efficacy of statin and diuretic therapy in primary prevention of cardiovascular diseases

1. PRESENTED BY:
HIRDESH CHAWLA
JUNIOR RESIDENT III

2. Cholesterol Lowering in Intermediate-
Risk Persons without Cardiovascular
Disease

3.  Introduction
 Background
 Objectives
 Study Design
 Outcome
 Inclusion and Exclusion criteria
 Participants
 Trial Procedures
 Results
 Drawbacks and Limitations

4.  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.

5.  It showed that combined daily administartion 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.

6.  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

7. 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.

8. 
To evaluating 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

9.  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

10.  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.
 SECONDARY OUTCOME
 The secondary outcome was second coprimary outcome with
angina with evidence of ischemia
ENDPOINT

11.  The trial included men 55 years of age or older and women 65 years of
age or older who had at least one of the following cardiovascular risk
factors:

Elevated waist-to-hip ratio(>=0.85 in women and >=0.90 in men)

History of a low level of high-density lipoprotein cholesterol(<50
mg/dl(women) or <38.6mg/dl(men))

Current or recent tobacco use(in last 5 years)

Dysglycemia

Family history of premature coronary disease

Mild renal dysfunction(eGFR<60 or microalbuminuria or Cr>1.4mg/dl)
◦
Trial also included women <60 years of age with 2 of the following risk
factors.
INCLUSION CRITERIA

12. • Participants with cardiovascular disease and systemic hypotension.
• Those with an indication for statins, ACEIs,ARBs or thiazide diuretics
• Those with a contraindication for statins, ACEIs,ARBs or thiazide diuretics (like
hypersensitivity etc.)
• These patients were identified on the basis of clinical judgement of local
physicians,usual practice and guidelines.
• Patients with eGFR<45 ml/min/1.73m^2 or Cr>2 mg/dL
• Inflammatory muscle disease or high CK(>3 of ULN)
• Chronic liver disease or high LFT(>3ULN)
• Treatment with cyclosporine and fibrates

13. • 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.

14.  Participants were entered in single blinded running phase and were given
active treatment for 4 weeks(combination therapy)
 Participants who didn’t have adverse events and adhered to treatment
were randomly assigned to two groups –one receiving therapy and other
placebo
 Follow up visits occur at 6 weeks and then 6 months after randomization
and every 6 months therafter
 Blood pressure was recorded at each visit in first year and yearly
 thereafter.
 Lipid levels were measured at baseline and then 1yr,3 yr and at the end of
trial in subsample of 10-20% of participants.

16.  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%.
ADHERENCE TO TREATMENT

26.  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.

27.  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

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

29.  Combined lowering of LDL cholesterol and blood pressure can
potentially have a bigger effect in reducing cardiovascular events
than either intervention alone. Because 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

30.  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.
STUDY DESIGN

32.  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.

39. Coronary Revascularization

40.  There was increased incidence of muscle pain and weakness which was same in rosuvastatin
group as in combination therapy group.
 There was increased incidence of dizziness,light headedness and hypotension which was same in
dual antihypertensive therapy as in combination therapy group
 However the rates of serious adverse events and permanent discontinuation didn’t differ
significantly among any of the groups as compared to placebo 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))

42. 
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)
Conclusion

43.  Without Cardiovascular risk or diabetes,40 -75 yrs old and 7.5
% or more risk for having a heart attack or stroke in 10 yrs
 With history of CV disease(MI,stroke,stable or unstable
angina,TIA,peripheral artery disease,revascularization
 21 yrs and older with LDL>190 without secondary cause(high
saturated diets,drugs)
 Type 1 or type 2 diabetes 40-75 yrs old with LDL 70-189mg/dl

44.  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