ASCOT-BPLA

In Review

Dahlof et al. "Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm". The Lancet. 2005. 386:895-906.
PubMed • Full text • PDF

Clinical Question

Among hypertensive patients at high risk of cardiovascular disease, does a combination regimen of amlodipine and perindopril prevent more cardiovascular events than atenolol and bendroflumethiazide?

Bottom Line

Amlodipine and perindopril does not reduce cardiovascular morbidity and mortality compared to atenolol and bendroflumethiazide. However, the trial was underpowered as it was stopped early due to a significant reduction in all cause-mortality in the amlodipine and perindopril arm. Secondary outcomes suggest a possible reduction in cardiovascular morbidity and mortality using amlodipine and perindopril, although this may be ascribed to differences in blood pressure between the two study arms.

Major Points

Intensive blood pressure lowering regimens had been shown in multiple randomized control trials to reduce cardiovascular moribidity and mortality. However, the size of benefit was significantly less than predicted compared to previous observational studies. It was hypothesized that adverse side effects of older antihypertensive agents, such as beta-blockers and diuretics, was partially offsetting the benefit of blood pressure reduction. At the time, calcium channel blockers (CCBs) and ACE inhibitors (ACEIs) were novel antihypertensive agents hypothesized to have less adverse metabolic effects and provide additional cardiovascular protection beyond its blood pressure effects.

Published in 2005, the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA) was conducted to determine if a combination antihypertensive regimen of a CCB (amlodipine) and ACEI (perindopril) was superior in preventing cardiovascular morbidity and mortality compared to a B-blocker (atenolol) and a thiazide diuretic (bendroflumethiazide).

ASCOT-BPLA is one of the first major studies to compare combination antihypertensive regimens. Although the trial design started patients with monotherapy with titration to combination therapy, only a minority of patients (15%) remained on monotherapy in each arm by the end of the study.

The trial was stopped prematurely due to a large difference in all-cause mortality between the two treatment groups. The primary composite outcome of non-fatal myocardial infarction and fatal coronary heart disease demonstrated a non-statistically significant reduction of 10% in the amlodipine ancd perindopril group. The lack of statistical significance may have been due to early trial termination, as the trial did not meet the pre-specified number of primary events (903 of 1150).

A composite coronary endpoint of nonfatal MIs, fatal CHD, new onset angina, and all strokes was reduced by 14% in the amlodipine-based arm. The amlodipine-based arm also showed statistically significant reductions in all-cause mortality (11%), cardiovascular mortality, (24%), all strokes (23%), and a combination endpoint of non-silent non-fatal MIs and fatal CHD (13%). The amlodipine-based arm had a significantly lower blood pressure than the atenolol-based arm throughout the entire study that may explain the differences in outcomes.

Of note, the amlodipine-based arm demonstrated a significant reduction in new onset diabetes mellitus (30%). There was also a significant reduction in the development of peripheral arterial disease (35%) and renal impairment (15%).

Guidelines

Eighth Joint National Committee Guidelines (JNC 8) (2014, adapted)

The main objective of hypertension treatment is to attain and maintain goal BP. If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in recommendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB). The clinician should continue to assess BP and adjust the treatment regimen until goal BP is reached. If goal BP cannot be reached with 2 drugs, add and titrate a third drug from the list provided. (Expert Opinion – Grade E)

Design

• Multicenter, multinational double-blinded randomized control trial
• N=19257
  • Amlodipine-based regimen (n=9639)
  • Atenolol-based regimen (n=9618)
• Follow-up: median 5.5 years, trial discontinued prematurely
• Analysis: Intention-to-treat
• Primary outcome:
  • Composite endpoint of non-fatal myocardial infarction (including silent) and fatal CHD
• Secondary outcomes:
  • Non-fatal myocardial infarction (excluding silent) and fatal CHD
  • Total coronary events
  • Total cardiovascular events and procedures
  • All-cause mortality
  • Cardiovascular mortality
  • Fatal and non-fatal stroke
  • Fatal and non-fatal heart failure
• Tertiary outcomes:
  • Silent myocardial infarction
  • Unstable angina
  • Chronic stable angina
  • Peripheral arterial disease
  • Life threatening arrhythmias
  • Development of diabetes mellitus
  • Development of renal impairment
• Post-Hoc Endpoints:
  • Primary endpoint + coronary revascularization procedures
  • Cardiovascular death + myocardial infarction + stroke

Population

Inclusion Criteria

• 40-79 years
• Hypertension, either of:
  • Untreated hypertension with sBP > 160mmHg or dBP > 100mmHg, or both
  • Treated hypertension with sBP > 140mmHg or dBP > 90 mmHg, or both
• Three or more cardiovascular risk factors, defined as:
  • Left ventricular hypertrophy (by ECHO or ECG)
  • Type 2 diabetes
  • Peripheral arterial disease
  • Previous stroke or TIA
  • Male gender
  • Age >= 55 years
  • Microalbuminuria or proteinuria
  • Smoking
  • Ratio of plasma total cholesterol to HDL-cholesterol >=6
  • Family history of premature CHD

Exclusion Criteria

• Previous myocardial infarction
• Currently treated angina
• Cerebrovascular events within previous 3 months
• Fasting triglycerides higher than 4.5 mmol/L
• Heart failure
• Uncontrolled arrhythmias
• Clinically important hematological or biochemical abnormality on routine screening

Baseline Characteristics

From the amlodipine-based regimen arm.

Demographics

• Female: 23%
• Age: 63.0 years
• Age > 60y: 63%
• White: 95%
• Smoker, current: 33%
• Alcohol: 8 units per week
• Systolic BP: 164.1 mmHg
• Diastolic BP: 94.8 mmHg
• Heart rate: 71.9 BPM
• Body mass index: 28.7
• Body weight: 84.6 kg
• Total cholesterol: 5.9 mmol/L
• LDL cholesterol: 3.8 mmol/L
• HDL cholesterol: 1.3 mmol/L
• Triglycerides: 1.8 mmol//L
• Glucose: 6.2 mmol/L
• Creatinine: 87.7 mcmol/L

Medical History

• Previous stroke or TIA: 11%
• Diabetes: 27%
• Left ventricular hypertrophy: 22%
• Atrial fibrillation: 1%
• ECG abnormalities, excluding LVH: 23%
• Peripheral vascular disease: 6%
• Other cardiovascular disease: 6%

Drug Therapy

• Previous antihypertensive treatments:
  • None: 19%
  • 1: 44%
  • 2 or more: 36%
• Lipid lowering therapy: 11%
• Aspirin use: 19%

Interventions

• Target blood pressure: <140/90 without diabetes, <130/80 with diabetes
• Follow-up at 6 weeks, 3 months, 6 months and every 6 months subsequently
• Medications were titrated at every visit to the specified target blood pressures
• Calcium channel blocker-based regimen treatment algorithm:
  • Step 1: Amlodipine 5mg
  • Step 2: Amlodipine 10mg
  • Step 3: Amlodipine 10mg + perindopril 4mg
  • Step 4: Amlodipine 10mg + perindopril 8mg
  • Step 5: Amlodipine 10mg + perindopril 8mg + doxazosin 4mg
  • Step 6: Amlodipine 10mg + perindopril 8mg + doxazosin 8mg
• Beta blocker based regimen treatment algorithm:
  • Step 1: Atenolol 50mg
  • Step 2: Atenolol 100mg
  • Step 3: Atenolol 100mg + bendroflumethiazide 1.25mg + potassium
  • Step 4: Atenolol 100mg + bendroflumethiazide 2.5mg + potassium
  • Step 5: Atenolol 100mg + bendroflumethiazide 2.5mg + potassium + doxazosin 4mg
  • Step 6: Atenolol 100mg + bendroflumethiazide 2.5mg + potassium + doxazosin 8mg

Outcomes

Presented as CCB based regimen vs. beta-blocker based regimen.

Primary Outcome

Non-fatal myocardial infarction (including silent) and fatal CHD

5% [n=429] vs. 5% [n=474] (HR = 0.90; 95% CI 0.79-1.02; P=0.10)

Secondary Outcomes

Non-fatal myocardial infarction (excluding silent) + fatal CHD

4% vs. 5% (HR 0.87; 95% CI 0.87-1.00; P=0.05)

Total coronary endpoint

8% vs. 9% (HR 0.87; 95% CI 0.79-0.96; P=0.007)

Total cardiovascular events and procedures

14% vs. 17% (HR 0.84; 95% CI 0.78-0.90; P<0.0001)

All-cause mortality

8% vs. 9% (HR 0.89; 95% CI 0.81-0.99; P=0.02)

Cardiovascular mortality

3% vs. 5% (HR 0.76; 95% CI 0.65-0.90; P=0.001)

Fatal and non-fatal stroke

3% vs. 4% (HR 0.77; 95% CI 0.66-0.89; P=0.0003)

Fatal and non-fatal heart failure

1% vs. 2% (HR 0.84; 95% CI 0.66-1.05; P=0.13)

Tertiary Endpoints

Silent myocardial infarction

0.4% vs. 0.3% (HR 1.27; 95% CI 0.80-2.00; P=0.31)

Unstable angina

1% [n=73] vs. 1% [n=106] (HR 0.68; 95% CI 0.51-0.92; P=0.01)

Chronic stable angina

2% vs. 2% (HR 0.98; 95% CI 0.81-1.19; P=0.83)

Peripheral arterial disease

1% vs. 2% (HR 0.65; 95% CI 0.52-0.81; P=0.0001)

Life-threatening arrhythmias

0.3% vs. 0.3% (HR 1.07; 95% CI 0.62-1.85; P=0.80)

Development of diabetes mellitus

6% vs. 8% (HR 0.70; 95% CI 0.62-0.78; P<0.0001)

Development of renal impairment

4% vs. 5% (HR 0.85; 95% CI 0.75-0.72; P=0.02)

Post-Hoc Endpoints

Primary endpoint + coronary revascularization procedures

6% vs. 7% (HR 0.86; 95% CI 0.77-0.96; P=0.006)

Cardiovascular death + myocardial infarction + stroke

8% vs. 10% (HR 0..84; 95% CI 0.76-0.92; P=0.0003)

Adverse Events

• Bradycardia: 0.4% vs. 6% (p<0.0001)
• Chest pain: 8% vs. 9% (p=0.004)
• Diarrhea: 4% vs. 6% (p<0..0001)
• Cough: 19% vs. 8% (p<0.0001)
• Dizziness: 12% vs. 16% (p<0.0001)
• Dyspnea: 6% vs. 10% (p<0.0001)
• Eczema: 5% vs. 4% (p=0.0002)
• Erectile dysfunction: 6% vs. 7% (p<0.0001)
• Joint swelling: 14% vs. 3% (p<0.0001)
• Lethargy: 2% vs. 5% (p<0.0001)
• Peripheral edema: 23% vs. 6% (p<0.0001)
• Peripheral coldness: 1% vs. 6% (p<0.0001)
• Vertigo: 7% vs. 8% (p=0.004)

Other

• Patients on minimum dual therapy by end of trial: 78%
• Patients on monotherapy by end of trial: 15% vs. 9%
• Average time on minimum of dual therapy: 49.5% vs. 54.9%
• Difference in BP throughout trial: -2.7/-1.9 mmHg in amlodipine-based arm
• Difference in BP at 3 months: -5.9/-2.4 mmHg in amlodipine-based arm
• BP at end of trial: 136/77 vs. 137/79
• BP target reached, overall: 53%
  • Diabetics: 32%
  • Non-Diabetics: 64%

Criticisms

• Population included few non-white individuals
• Did not reach prespecified number of primary endpoint events; possibly underpowered to detect a statistical difference
• Blood pressures significantly lower in the amlodipine-arm during the first six months, and was lower throughout the trial on average
  • Atenolol instead of a diuretic was used as the starting agent, which is significantly slower at reducing BP initially; the study suggests that the combination of older therapies is less effective but may have come to different results if a diuretic was presented as the initial therapy
• Despite the lowering of overall and cardiovascular mortality, secondary endpoints may not be an acceptable for changing clinical practice

Funding

• Financial support mainly provided by Pfizer, manufacturer of Norvasc (amlodipine)
• Several writers with conflicts of interest, receiving personal funding for blood pressure or lipid lowering drugs