AFCAPS-TexCAPS

In Review

Downs JR, et al. "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS". JAMA. 1998. 279(20):1615-1622.
PubMed • Full text

Clinical Question

Among patients with average cholesterol levels without atherosclerotic cardiovascular disease, is lovastatin for primary prevention of acute coronary events, as compared to placebo?

Bottom Line

Among patients with average cholesterol levels without atherosclerotic cardiovascular disease, lovastatin is effective for primary prevention of acute coronary events, as compared to placebo. Lovastatin demonstrated good safety profile.

Major Points

HMG-CoA reductase inhibitors (statins) have been shown to reduce cardiovascular (CV) mortality and morbidity in certain high risk patient groups. The 4S study observed the benefit of simvastatin in patients with prior MI or angina and hyperlipidemia. The LIPID study reported the benefit of Pravastatin in patients with coronary artery disease (CAD) and different cholesterol levels.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) studied the effect of cholesterol lowering with lovastatin in patients with moderately elevated lipid levels without clinically evident atherosclerotic disease, including previous MI, claudication, stroke, uncontrolled hypertension or diabetes mellitus. The trial randomized 6,605 patients to receive lovastatin 20 mg daily (titrated to 40 mg if necessary) or placebo. The primary outcome was first acute major coronary event, including fatal or nonfatal MI, unstable angina, or sudden cardiac death

The trial reported that lovastatin reduced the risk of the primary outcome (6.8% vs 10.9% in placebo [RR 0.63; 95% CI 0.50-0.79; P<0.001]). There was no LDL-C threshold evident below which no benefit would be obtained. The reduction in risk did not differ according to pre-treatment cholesterol levels. Lovastatin did not significantly increase the risk of myopathy, CK or ALT/AST levels, non-cardiovascular mortality or cancer. Subsequently, the safety profile of lovastatin has also been confirmed in a long-term follow up data published in 2001.

The trial was included in a meta-analysis which concluded that intensive LDL-C lowering with statins is safe. Reduction by 1·0 mmol/L is associated with a reduction of major vascular events risk by 20% approximately without any evidence of a threshold level. In addition, a Cochrane review concluded that statins are effective for the primary prevention of CVD.

Guidelines

ACC/AHA Cholesterol Guidelines (2013, adapted)

• Secondary prevention with high-intensity statin therapy for patients ≤75 years in age with clinical ASCVD (i.e. stable CAD) unless contraindicated (grade A, class I, level A)
• Moderate-intensity therapy for above group if contraindication to high-intensity statin therapy or risk for statin-associated adverse events (grade A, class I, level A)
• For patients ≥75 years with clinical ASCVD, evaluate risks and benefits when initiating high- or moderate-intensity statin therapy (grade E, class IIa, level B)
• No recommendation for specific targets for LDL- and non-HDL-cholesterol for primary or secondary prevention of ASCVD.
• Definition of intensity of statin therapy as:
  • High-intensity (LDL reduction ≥50%): Atorvastatin 40-80 mg, rosuvastatin 20-40 mg
  • Moderate-intensity (LDL reduction 30-<50%): Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg BID, pitavastatin 2-4 mg
  • Lower-intensity (LDL reduction <30%): Simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, pitavastatin 1 mg

Design

• Multi-center, randomized, placebo-controlled trial
• N=6,605
  • Placebo (n=3,301)
  • Lovastatin (n=3,304)
• Setting: 94 centers in Texas, US
• Enrollment: May 1990 to February 1993
• Mean follow-up: 5.2 years
• Analysis: intention-to-treat
• Primary outcome: first acute major coronary event, including fatal or nonfatal MI, unstable angina, or sudden cardiac death

Population

Inclusion Criteria

• Males aged 45-73 years and post-menopausal females aged 55-73 years
• Cholesterol entry criteria:
  • total cholesterol 4.65-6.82 mmol/L (180-264 mg/dL)
  • LDL-C 3.36-4.91mmol/L (130-190 mg/dL)
  • HDL-C ≤1.16 mmol/L (45 mg/dL) for men or ≤1.22 mmol/L (47 mg/dL) for women
  • triglyceride ≤4.52 mmol/L (400 mg/dL)

Exclusion Criteria

• previous MI, angina, claudication, cerebrovascular accident, TIA
• uncontrolled hypertension
• secondary hyperlipidemia
• type 1 or type 2 diabetes mellitus either on insulin or with HbA_1c ≥10% (20% above upper limit of normal)
• body weight >50% greater than the ideal limit for height, according to the 1983 Metropolitan tables
• nephrotic syndrome
• noncompliance to treatment
• limited life expectancy

Baseline Characteristics

From the lovastatin group

• Demographics: males 85%, male age 58±7 years, female age 62±5 years, Caucasian 89%
• Male BMI 27.1±3.1 kg/m², Female BMI 26.4±3.5 kg/m², BP 138/78 mm Hg
• Other CV risk factors:
  • hypertension 22%, diabetes mellitus 6.8%, current smoker 13%, family history of premature CVD, 15%
  • alcohol consumption: males 49%, 6.3±6.2 drinks/week; females 31%, 3.5±3.7 drinks/week
• Medications: aspirin 17.3%, beta-blocker 4.3%, calcium channel blockers 5.2%, ACE-inhibitors 7.4%, diuretics 6.1%, alpha blockers 2.1%; oral hypoglycemics 1.2%

From all patients:

• Lipid level: LDL 3.89±0.43 mmol/L (150±17 mg/dL), male HDL 0.94±0.14 mmol/L (36±5 mg/dL), female HDL 1.03±0.14 mmol/L (40±5 mg/dL), triglyceride 1.78±0.86 mmol/L (158±76 mg/dL), total cholesterol 5.71±0.54 mmol/L (221±21 mg/dL)

Interventions

• All patients first completed a 12-week American Heart Association Step I diet run-in, including a 2-week placebo treatment before randomization
• Patients were eligible if their lipid levels met entrance criteria at both 4 and 2 weeks prior to randomization
• Elligible participants were randomized to receive either lovastatin 20 mg/day, or placebo
• After 3 months, lovastatin was increased to 40 mg/day if the LDL-C level was >2.84 mmol/L (110 mg/dL)
• Advice on diet and modification of other risk factors were provided throughout the trial
• Adherence to regimen was confirmed by pill counts, which showed a 99% compliance for ≥75% of the time
• The trial was terminated on July 3, 1997 on the basis of having achieved efficacy

Outcomes

Presented as lovastatin vs. placebo

Primary Outcome

First major acute coronary event

6.8% vs 10.9% (RR 0.63; 95% CI 0.50-0.79; P<0.001)

Secondary Outcomes

Revascularization

6.2% vs. 9.3% (RR 0.67; 95% CI 0.52-0.85; P<0.001)

Unstable angina

3.5% vs. 5.1% (RR 0.68; 95% CI 0.49-0.95; P=0.02)

Fatal and nonfatal MI

3.3% vs. 5.6% (RR 0.60; 95% CI 0.43-0.83; P=0.002)

Fatal and nonfatal CV events

11.5% vs. 15.3% (RR 0.75; 95% CI 0.62-0.91; P=0.003)

Fatal CV events

1% vs. 1.4% (RR and P-value not reported)

Fatal and nonfatal coronary events

9.6% vs. 12.8% (RR 0.75; 95% CI 0.61-0.92; P=0.006)

Fatal CHD events

0.6% vs. 0.9% (RR and P-value not reported)

Additional outcomes

Total cholesterol at 1 year

4.75±0.62 mmol/L (184±24 mg/dL) vs. 5.90±0.72 (228±28 mg/dL)

18% reduction from baseline vs. 0.9% increase (P<0.001)

LDL-C at 1 year

2.96±0.52 mmol/L (115±20 mg/dL) vs. 4.04±0.63 (156±25 mg/dL) (P<0.001)

25% reduction from baseline vs. 1.5% increase (P<0.001)

Triglyceride at 1 year

1.61±0.82 mmol/L (143±73 mg/dL) vs. 1.84±0.93 (163±82 mg/dL) (P<0.001)

15% reduction from baseline vs. 2.3% reduction (P<0.001)

HDL-C at 1 year

1.02±0.21 mmol/L (39±8 mg/dL) vs. 0.97±0.2 (38±8 mg/dL) (P<0.001)

6% increase from baseline vs. 1.2% increase (P<0.001)

Subgroup Analysis

There was no significant interaction with age, sex, smoking status, presence of hypertension, family history of CHD, diabetes, LDL-C and HDL-C level at baseline.

Adverse Events

All-cause mortality

4.6/1000 patient-years vs. 4.4/1000 patient-years (P=NS)

Cardiovascular causes: 1/1000 patient-years vs. 1.4/1000 patient-years (P=NS)

Non-cardiovascular causes: 3.6/1000 patient-years vs. 3/1000 patient-years (P=NS)

Fatal and nonfatal cancer

15.1/1000 patient-years vs. 15.6/1000 patient-years (P=0.75)

Adverse events

Serious events: 34.2% vs. 34.1% (P=NS)

Leading to discontinuation: 13.6% vs. 13.8% (P=NS)

ALT/AST ≥3 times upper limit of normal (ULN): 0.6% vs. 0.3% (P=NS)

Drug-related ALT elevation: 3.3% vs. 2.1% (P=0.003)

CK ≥3 times ULN: 0.7% (lovastatin 20 mg) vs. 0.6% (lovatstatin 40 mg) vs. 0.6% (placebo) (P=NS)

Myalgia: 0.3% vs. 0.3% (P=NS)

Rhabdomyolysis: 1 vs. 2 patients

there were no cases of myopathy reported

Criticisms

• Due to the low cardiovascular risk of the enrolled patients, the absolute risk reduction of 0.2% per year was much smaller than demonstrated in previous trials. This is equivalent to a NNT of 86 for preventing 1 CHD event over 5 years.
• At the time of the trial, it was uncertain of treating the general patient population by the same lipid criteria in the trial would be feasible or cost-effective.

Funding

Merck & Co Inc