The HOPE Study and MICRO-HOPE Substudy: effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus

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1 The HOPE Study and MICRO-HOPE Substudy: effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus VINOD PATEL, 1 SRINIVAS PANJA, 1 ASOK VENKATARAMAN 2 Background ACE inhibitors have a special role in diabetes care. They have been proven to reduce urinary albumin excretion and reduce the rate of progression of diabetic nephropathy and retinopathy. 1-3 There is proven benefit post myocardial infarction, with a greater beneficial effect in patients with diabetes in comparison to those without. 4 The effect of ACE inhibitors in patients who have low ejection fractions or overt cardiac failure is well described. More recent studies indicate other benefits of ACE inhibitors such as improving dyslipidaemia and insulin sensitivity. Cardiovascular disease is the commonest cause of mortality among patients with type 2 diabetes. A recent study reports the standardised mortality ratio to be considerably higher in people with diabetes with the vast majority of the excess due to cardiovascular disease (type 1 diabetes: women x 6.41, men x 2.94, type 2 diabetes: women x 1.6, men x 1.41). 6 Patients with type 2 diabetes who have no evidence of previous coronary heart disease were found to be at the same risk of myocardial infarction and cardiovascular death as non-diabetic patients who had already suffered from a myocardial infarction. 7 The diabetes subject cohort of the HOPE Study, (Heart Outcomes Prevention Evaluation Study), sought to investigate whether ACE inhibitor treatment with ramipril in high-risk patients with diabetes lowers the risk of cardiovascular events. 8 Within this main study the MICRO-HOPE substudy investigated the effect of ACE inhibitor treatment with ramipril on microalbuminuria and diabetic retinopathy. 9 The aim of this article is to offer a clinical summary of the above studies and suggest recommendations for clinical practice. Key words: diabetes, cardiovascular disease, microvascular complications, HOPE study, ACE inhibitor. Diabetes and Endocrinology Centre, 1 Coronary Care Unit, 2 George Eliot Hospital NHS Trust, Nuneaton, UK. Correspondence to: Dr Vinod Patel Diabetes and Endocrinology Centre, George Eliot Hospital NHS Trust, College Street, Nuneaton, Warwickshire, CV1 7DJ, UK. Tel: +44 () ; Fax: +44 () vinod.patel@geh-tr.wmids.nhs.uk Br J Diabetes Vasc Dis 21;1:44 1 Methodology Subjects: People with diabetes age or more with previous history of cardiovascular disease, (coronary artery disease, stroke, peripheral vascular disease) or one cardiovascular risk factor (total cholesterol >.2 mmol/l, HDL cholesterol.9 mmol/l, hypertension, known microalbuminuria, current smoking status). Exclusion criteria: Dipstick positive proteinuria, established diabetic nephropathy, severe renal disease, hyperkalaemia, congestive cardiac failure, low ejection fraction, (< 4%), uncontrolled hypertension, recent myocardial infarction or stroke. Sites: Study conducted in 281 centres in 19 countries in North and South America and Europe, (Argentina, Austria, Belgium, Brazil, Canada, Denmark, Finland, France, Germany, Ireland, Italy, Mexico, Netherlands, Norway, Spain, Sweden, Switzerland, UK, USA). Ethics: The HOPE Study protocol was approved locally by Ethics Committees and all subjects provided written informed consent. Study design: The study was a 2 x 2 design with randomisation of subjects to 1 mg ramipril or placebo taken once-daily in the evening and 4 IU of Vitamin E or placebo daily. Follow-up visits at one month and then every six months. Duration of study was 4. years. Treatment: The initial running period 2. mg ramipril for 7 1 days, continued into the study if creatinine concentration 2 µmols or lower and potassium <. mmol/l or lower. Primary end point: Development of myocardial infarction, stroke, cardiovascular death. Secondary end point: Total mortality admission to hospital for congestive cardiac failure, unstable angina, cardiovascular and revascularisation, overt nephropathy, heart failure, worsening angina, development of diabetes in subjects with no history of diabetes. Other points: Patients were judged to have type 2 diabetes if they developed diabetes at age 3 years or older or were not taking insulin. Hypertension was defined as taking drugs to treat hypertension or blood pressure greater than 16/9 mmhg. MICRO-HOPE Substudy: Urinary albumin excretion measured at baseline one year end of study by the albumin and creatinine ratio in a first morning sample. Microalbuminuria defined as an albumin/creatinine ratio of 2 mg/mmol or higher in men and women. Overt nephropa- 44 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

2 thy defined as 24-hour urine albumin 3 mg or greater or 24-hour urine total protein mg or greater, or albumin/creatinine ratio greater than 36 mg/mmol. Statistical analysis This study was adequately powered to detect relative risk reduction in the rate of myocardial infarction, stroke or cardiovascular disease. The study was ended six months earlier than the five years planned on the recommendation of the independent data safety and monitoring board. Intention to treat analysis. Results reported as relative risk reductions, Kaplan-Meier curves to estimate survival. ANOVA analysis adjusted for baseline values. Cox s regression model for interactions. Results There were 9,41 participants in the HOPE Study of which 3,64 had diabetes (39.3%). The results are presented on this group alone. Some patients (n=77) participated in another substudy in which they only received 2. mg of ramipril and therefore the main data set is on the 3,77 subjects receiving 1 mg ramipril. Mean age % female. 6% previous history of hypertension. At the end of study 6% in the placebo group and 66% in the ramipril group were still taking the study drugs at the end of the 4. years of the study. At four years 12% of the ramipril group and 1% of the placebo group were taking open label ACE inhibitors. Reasons for stopping ramipril were cough, dizziness, angioedema, hypertension or clinical event. The reasons for open label ACE inhibitor use in the placebo group were heart failure, proteinuria or hypertension. Primary outcomes Combined primary outcome of myocardial infarction, stroke or cardiovascular death reduced by 2%, (ramipril 1.3% versus 19.8% placebo). Myocardial infarction reduced 22%, (ramipril 1.2% versus 12.9% placebo). Stroke reduced 33%, (ramipril 4.2% versus 6.1% placebo). Cardiovascular death reduced 37%, (ramipril 6.2% versus placebo 9.7%). Secondary outcomes Total mortality reduced 24% Revascularisation reduced 17% Overt nephropathy reduced 24% Overt nephropathy, laser, therapy or dialysis reduced 16%. Other outcomes Any heart failure reduced 2%. Transient ischaemic attacks reduced 26%. Worsening angina reduced 13%, (p=.7). The benefit of ramipril was noted irrespective of whether subjects had a history of previous cardiovascular events, hypertension or microalbuminuria, or whether the patients had type 1 or 2 diabetes. At the end of the study there is no significant difference in HbA 1C % values. Blood pressure difference was 2.47/1. in favour of ramipril. After adjustment and changes in blood pressure, ramipril had the same effect on primary outcomes as before adjustment. Vitamin E had no significant effect. Treatment of 1, patients with ramipril for four years will prevent about 1 events in approximately 7 patients. 8 Clinical practice comments ACE inhibition significantly reduced the risk of major cardiovascular outcomes by 2 3% in a broad range of patients with diabetes, years of age or greater. These results would apply to the vast majority of our patients with diabetes as 7% have hypertension, another 7% have dyslipidaemia, 2% smoke and 1% have microalbuminuria. The results of the HOPE and MICRO-HOPE study therefore apply to around 8% of patients with diabetes in the study age group. Ramipril also reduced the risk of the development of overt nephropathy, renal failure or need for laser treatment. The treatment effect is comparable to other cardiovascular prevention measures such as aspirin prophylaxis, statin treatment for dyslipidaemia and treatment of hypertension. 1,11 The number needed to treat to prevent a major cardiovascular or microvascular event would be 1 high-risk patients with diabetes for 4. years to prevent one individual from having a myocardial infarction, stroke, cardiovascular death, admission to hospital for cardiac failure, revascularisation, development of overt nephropathy, laser treatment for sight threatening diabetic retinopathy or renal dialysis. This equates to a drug cost of to prevent one of the above events. It is probably fair to state that the risk reduction in cardiovascular events is greater than a blood pressure effect alone. However, this requires further close scrutiny as the ramipril group had a distinctly lower blood pressure (by 2.47/1. mmhg) with a probable greater effect on the 24- hour ambulatory blood pressure. The cardiovascular protective effects of ACE inhibitors may be due to an effect on the endothelium via angiotensin II. The latter is a powerful vasoconstrictor which promotes vascular smooth muscle proliferation by induction of protooncogenes and various growth factors. Angiotensin II stimulates the release of endothelin. It also inhibits fibrinolysis and promotes thrombosis. ACE inhibition will therefore reduce plaque rupture and cardiovascular events. Bradykinin which is increased with ACE inhibitor treatment is a vasodilator and would have the opposite effects of angiotensin II. The results of this study concord with other studies with ACE inhibitors. For example the Captopril Prevention Project which found 14% reduction in rate of myocardial infarction, stroke or cardiovascular death in patients taking VOLUME 1 ISSUE 1. AUGUST 21 4

3 Figure 1. HOPE - Primary outcomes Figure 3. HOPE - Other outcomes nnt 167/yr 22% nnt 1/yr 2% nnt 237/yr 33% nnt 128/yr 37% nnt 196/yr 13% nnt 18/yr 16% nnt 196/yr 2% nnt 3/yr 26% MI Combined CVA CV death Worsening angina Overt nephropathy Any heart failure TIA Figure 2. HOPE - Secondary outcomes Table 1. A strategy to reduce cardiovascular mortality in diabetes care 18 2 nnt 141/yr 24% nnt 237/yr 24% Primary prevention by treatment of cardiovascular risk factors nnt 188/yr 17% Revascularisation Mortality Nephropathy Exercise, healthy diet, obesity management, smoking cessation Control of hypertension (BP 14/8) Glycaemic control (HbA lc 7%) Cholesterol reduction with statins (T. chol., LDL 3., HDL.9) Secondary prevention of cardiovascular disease Aspirin 7 mg od Beta blockers ACE inhibitors Intensive insulin therapy (Digami protocol) 19 Cholesterol reduction with statins Other preventive measures Ramipril 1 od (HOPE study) Aspirin 7 mg od 2 Surgical treatment of coronary heart disease Interventional cardiology Surgical captopril. 12 However other studies have shown no distinct benefit of ACE inhibitors over beta blockers. 13 The beneficial effect of ramipril was independent of whether the subject was already taking cardiovascular disease prevention agents such as aspirin, beta blockers or lipid-lowering agents. With respect to microvascular outcomes, these results concord with the results of the Eurodiab Controlled trial of Lisinopril in insulin-dependent diabetes (EUCLID) nephropathy and the EUCLID retinopathy studies (using lisinopril 2 mg od), although these were type 1 diabetes mellitus patients only. Microvascular complications may have improved due to a beneficial effect on microvascular autoregulation. 14 The HOPE Study contained a comparable number of patients as the UKPDS in an equally well designed study. The results should therefore be taken seriously with the findings implemented in clinical practice. Ramipril now has a license for reducing the risk of myocardial infarction/cardiovascular disease or need for revascularisation procedures in diabetic patients of years or more who have one or more of the following clinical findings: Hypertension (greater than 16/9 mmhg), dyslipidaemia, cholesterol (greater than.2, HDL <.9), current smoker, known microalbuminuria, clinical evidence of previous vascular disease. Other indications for ACE inhibitors including mild to moderate hypertension, congestive cardiac failure as adjunct to diuretic therapy and reduction in mortality in patients surviving acute myocardial infarction with clinical evidence of heart failure. Lisinopril 48 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

4 Table 2. Risk reductions and NNT values for recent large trials in diabetes care 17 UKPDS- glycaemic control UKPDS metformin UKPDS-Hypertension HOPE trial 1 subtrial 16 trial 1 MICRO-HOPE End point RR nnt/yr RR nnt/yr RR nnt/yr RR nnt/yr any Diabetes end point.1% % % Death from diabetes - -.2% % Death from all causes % % 141 Myocardial infarction 2.7% 37 7% % 167 Stroke % % 237 Microvascular complications 2.8% % %* 18* * overt nephropathy, laser therapy, or dialysis; RR = risk reduction; also has a licence for prevention of nephropathy in albuminuric patients with normotensive type 1 diabetes and hypertensive type 2 diabetes. Rather than risk reductions from a health planning point of view, it is probably better to look at number needed to treat (NNT) to prevent an event. NNT is calculated as 1%/absolute % reduction in risk and denotes the number of subjects who must receive the study treatment to prevent one event. To illustrate its use, consider treatment A which reduces risk of Event X from 1% per year to % (also a risk reduction of %). The NNT is 1%/1 = 2 per year. Now consider treatment B which reduces risk of Event Y from 1% per year to.% (also a risk reduction of %). The NNT is 1%/1.. = 2 per year. Clearly the NNT is a valuable concept in considering treatment effects and calculating costs of healthcare. The risk reduction and NNTs for the main outcomes are shown in figures 1 3. NNT s are shown in graphs 1, 2 and 3 with comparisons to the main United Kingdom Prospective Diabetes Study (UKPDS) studies shown in table 1. How to use ramipril 2. mg once a day for one week, mg for three weeks and then 1 mg daily. In clinical practice ramipril is frequently given mg od for one week followed by 1 mg od. Urea, potassium and creatinine levels should be checked after 2 4 weeks on ACE inhibition with the ACE inhibitor discontinued if the urea rises by % or more or if the creatinine rises by more than 2%. Attention to other drugs which worsen renal parameters (diuretics and other vasodilators) may allow continued use of ACE inhibitors. Conclusion At the average age of diagnosis of diabetes ( years), the estimated life expectancy is reduced by seven years in women and five years in men, 8% of these premature deaths are due to cardiovascular disease. 6 All diabetes care programmes should aim to reduce cardiovascular disease by an aggressive strategy to decrease blood pressure to the target of 14/8 mmhg or lower, improve glycaemic control to a target HbA 1C of 7% or lower, lipid lowering (total cholesterol < mmol/l, LDL < 3 mmol/l, HDL >.9 mmol/l), smoking cessation, aspirin treatment, together with due attention to healthy eating, exercise and weight reduction. The HOPE and MICRO-HOPE Study clearly shows the beneficial effect of adding an ACE inhibitor into this strategy (table 2). References 1. Lewis EJ, Hunsickler LG, Bain RP, Rohde RD. The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: The EUCLID Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997;349: Chaturvedi N, Sijolie AK, Stephenson JM et al. and the EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with Type 1 diabetes. Lancet 1998;31: GISSI-3 study group. Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343: 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 Cardiology 1996;77: Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM. Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. BMJ 21;7299: Haffner SM, Lehto S, Rönnemaa T et al. Kaplan-Meier estimates of the probability of death from coronary heart disease in subjects who had not had a previous myocardial infarction. N Engl J Med 1998;339: The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2;342: The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO- HOPE substudy. Lancet 2;3: Pyorali K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prog- THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

5 nosis of diabetic patients with coronary heart disease. Diabetes care 1997;2: UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998;317: Hansson L, Lindholm LH, Niskanen L et al. Effect of ACE-inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;33: UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ 1998;317: Patel V, Rassam SMB, Chen HC, Kohner EM. Effect of angiotensin-converting enzyme inhibition with perindopril and β-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism 1998;47(Supp 1): UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;32: UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;32: Stratton IM, Cull CA, Manley SE et al. Relation between diabetes and hyperglycaemia and cardiovascular disease has not been resolved (authors reply). BMJ 21;322: Miles Fisher B. Results of the Heart Outcomes Prevention Evaluation (HOPE) Study: Implications for the care of people with diabetes. Modern Diabetes Management 2;1: Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314: Aspirin and diabetes (Fact sheet 21). Diabetes Update, Diabetes UK Summer 21. VOLUME 1 ISSUE 1. AUGUST 21 1