HOPE TRIAL 1-4 2019 UPDATED

1. Heart
Outcomes
Prevention
EvaluationDR SHIVAOM CHAURASIA
RESIDENT
INTERNAL MEDICINE

3. Design
 Multicenter, double-blind, 2x2 factorial, randomized, placebo-
controlled trial
 N=9,297
 Ramipril (n=4,645)
 Placebo (n=4,652)
 Setting: 267 centers in US, Canada, Europe, South America
 Enrollment: 1993-1995
 Follow-up: Up to 5-years but terminated early in March 1999
 Analysis: Intention-to-treat
 Primary outcome: Composite of MI, CVA, or CV death

4.  Inclusion Criteria
 Age ≥55 years at high risk for CV events because of:
 History of CAD, CVA, PAD
 DM plus one other CV risk factor (HTN, smoking, microalbuminuria)
 Exclusion Criteria
 Heart failure or LVEF <40%
 Already taking ACE inhibitor or vitamin E
 Uncontrolled HTN or overt nephropathy
 MI or CVA within previous four weeks

5. RESULTS
 The HOPE Study showed that ramipril was well tolerated,with the large
majority of patients continuing on the full 10 mg dose.
 The primary end point was defined as a combination of cardiovascular
death, non-fatal myocardial infarction, and non-fatal stroke.
 The trial was stopped early (after 4.5 years) on the advice of the Data
Monitoring Committee because of the consistent and overwhelming
evidence of benefit in the ramipril allocated group.
 This represents a reduction in relative risk of 22% with unusually tight
confidence intervals

6.  The individual components of the composite end point were also
reduced highly significantly by 32% for stroke,20% for MI and 26%
for cardiovascular death.
 Ramipril also significantly reduced the relative risk of experiencing
several other clinical endpoints including heart failure (by 23%) and
revascularisation procedures(by 15%).
 All cause mortality was reduced by 16%.
 Non-cardiovascular mortality was reassuringly equal in the ramipril
and placebo groups.

7. Criticisms
 Patients with reduced LVEF were not entirely
excluded.
 Many patients were not receiving Oral Medical
Treatment for comorbidities, such as CAD

8. CONCLUSION
 HOPE trial found that a 10 mg dose of ramipril in comparison
with placebo significantly reduced by 22 % the incidence of
death, myocardial infarction, stroke and death from
cardiovascular causes.

10. BACKGROUND
 In observational studies, lower homocysteine levels are associated
with lower rates of coronary heart disease and stroke.
 Folic acid and vitamins B6 and B12 lower homocysteine levels.
 Assessing whether supplementation reduced the risk of major
cardiovascular events in patients with vascular disease.

11. METHOD
 Randomly assigned 5522 patients 55 years of age or
older who had vascular disease or diabetes to
daily treatment either with the combination of 2.5
mg of folic acid, 50 mg of vitamin B6, and 1 mg of
vitamin B12 or with placebo for an average of five
years.
 The primary outcome was a composite of death from
cardiovascular causes, myocardial infarction, and
stroke.

12. Study Design
 HOPE-2 was a randomized, double-blind, placebo controlled trial
evaluating whether therapy with homocysteine-lowering B vitamins
reduces the risk of major vascular events in a high-risk population.
 The study was coordinated by the Population Health Research
Institute at McMaster University in Hamilton, Ontario, and sponsored
by the Canadian Institutes of Health Research.
 An independent data and safety monitoring board monitored the safety
of the participants and the overall quality and scientific integrity of the
study.

13. Study Population
 Men and women 55 years of age or older who had a history of
vascular disease (coronary, cerebrovascular, or peripheral vascular)
or diabetes and additional risk factors for atherosclerosis were
enrolled, irrespective of their homocysteine levels, from countries
with mandatory folate fortification of food (Canada and the United
States) and countries without mandatory folate fortification (Brazil,
western Europe, and Slovakia).
 Patients who were taking vitamin supplements containing more
than 0.2 mg of folic acid per day were excluded.

14. Study Intervention
 Patients were randomly assigned to receive a combined pill
containing 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of
vitamin B12 (active treatment) or matching placebo daily.
 All study investigators, personnel, and participants were unaware of
the randomization procedure and the treatment assignments.

15. Follow-up and Laboratory Evaluation
 After randomization, patients were evaluated every six months
 Blood samples were collected at randomization, at two years, and at
the end of the study in a randomly selected subgroup of patients after
an overnight fast, with proportional representation from countries with
folate fortification of food and countries without folate fortification and
with expected significant differences in dietary habits.

16. RESULTS
 Mean plasma homocysteine levels decreased by 2.4 μmol per liter
(0.3 mg per liter) in the active-treatment group and increased by
0.8 μmol per liter (0.1 mg per liter) in the placebo group.
 As compared with placebo, active treatment did not significantly
decrease the risk of death from cardiovascular causes myocardial
infarction or any of the secondary outcomes.
 Fewer patients assigned to active treatment than to placebo had a
stroke.

17. HOPE 2 TRIAL 2006
 It showed that combined daily administration of 2.5 mg of
folic acid,50 mg of vitamin B6 and 1mg of vitamin B12 for 5
years had NO beneficial effects on major vascular events in a
high risk vascular population.

18. CONCLUSIONS
 Supplements combining folic acid and vitamins B6 and
B12 did not reduce the risk of major cardiovascular
events in patients with vascular disease.

20. POINTS OF DISCUSSION
 Introduction
 Background
 Objectives
 Study Design
 Outcome
 Inclusion and Exclusion criteria
 Participants
 Trial Procedures
 Results
 Drawbacks and Limitations

21. INTRODUCTION
 Cardiovascular diseases causes 18 million deaths
globally per year and similar number of nonfatal
cardiovascular events.
 Elevated LDL accounts for approx. half of the
population attributable risk of myocardial infarction and
approx. one quarter risk of ischemic stroke

22. BACKGROUND
 The role of lowering LDL cholesterol levels with statins in the
primary prevention of cardiovascular events among persons without
cardiovascular disease, regardless of lipid levels, inflammatory
markers, hypertension status, or diabetes status, has not been
established.

23. OBJECTIVE
 To evaluate the long-term effects of rosuvastatin at a dose
of 10 mg per day (without dose adjustment or lipid targets)
among persons of various ethnic backgrounds on six
continents who did not have cardiovascular disease and
were at intermediate risk(defined as annual risk of major
cardiovascular event approx. 1% (based on INTERHEART
risk score of 10-15)).
 To evaluate blood pressure lowering with candesartan 16mg
plus hydrochlorthiazide 12.5mg in prevention of
cardiovascular events among the same group of people.
 Combination of both the interventions and its role.

24. STUDY DESIGN
 2X2 Factorial trial
 N= 12,705 participants
 Participants from 21 countries and 228 centres who did not have
cardiovascular disease and were at intermediate risk
 Treatment: Rosuvastatin at a dose of 10 mg per day or placebo.
 Follow-up was 5.6 years

25. ENDPOINT
 PRIMARY OUTCOME
 The first outcome was the composite of death from
cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke.
 The second outcome additionally included
revascularization, heart failure, and resuscitated
cardiac arrest.

26. SECONDARY OUTCOME
 The secondary outcome was second coprimary outcome with
angina with evidence of ischemia.

27. INCLUSION CRITERIA
 Women ≥65 years and men ≥55 years
 1 or more CV risk factors
 Waist/hip ratio ≥0.85 (women) or ≥0.90 (men)
 Smoker or recent ex-smoker (last 5 years)
 HDL < 1.3mmol/L (women) or < 1.0mmol/L (men)
 Dysglycemia
 Early renal dysfunction (eGFR<60, Cr>1.4mg/dL, microalbuminuria)
 excluded if hypertensive (BP > 130/80) or proteinuria present
 Family history of early CHD (M<55y, F<65y)

28. EXCLUSION CRITERIA
 Documented, clinically manifest atherothrombotic CVD
 Any statin, ARB, ACE inhibitor, or thiazide indication
 Statin, ARB, or thiazide contraindication
 Chronic liver disease or high LFTs (3x ULN)
 Inflammatory muscle disease or high CK (3x ULN)
 Moderate renal dysfunction (eGFR<45 or Cr>2mg/dL)
 Fibrate or cyclosporine treatment
 Symptomatic hypotension
 Serious condition interfering with trial completion or participation
 Use of experimental pharmacological agent

29. PARTICIPIANTS
 The mean age of participants was 65.7 years.
 Mean body mass index was 27.1 kg/m2
 Mean systolic blood pressure was 138.1 mm Hg
 Mean LDL cholesterol levels were 127.8 mg/dl
 Median fasting plasma glucose was 95.4 g/dl
 46.2% of the participants were women
 5.8% had diabetes and of them 44% were on medications.
 Median trial period was 5.6 years.

30. TRIAL PROCEDURES
 Eligible patients underwent a single-blind run-in phase
receiving both cholesterol & BP-lowering agents for 4
weeks, and were excluded for poor adherence or
unacceptable adverse events
 Randomization in 2 by 2 factorial design:
 Randomization A: Lipid-lowering Arm vs. Placebo
 Randomization B: BP-Lowering Arm vs. Placebo
 Arm-Specific Interventions
 Lipid-lowering Arm: rosuvastatin 10mg daily
 BP-lowering arm: candesartan 16mg daily and
hydrochlorothiazide 12.5mg daily

31.  General Interventions
 Individualized structured lifestyle advice
 Follow-up
 Visits at 6 weeks, 6 months, then every 6 months thereafter
 Blood pressure measured at every visit in the first year, then
annually
 Lipid levels at 1 year, 3 years and end of trial in an ethnically
representative subsample of 10-20% of participants

32. RESULTS

33. ADHERENCE TO
TREATMENT
 In the Rosuvastatin group, 88.0% were taking the
assigned regimen at 1 year, 83.5% at 3 years, and
75.5% at 5 years;
 The corresponding rates in the placebo group were
87.8%, 83.0%, and 73.2%.

36. Mean Triglyceride levels
were 21.2 mg/DL lower as
compared to placebo

39. Second Coprimary Outcome

40. STROKE

41. MYOCARDIAL
INFARCTION

42. CORONARY
REVASCULARIZATION

43. DRAWBACKS AND
LIMITATIONS
 Higher rate of muscle weakness or pain in statin group of pts.(but
this was reversible completely with temporary
discontinuation)(367 versus 294)
 Only one case of rhabdomyolysis was reported in rosuvastatin
group.
 More cases of cataract surgery in rosuvastatin group(seen in
observational studies).(241 versus 194)
 Though there is substantial decrease in risk of ischemic
stroke,there is Increase in risk of hemorrhagic stroke(11 vs 8) in
rosuvastatin group of patients.
 Funding was being contributed by company Crestor(which single
handedly manufactures rosuvastatin)
 Doubts on long term use in underpriviledged countries.
 There are no clear cut indication as to when to start the treatment.

44. CONCLUSION
 HOPE -3 is a trial of a fixed dose of rosuvastatin indicating
that a simple approach to treatment, without routine blood
tests to initiate or monitor statin therapy, is effective.
 This approach avoids the costs of frequent clinic visits,
thereby facilitating the use of rosuvastatin in primary care.
 It may have the potential to substantially reduce the rates of
premature cardiovascular events globally

45. Heart Outcomes Prevention
Evaluation (HOPE)–3 trial
 Blood-Pressure and Cholesterol Lowering in Persons
without Cardiovascular Disease

46. BACKGROUND
 Combined lowering of LDL cholesterol and blood
pressure can potentially have a bigger effect in
reducing cardiovascular events than either
intervention alone.
 The majority of cardiovascular events occur in
persons at average risk with no previous
cardiovascular disease, a strategy of broad
population-based treatment of LDL cholesterol and
blood pressure could be more effective than targeting
only high-risk persons

47. STUDY DESIGN
 TREATMENT: Rosuvastatin (10 mg per day) or
placebo and candesartan (16 mg per day) plus
hydrochlorothiazide (12.5 mg per day) or placebo.
 N= 3180 participants; combined therapy (with
rosuvastatin and the two antihypertensive agents)
 N= 3168 participants; dual placebo.

48. RESULTS

49. OUTCOMES
 Mean systolic blood pressure was 6.2 mm Hg lower in
combination group than in dual placebo.
 Mean diastolic blood pressure was 3.2 mm Hg lower in
combination group than in dual placebo.
 Mean LDL cholesterol was lower by 33.7 mg/dl in combination
group.

51. SYSTOLIC BLOOD
PRESSURE

52. LDL-c

53. STROKE

54. MYOCARDIAL
INFARCTION

55. CORONARY
REVASCULARIZATION

56. DRAWBACKS AND
PITHOLES
 Increased incidence of muscle pain and weakness which was same
in rosuvastatin group as in combination therapy group.
 Increased incidence of dizziness,light headedness and hypotension
which was same in dual antihypertensive therapy as in combination
therapy group
 There were no significant differences between the combined-therapy
group and the dual placebo group in the rate of new-onset diabetes,
renal dysfunction, syncope, liver-function abnormalities, eye
problems, or cancers.
 Results were more complicated and no significant difference in
clinical outcome but there was significant differences based on
prespecified subgroups of blood pressure at baseline(>143.5mm
Hg-benefit, patients with lower third subgroup had harmful
effect(<=131.5 mm Hg))

58. CONCLUSION
 The combination of rosuvastatin (10 mg per day),
candesartan (16 mg per day), and
hydrochlorothiazide (12.5 mg per day) was
associated with a significantly lower rate of
cardiovascular events than dual placebo among
persons at intermediate risk who did not have
cardiovascular disease.
 (29% lower relative risk and 1.4 percentage point lower
absolute risk of the first primary outcome)

59. SUMMERY HOPE 3
 Statins have a proven role in decreasing cardiovascular
mortality in high risk and intermediate risk patients.
 Lifestyle modifications should always be encouraged and
should be considered before starting any pharmacologic
therapy.
 Associated with minimal side effects and hence can be safely
given lifelong
 Dual antihypertensive therapy has role only in those
subgroup of patients with blood pressure on the higher side.
 Regardless of lipid targets and any goals, statin can be
safely given and is thus cost effective avoiding
unnecessary lab tests in follow ups.
 However the therapy should always be individualised as per
the patient’s profile.

67. CONCLUSION
 A healthcare strategy guided by healthcare workers with
tablet algorithms, which involves primary care and the
family environment, in addition to providing free
antihypertensive medication and statins, substantially
improved CV risk and blood pressure control

69. References
 The HOPE Study (Heart Outcomes Prevention
Evaluation) Peter Sleight (HOPE 1)
 Homocysteine Lowering with Folic Acid and B Vitamins
in Vascular Disease (The Heart Outcomes Prevention
Evaluation (HOPE) 2 Investigators*)
 Blood-Pressure and Cholesterol Lowering in Persons
without Cardiovascular Disease(HOPE 3)
 A community-based comprehensive intervention to
reduce cardiovascular risk in hypertension (HOPE 4):
a cluster-randomised controlled trial

70. THANK YOU