Effect of High-Dose Angiotensin II Receptor Blocker Monotherapy Versus ARB Plus Calcium Channel Blocker Combination on Cardiovascular Events in Japanese Elderly High-Risk Hypertensive Patients - OSCAR

Description:

Although the benefits of high-dose angiotensin-receptor blocker (ARB) therapy in patients with diabetic nephropathy and congestive heart failure (CHF) are well known, it is unclear if this is true for high-risk patients with hypertension as well. The current trial sought to compare outcomes with high-dose ARB versus low-dose ARB, along with a calcium channel blocker (CCB), in elderly Japanese patients with at least one cardiovascular (CV) risk factor.

Hypothesis:

High-dose ARB would be superior to low-dose ARB + CCB in elderly patients with at least one CV risk factor.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Outpatients ages 65-84 years
  • Olmesartan 20 mg/day monotherapy with systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg
  • At least one of the following CV risk factors:
    • Cerebrovascular disease
    • Cardiac disease
    • Vascular disease
    • Renal dysfunction
    • Type 2 diabetes mellitus

 

Number of enrollees: 1,164
Duration of follow-up: 3 years
Mean patient age: 73.6 years
Percentage female: 56%

Exclusions:

  • Contraindication to ARB/CCB

Primary Endpoints:

Composite of:

  • Fatal and nonfatal CV events
    • Cerebrovascular disease
    • Coronary artery disease
    • HF
    • Other arteriosclerotic diseases
    • Diabetic microvascular diseases
    • Renal dysfunction
  • Non-CV death

Secondary Endpoints:

  • Incidence of each CV event
  • BP (systolic, diastolic) change
  • Serious adverse events other than primary endpoints

Drug/Procedures Used:

All patients underwent a run-in period during which they received 20 mg olmesartan daily. Patients were then randomized to receive either olmesartan 40 mg daily, or olmesartan 20 mg daily + a CCB (either azelnidipine or amlodipine).

Principal Findings:

A total of 1,217 patients were randomized, of which 1,164 patients were evaluable. Of these, 578 received high-dose ARB, and 586 received low-dose ARB + CCB. Baseline characteristics were fairly similar between the two arms, except for body mass index, which was slightly higher in the high-dose ARB arm. The average blood pressure (BP) was 158/85 mm Hg, with a heart rate of 73 bpm. About 70% had a history of CV disease, including 3% with myocardial infarction, 8% with CHF, and 18% with stroke. About 54% of the patients had type 2 diabetes.

At 3 years, both systolic BP and diastolic BP were reduced in both arms, but to a larger extent in the low-dose ARB + CCB arm than the high-dose ARB arm. Systolic BP and diastolic BP were 136 mm Hg/133.4 mm Hg, and 74.6 mm Hg/73.1 mm Hg in the high-dose ARB versus low-dose ARB + CCB arms, respectively (p < 0.05). The primary composite endpoint of fatal and nonfatal CV events and non-CV death was similar between the high-dose ARB and low-dose ARB + CCB arms (10.0% vs. 8.2%, hazard ratio [HR] 1.31, 95% confidence interval [CI] 0.89-1.92, p = 0.17). Similarly, fatal and nonfatal CV events (8.5% vs. 6.3%, p = 0.09), cerebrovascular disease (4.2% vs. 2.6%, p = 0.08), CHF (2.1% vs. 1.4%, p = 0.33), and diabetic complications (0.3% vs. 0.7%, p = 0.47) were similar between the two arms.

On subgroup analysis, the incidence of the primary composite outcome was higher in the high-dose ARB arm in patients with established CV disease (12.6% vs. 8.4%, HR 1.63, 95% CI 1.06-2.52, p = 0.03). In the subgroup with type 2 diabetes and no other comorbidities, there was a trend toward benefit for the primary endpoint in the high-dose ARB arm (p = 0.14). Serious adverse events were similar between the two arms (8.1% vs. 8.7%, p = 0.75).

Interpretation:

The results of the OSCAR trial indicate that there is no difference in clinical outcomes between high-dose ARB and low-dose ARB + CCB in elderly Japanese patients with at least one CV risk factor, despite a greater reduction in BP in the low-dose ARB + CCB arm. However, in patients with established CV disease, low-dose ARB + CCB was superior to high-dose ARB alone.

The mechanism of benefit in this subgroup is unknown, but could be due to chance, or due to complementary actions of ARBs and CCBs. This will need to be tested in other populations as well, since ethnic and racial differences also determine responsiveness to many antihypertensive agents.

References:

Presented by Dr. Hisao Ogawa at the ACC.11/i2 Summit, New Orleans, LA, April 5, 2011.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension

Keywords: Myocardial Infarction, Stroke, Diabetes Mellitus, Type 2, Comorbidity, Risk Factors, Diabetic Nephropathies, Tetrazoles, Heart Rate, Calcium Channel Blockers, Imidazoles, Body Mass Index, Heart Failure, Amlodipine, Confidence Intervals, Hypertension


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