PRESENTED BY:HIRDESH CHAWLA

JUNIOR RESIDENT III

Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular

Disease

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

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.

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.

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

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.

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

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

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

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

• 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

• 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.

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.

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

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.

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

Blood-Pressure and Cholesterol Lowering

in Persons without Cardiovascular Disease

Heart Outcomes Prevention Evaluation (HOPE)–3 trial

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

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

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.

Coronary Revascularization

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))

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

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

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