LANDMARK STUDY
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 VENKATARAMAN2
Background
Methodology
A
● Subjects: People with diabetes age 55 or more with
CE 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.5 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.
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Key words: diabetes, cardiovascular disease, microvascular
complications, HOPE study, ACE inhibitor.
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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, CV10 7DJ, UK.
Tel: +44 (0)2476 351351; Fax: +44 (0)2476 865210
E-mail: vinod.patel@geh-tr.wmids.nhs.uk
Br J Diabetes Vasc Dis 2001;1:44–51
44
previous history of cardiovascular disease, (coronary artery
disease, stroke, peripheral vascular disease) or one
cardiovascular risk factor (total cholesterol > 5.2 mmol/L,
HDL cholesterol ≤ 0.9 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,
(< 40%), 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 10 mg ramipril or placebo taken
once-daily in the evening and 400 IU of Vitamin E or placebo daily. Follow-up visits at one month and then every six
months. Duration of study was 4.5 years.
Treatment: The initial running period 2.5 mg ramipril for
7– 10 days, continued into the study if creatinine concentration 200 µmols or lower and potassium < 5.5 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 30 years or older or were
not taking insulin. Hypertension was defined as taking
drugs to treat hypertension or blood pressure greater than
160/90 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-
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
LANDMARK STUDY
thy defined as 24-hour urine albumin 300 mg or greater or
24-hour urine total protein 500 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.
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 HbA1C% values.
● Blood pressure difference was 2.47/1.00 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 1,000 patients with ramipril for four years will
prevent about 150 events in approximately 70 patients.8
Clinical practice comments
● ACE inhibition significantly reduced the risk of major car-
Results
● There were 9,541 participants in the HOPE Study of which
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3,654 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 2.5 mg of
ramipril and therefore the main data set is on the 3,577 subjects receiving 10 mg ramipril.
Mean age 65.4. 37% female. 56% previous history of
hypertension. At the end of study 65% in the placebo group
and 66% in the ramipril group were still taking the study
drugs at the end of the 4.5 years of the study.
At four years 12% of the ramipril group and 15% 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
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● Combined primary outcome of myocardial infarction, stroke
or cardiovascular death reduced by 25%, (ramipril 15.3%
versus 19.8% placebo).
● Myocardial infarction reduced 22%, (ramipril 10.2% 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%).
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Secondary outcomes
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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 20%. Transient ischaemic attacks
reduced 26%. Worsening angina reduced 13%, (p=0.057).
The benefit of ramipril was noted irrespective of whether
subjects had a history of previous cardiovascular events,
VOLUME 1 ISSUE 1 . AUGUST 2001
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diovascular outcomes by 25–30% in a broad range of
patients with diabetes, 55 years of age or greater. These
results would apply to the vast majority of our patients with
diabetes as 70% have hypertension, another 70% have
dyslipidaemia, 20% smoke and 10% have microalbuminuria. The results of the HOPE and MICRO-HOPE study
therefore apply to around 85% 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.10,11
The number needed to treat to prevent a major cardiovascular or microvascular event would be 15 high-risk patients
with diabetes for 4.5 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 £11 340 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
2.47/1.00 mmHg) with a probable greater effect on the 24hour 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
45
LANDMARK STUDY
Figure 3. HOPE - Other outcomes
Figure 1. HOPE - Primary outcomes
nnt 128/yr
37%
40
30
nnt 237/yr
33%
35
nnt 300/yr
26%
25
nnt 196/yr
20%
30
20
RR (%)
RR (%)
nnt 100/yr
25%
nnt 167/yr
22%
25
20
15
nnt 180/yr
16%
nnt 196/yr
13%
10
15
10
5
5
0
Worsening
angina
0
MI
Combined
CVA
CV death
Overt
nephropathy
Any heart
failure
TIA
nnt = number needed to treat
nnt = number needed to treat
Figure 2. HOPE - Secondary outcomes
nnt 141/yr
24%
25
Table 1.
nnt 237/yr
24%
Primary prevention by treatment of cardiovascular risk factors
●
RR (%)
20
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nnt 188/yr
17%
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15
A strategy to reduce cardiovascular mortality in diabetes
care18
Exercise, healthy diet, obesity management, smoking cessation
Control of hypertension (BP ≤ 140/80)
Glycaemic control (HbAlC ≤ 7%)
Cholesterol reduction with statins (T. chol ≤ 5.0, LDL ≤ 3.0, HDL ≥ 0.9)
Secondary prevention of cardiovascular disease
10
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5
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0
Revascularisation
Mortality
Nephropathy
Aspirin 75 mg od
Beta blockers
ACE inhibitors
Intensive insulin therapy (Digami protocol)19
Cholesterol reduction with statins
Other preventive measures
nnt = number needed to treat
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Ramipril 10 od (HOPE study)
Aspirin 75 mg od 20
Surgical treatment of coronary heart disease
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 20
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 imple-
48
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Interventional cardiology
Surgical
mented 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 55 years or more who have one or more of the
following clinical findings: Hypertension (greater than
160/90 mmHg), dyslipidaemia, cholesterol (greater than 5.2,
HDL < 0.9), 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
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
LANDMARK STUDY
Table 2.
Risk reductions and NNT values for recent large trials in diabetes care17
UKPDS- glycaemic control
trial15
UKPDS – metformin
subtrial16
UKPDS-Hypertension
trial1
HOPE
MICRO-HOPE
End point
RR
nnt/yr
RR
nnt/yr
RR
nnt/yr
RR
nnt/yr
any Diabetes end point
5.1%
196
13.5%
74
16.5%
61
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Death from diabetes
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5.2%
192
6.6%
152
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Death from all causes
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7.1%
141
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24%
141
Myocardial infarction
2.7%
370
7%
143
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22%
167
Stroke
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5.1%
196
33%
237
Microvascular complications
2.8%
357
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7.2%
138
16%*
180*
* overt nephropathy, laser therapy, or dialysis; RR = risk reduction; nnt = number needed to treat
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
100%/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 10% per year to 5% (also a risk
reduction of 50%). The NNT is 100%/10–5 = 20 per year.
Now consider treatment B which reduces risk of Event Y from
1% per year to 0.5% (also a risk reduction of 50%). The NNT
is 100%/1.0–0.5 = 200 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
2.5 mg once a day for one week, 5 mg for three weeks and then
10 mg daily. In clinical practice ramipril is frequently given 5 mg
od for one week followed by 10 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
50% or more or if the creatinine rises by more than 20%.
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 (55 years), the estimated life expectancy is reduced by seven years in women and
five years in men, 80% of these premature deaths are due to car-
50
diovascular disease.6 All diabetes care programmes should aim to
reduce cardiovascular disease by an aggressive strategy to
decrease blood pressure to the target of 140/80 mmHg or lower,
improve glycaemic control to a target HbA1C of 7% or lower,
lipid lowering (total cholesterol < 5 mmol/L, LDL < 3 mmol/L, HDL
> 0.9 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).
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