertheless, we adjusted analysis of the albumin/creatinine ratio for the laboratory in which it was measured and all 24 h urine results were adjudicated centrally. Moreover, a beneficial effect of ramipril was seen despite the increased variability because of the different laboratories, which would lead to an underestimate of the effect of ramipril on overt nephropathy.
The results are also limited by the fact that overt nephropathy was not confirmed by a renal biopsy--a point that may be important because of observations of a high rate of non-diabetic renal disease in people with type 2 diabetes.32,33 Nevertheless, a report and review of morphological data from several studies suggests that clinical proteinuria is a reliable marker for overt diabetic nephropathy in people with type 2 diabetes.34 Moreover, our results were unchanged after use of a more stringent definition for diabetic nephropathy (a positive 24 h urine collection plus a history of retinopathy that was treated with laser therapy). In addition, epidemiological studies show a high rate of renal failure in people with type 2 diabetes and overt nephropathy defined on the basis of clinical proteinuria alone.33 For retinopathy alone, these results are clearly limited by the fact that retinal photographs were not taken. Nevertheless, a history of laser therapy for diabetic retinopathy is likely to be highly specific, but not sensitive, for serious diabetic retinopathy.
Because the HOPE study was not designed to be a trial of the effect of lowering blood pressure, only general comparisons can be made with other studies. In the HOPE study, ramipril was added to participants' current treatments at randomisation and was not titrated to achieve prespecified blood pressures. Therefore, ACE inhibition with ramipril is most appropriately viewed for this study as a preventive intervention with multiple mechanisms of benefit, including lowering of blood pressure. Its addition to other proven prevention strategies such as decreasing blood pressure, glycaemic control, lipid lowering, stopping smoking, and aspirin should further lower the risk of cardiovascular and microvascular events in people with diabetes.
Writing committee--H C Gerstein, S Yusuf, JFE Mann, B Hoogwerf, B Zinman, C Held, M Fisher, B Wolffenbuttel, J Bosch, L Richardson, J Pogue, J-P Halle. International steering committee--S Yusuf, P Sleight, G Dagenais, T Montague, J Bosch, J Pogue, W Taylor, L Sardo (Canada); M Arnold, R Baigrie, R Davies, H Gerstein, P Jha, D Johnstone, C Joyner, R Kuritzky, E Lonn, B Mitchell, A Morris, B Sussex, K Teo, R Tsuyuki, B Zinman (USA); J Probstfield, J Young (Argentina); R Diaz, E Paolasso (Brazil); A Avezum, L Piegas (Europe); J Mann, B Wolffenbuttel, J Ostergren (Mexico); E Meaney. Canadian regional coordinators--M Aprile, D Bedard, J Cossett, G Ewart, L Harris, J Kellen, D LaForge, A Magi, J Skanes, P Squires, K Stevens. Coordination--J Bosch, F Cherian, I Holadyk-Gris, P Kalkbrenner, E Lonn, F Mazur, M McQueen, M Micks, S Monti, J Pogue, L Sardo, K Thompson, L Westfall, S Yusuf, L Richardson, N Raw, M Genisans, R Diaz, E Paolasso, A Avezum, L Piegas. Diabetes subcommittee--H Gerstein, B Zinman. Events adjudication committee--G Dagenais, M Arnold, P Auger, A Avezum, I Bata, V Bernstein, M Bourassa, R Diaz, B Fisher, H Gerstein, J Grover, C Gun, M Gupta, C Held, R Hoeschen, S Kouz, E Lonn, J Mann, J Mathew, E Meaney, D Meldrum, C Pilon, R Ramos, R Roccaforte, R Starra, M Trivi. Substudies publication committee--R Davies, D Johnstone, E Lonn, J Probstfield, M McQueen. Data safety and monitoring board--D Sackett, R Collins, E Davis, C Furberg, C Hennekens, B Pitt, R Turner.
Argentina (101--J Braver, C Cuneo, M Diaz, C Dizeo, L Guzman, S Lipshitz, S Llanos, J Lopez, A Lorenzatti, R Machado, C Mackey, M Mancini, M Marino, F Martinez, A Matrone, R Nordaby, A Orlandini, G Romero, M Ruiz, M Rusculleda, S Saavedra, J San Damaso, J Serra, E Tuero, G Zapata, A Zavala. Austria (5)--M Grisold, W Klein, E Brosch. Belgium (55)--P Baumans, H Brusselmans, A Bodson, J Boland, J Cano, J-M Chaudron, J-P Degaute, D Duprez, G Heyndrickx, G Krzentowski, J Mockel, J Wautrecht. Brazil (196)--E Alexandre, C Amodeo, D Armaganijan, J Ayub, M Bertolami, L Bodanese, J Borges, B Caramelli, A Carvalho, O Coelho, G Dioguardi, A Faludi, J Ferreira Braga, M Fichino, R Franken, N Ghorayeb, M Goncalves de Souza, G Greque, A Guedes, T Kadri, T Kawamura, A Labrunie, F Malheiros, L Marafon, M Nakamura, N Nonohay, C Ogawa, R Pavanello, P Puech-Leao, F Ramires, J Ramires, M Sampaio, L Saraiva, F Savioli, A Seixas, M Shibata, A Souza, L Tanajura, O Ueti, D Vitola. Canada (1934)--F Armstrong, W Armstrong, B Baptie, M Basinger, N Bell, P Beresford, W Black, N Brass, M Browne, K Browne, R Brownoff, G Chaytors, W Cottier, R Donnelly, V Dzavik, A Edwards, P Felker, P Giannoccaro, M Goeres, P Greenwood, M Grose, L Grossman, S Gulamhusein, W Hui, F Hutchison, A Irving, L Kasian, L Kasza, L Korner, L Kvill, Z Lakhani, S Lam, R Lesoway, P Ma, V Martinez, D Meldrum, B Mitchell, D Mitchell, T Montague, A Musseau, T Muzyka, C Neffgen, J Neffgen, R Nichol, M O'Beirne, J Paradis, D Paterson, A Plesko, A Prosser, N Radomsky, D Roth, E Ryan, M Senaratne, M Simon, P Stenerson, J Stone, T Talibi, R Wedel, D Wyse (Alberta); F Altwasser, T Ashton, J Askew, V Bernstein, W Bishop, G Bloomberg, J Boone, L Breakwell, L Buller, K Calvert, G Carere, M Dahl, K Dawson, A Dodek, J Dufton, R Geddis, S Ghosh, J Heath, D Hilton, J Imrie, D Jay, M Kiess, P Klinke, J Kornder, P Lee, W Leong, J Lewis, N Lounsbury, L MacDonald, K MacDonald, A MacNeil, D MacRitchie, L McGee, L Mitchell, K Mulcahy, S O'Donoghue, A Pearce, L Perreault, P Polasek, S Rabkin, M Reilly, P Richardson, E Scoffield, R Sweeney, M Terwiel, C Thompson, K Wagner, J Webb, K Wedding, K Woo, M Wright, A Zutz (British Columbia); L Briol, R Hoeschen, P Mehta, I Mohammed, A Ong, G Ong (Manitoba); R Bessoudo, L O'Brien, L McLellan, J Milton (New Brunswick); F Elgar, C Joyce, D O'Keefe, M Parsons, M Ravalia, G Sherman, R Smith, G Worrall (Newfoundland); A Atkinson, S Barnhill, I Bata, L Crossman, D Folkins, R Hatheway, B Johnson, M MacFarlane, T Machel, J Morash, W Sheridan, M Shirley (Nova Scotia); I Anderson, M Arnold, R Baigrie, M Baird, T Baitz, A Barnie, M Basta, J Blakely, B Bozek, W Bradley, K Brown, G Burnham, W Cameron, M Cann, S Carroll, R Carter, N Chan, Y Chan, J Charles, M Cheung, C Cina, L Cleghorn, G Curnew, P Currado, R Davies, S DeGagne, P DeYoung, R Dhaliwal, H Dowell, M Drobac, J Dubbin, K Duffield, M Edmonds, E Fallen, D Feldman, D Fell, C Ferguson, L Finkelstein, G Fong, R Fowlis, M Fraser, L Frenette, J Fulop, A Glanz, E Goode, M Gupta, A Hanna, K Harris, A Hess, P Hierlihy, R Houlden, I Hramiak, B Hrycyshyn, R Iwanochko, I Janzen, P Kannampuzha, E Keely, R Kennedy, A Kenshole, E Kent, S Khan, W Kostuk, M Kowalewski, M Krupa, G Kumar, G Kuruvilla, K Kwok, C Lai, A Langer, J Laor, D Lau, T LaVallee, B Lent, P Liu, H Lochnan, M Lovell, D Lowe, T Mabb, S Maclean, K Man, L Marois, D Massel, E Matthews, R McManus, E McPhee, M McQueen, J McSherry, D Millar, F Miller, L Miners, J Misterski, G Moe, C Mulaisho, C Munoz, S Nawaz, C Noseworthy, H O'Keefe, L Oosterveld, A Panju, H Paquette, M Parkovnick, R Paterson, P Pflugfelder, S Powers, T Rebane, A Redda, E Reeves, J Ricci, Z Sasson, M Sayles, M Scott, M Sibbick, N Singh, R Southern, D Spence, L Sternberg, J Stewart, S Styling, B Sullivan, H Sullivan, M Sullivan, J Swan, J Taichman, K Tan, P Tanser, C Tartaglia, K Taylor, D Thomson, M Turek, T Vakani, A vanWalraven, M Varey, R Vexler, J Walters, A Weeks, M Weingert, S Wetmore, P Whitsitt, J Willing, C Wilson, J Wilson, G Wisenberg, M Wolfe, B Wolter, L Yao (Ontario); G Costain, E Hickey, E MacMillan (Prince Edward Island); N Aris-Jilwan, P Auger, P Banville, J Beaudoin, A Belanger, N Belanger, L Belleville, N Bilodeau, P Bogaty, M Boulianne, M Bourassa, J Brophy, M Brouillette, J Buithieu, C Calve, J Campeau, P Carmichael, S Carrier, J Chiasson, B Coutu, D Coutu, S Croteau, G D'Amours, N Dagenais, F Delage, J Deschamps, D Dion, Y Douville, F Dumont, R Dupuis, L Frechette, S Gauthier, P Gervais, G Giguere, R Giroux, D Gossard, G Gosselin, G Goulet, F Grondin, J Halle, L Henri, G Houde, M Joyal, N Kandalaft, A Karabatsos, G Kiwan, S Kouz, R Labbe, M Langlais, C Lauzon, M LeBlanc, J Lenis, S Leroux, R Loisel, K MacLellan, A Morissette, H Noel, F Ouimet, L Pedneault, J Piche, C Pilon, P Plourde, C Poirier, D Poisson, L Primeau, G Pruneau, C Remillard, B Roberge, M Robert, M Rodrique, C Roy, L Roy, M Ruel, M Samson, D Saulnier, D Savard, A Serpa, F Sestier, M Smilovitch, R Starra, R St-Hilaire, P Theroux, A Toupin-Halle, J Tremblay, H Truchon, J Turcotte, S Vachon, R Vienneau, P Wilson (Quebec); M Habib, N Habib, S Ahmed, M Hart, J Walker, M Walker, G Thomasse, L Meunier, Z Sayeed, J Lopez (Saskatchewan). Denmark (56)--H Juhl, K Kolendorf. Finland (5)--T Hamalainen. France (15)--H Gin, V Rigellau. Germany (106)--M Bohm, E Erdmann, P Forst, A Gordalla, R Hampel, C Hartmann, G Hasslacher, H Henrichs, J Hensen, R Hopf, E Kromer, T Martin, J Maus, B Mayer, S Miedlich, A Moeller, H Nast, R Oehmen-Britsch, R Paschke, B Prehn, G Riegger, R Riel, C Rosak, C Schroeder, B Schulze-Schleppinghoff, H Schunkert, R Schweda, A Stablein, U Stein, H Truchon, H Unger, H Wetzel. Ireland (6)--P Crean, U White. Italy (196)--F Aina, C Balzan, F Barbaresi, R Brancaleoni, M Brunazzi, C Brunelli, A Cambiano, S Caponnetto, M Casaccia, P Centofante, C Cernigliaro, A Cerni Goi, C Cicciarello, A Cotogni, U DeJoannon, P Dellavesa, L di Gerogio, S Di Luzio, A Fava, G Frigeni, E Gatto, P Giani, D Giorgi-Pierfranceschi, C Imparato, M Landoni, B Magnani, E Manicardi, B Mantovani, M Marini, U Martini, S Mazzantini, M Merni, E Miglierina, E Minelli, G Molinari, D Nanni, E Paciaroni, P Pareschi, M Pasqualini, F Perazzoli, A Polese, F Poletti, I Portioli, S Provasoli, S Repetto, G Rigatelli, R Roccaforte, E Romano, E Rossi, M Rugolotto, F Rusticali, G Saccomanno, C Simoni, N Stucci, P Terranova, C Tortul, M Velussi, M Vincenzi, P Vincenzi, D Zavaroni. Mexico (169)--E Cardona-Munoz, L Elizondo, M Fausto, R Galindo, F Gloria-Breceda, H Hernandez-Garcia, M Ibarra-Flores, J Illescas-Diaz, A Lopez-Alvarado, E Meaney, R Olvera-Ruiz, J Rivera-Capello, M Romero-Soltero, V Samaniego-Mendez, M Vidrio-Velazquez. Netherlands (127)--A Kruseman, H Mulder, J Sels, L van Doorn, N Vogel. Norway (6)--E Hjerkinn, A Reikvam. Spain (22)--X Albert, A Alvarez, M Cardona, F Garcia Cosio, R Gilabert, A Karoni, L Lopez-Bescos, R Masia, L Saenz, G Sanz. Sweden (243)--K Ahnberg, K Andersson, O Andersson, L Astrom, L Bergsten, H Bjorkman, C Borgman, P Cervin, C Dahlgren, L Ekholm, U-B Ericsson, C Eriksson, B Fagher, O Gertow, P Gillberg, A Hagg, A Hallberg, B Hansson, P Hansson, C Held, M Heinonen, R Henning, L Jacobsson, C Jagren, T Jonasson, T Kahan, P Katzman, B Kristensson, K Krogager, B Leijd, P Lennerhagen, L Ljungdahl, H Menyes, P Ohman, P-O Olsson, U Rosenqvist, L Ryden, G Sartor, P Sjostedt, L Smith, L Stahl, A Svensson, K Svensson, A Taghavi, T Thulin, E Torebo, P Weber, M Wysocki. Switzerland (28)--A Anesini, P Boman, R Cozzi, P Gerber, R Honegger, A Kick, W Kiowski, R Lehmann, B Lull, T Moccetti, E Pasotti, J Rojas, A Rossi, M Rossi, E Safwan, R Schindler, F Sessa, G Spinas. UK (138)--B Allan, L Cumming, B Fisher, S Heller, J Kennedy, C Kesson, R Lochiel, J Manns, E McGroarty, K Raeburn, M Small, S Struthers, I Wilkinson. USA (246)--E Brown, J Holt, G Perry (AL); B Singh, Y Szlachcic, M Vlachou, F Yee (CA); L Clegg, L Horwitz, M St John (CO); J Anderson, A Rashkow, K Schwartz (CT); L Abercrombie, G Cintron, D Garrett, J McHale, A Miller, J Sullebarger, G Tripp, R Zoble (FL); P Orander, M Sridharan, V Sridharan (GA); S Berger, M Davidson, J Geohas, N Islam, R Rajanahally, K Seikel, A Susmano, M Wentworth (IL); S Advani, R Rough, W Wickemeyer, N Young (IA); M Goldstein (MD); S Dinneen, M Farkouh, P Helgemoe, T Miller, M Parkulo, G Pierpont, J Weigenant (MN); M Rich, P Schmidt (MO); J Abrams, D Robbins (NM); M Bonora, G Cohen, M Constantinou, A Dimova, P Fitzpatrick, L Gage, S Graham, R Kohn, E Lader, J Powers, P Reiter, N Witt (NY); R Buchsbaum, B Donese, S Gupta, B Hoogwerf, P Suhan, A Suryaprasad, D Williams (OH); K Danisa, M Lowery, K Lyon, C Rae (OK); B Gandara, M Gramberg, J Grover (OR); M Amidi, M Bell, M DiTommaso (PA); J Day, J Durand, J Farmer, G Torre, M Vooletich (TX); J Gorham, B Gowing, C Kingry, K Lehmann, R Letterer, G Lorch, S Lwai, R Mack, J Nemanich, R Primm, R Utley, L Vaughn (WA). Monitors--A Bergentoft, C Borgman, E Brosch, A Engbers, M Flores, P Forst, L Frisenda, S Gerle, D Huber, F La Tour, R Lehtonen, C Luca, J S Keays, N Masterton, R Moore, J Morales-Virgen, Penson, C Persson, C Pina, D Plouffe, JC Reglier, J Riley, T Rolstad, P Ronsted, P Spinewine, L Styner, N van den Boom, S Yuki-Miyakoshi.
This study was funded by the Medical Research Council
of Canada (Grants MT12790 and UI12362); Hoechst-Marion
Roussel; AstraZeneca; King Pharmaceuticals; Natural
Source Vitamin E Association; NEGMA and the Heart and
Stroke Foundation of Ontario. Salim Yusuf was supported
by a Senior Scientist award of the Medical Research
Council of Canada, and a Heart and Stroke Foundation of
Ontario research chair.
1 Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 43444. [PubMed]
2 Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979; 241: 203538. [PubMed]
3 Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. BMJ 1983; 287: 86770. [PubMed]
4 Barrett-Connor E, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 1991; 265: 62731. [PubMed]
5 Goldbourt U, Yaari S, Medalie JH. Factors predictive of long-term coronary heart disease mortality among 10059 male Israeli civil servants and municipal employees: a 23 year mortality follow-up in the Israeli Ischemic Heart Disease Study. Cardiology 1993; 82: 10021. [PubMed]
6 Manson JE, Coldlitz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991; 151: 114147. [PubMed]
7 Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: Harris MI, Cowie CC, Stern MS, Boyko EJ, Reiber GE, Bennett PH, eds. Diabetes in America, 2nd edn. Washington: National Institutes of Health, 1995: 42948.
8 Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999; 48: 93742. [PubMed]
9 Morrish NJ, Stevens LK, Fuller JH, Keen H, Jarrett RJ. Incidence of macrovascular disease in diabetes mellitus: the London follow-up to the WHO multinational study of vascular disease in diabetics. Diabetologia 1991; 34: 58489. [PubMed]
10 ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: early treatment of diabetic retinopathy study report 14. JAMA 1992; 266: 1292300. [PubMed]
11 Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Eight to nine year mortality in known non-insulin dependent diabetes and controls. Kidney Int 1992; 42: 73135. [PubMed]
12 Neil A, Hawkins M, Potok M, Thorogood M, Cohen DA, Mann J. A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care 1993; 16: 9961003. [PubMed]
13 Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999; 281: 129197. [PubMed]
14 Zuanetti G, Latini R, Maggioni AP, Franzosi M,
15 Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 61116. [Text]
16 UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 70313. [PubMed]
17 UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 71320. [PubMed]
18 Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipiine Cardiovascular Events Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21: 597603. [PubMed]
19 Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL,
20 Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol 1996; 77: 101720. [PubMed]
21 Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998; 351: 2831. [Text]
22 Gerstein HC, Bosch J, Pogue J, et al. Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes: the MICRO-HOPE study. Diabetes Care 1996; 19: 122528. [PubMed]
23 HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluations) Study: the design of a large, simple randomized trial of an angiotensin converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Can J Cardiol 1996; 12: 12737. [PubMed]
24 The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients. N Engl J Med 2000 (in press).
25 Yusuf S, Lonn E. Anti-ischemic effects of ACE inhibitors: a review of current clinical evidence and ongoing clinical trials. Eur Heart J 1998; 19: J3644. [PubMed]
26 Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension: Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996; 276: 188692. [PubMed]
27 Lonn EM, Yusuf S, Jha P, et al. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994; 90: 205669. [PubMed]
28 Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354: 175156. [Text]
29 Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7 year follow-up study. Arch Intern Med 1996; 156: 28689. [PubMed]
30 Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 57781. [PubMed]
31 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 145662. [PubMed]
32 Parving HH, Gall MA, Skott P, et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 1992; 41: 75862. [PubMed]
33 Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999; 341: 112733. [PubMed]
34 Olsen S, Mogensen CE. How often is NIDDM
complicated with non-diabetic renal disease? An analysis
of renal biopsies and the literature. Diabetologia 1996; 39: 163845. [PubMed]