Ms. Barnstable is a 66 year-old woman who is seeing you for an annual physical check-up today. She does not take any medications and is a smoker. She asks if there are drugs that she should be taking to lower her risks for heart attacks and strokes. Besides smoking cessation counseling, what do you tell her about drugs for primary prevention of CV events?
What is the Heart Outcomes Prevention Evaluation (HOPE)-3 trial?
In this trial, recently reported in three papers in NEJM, investigators asked whether giving fixed doses of rosuvastatin and candesartan/hydrochlorothiazide to adults who do not have cardiovascular disease but have an intermediate risk of cardiovascular events (annual risk of about 1%) regardless of cholesterol levels, inflammatory markers status, or hypertension status can prevent future cardiovascular events.
The investigators employed a 2 x 2 factorial design to simultaneously test multiple different hypotheses. They randomized 12,705 adults (men ≥55 year-old and women ≥65 year-old) from 21 countries to receive either rosuvastatin (10 mg daily) or placebo, and to receive either candesartan/hydrochlorothiazide (16mg/12.5 mg daily) or placebo.
Three comparisons were analyzed:
There were two co-primary outcomes:
- The composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke
- The first composite outcome plus resuscitated cardiac arrest, heart failure, and revascularization
Who are in the study?
The mean age was 65.7 years and 46% of the participants were women. The baseline mean LDL cholesterol level was 128 mg/dL and mean blood pressure was 138/82 mm Hg.
What were the results?
During the median follow-up time of 5.6 years, rosuvastatin lowered the mean LDL cholesterol level by 35 mg/dL and the anti-hypertensive drugs lowered the mean systolic/diastolic BP by 6/3 mm Hg.
The rate of the first co-primary outcome (composite of CV death, nonfatal stroke, and nonfatal MI) was significantly lower in the combination therapy group compared to dual-placebo (3.6% vs. 5.0%; HR 0.71, 95% CI 0.56 to 0.9; P=0.005). The rate of the second co-primary outcome (composite of first co-primary plus resuscitated cardiac arrest, heart failure, and revascularization) was also lower with combination therapy (4.3% vs. 5.9%; HR 0.72; 95% CI 0.57 to 0.89; P=0.003).
What were the results of blood-pressure treatment alone and statin therapy alone?
The rate of the first co-primary outcome was lower with rosuvastatin versus placebo (3.7% vs. 4.8%; HR 0.76; 95% CI 0.64 to 0.91; P=0.002). These results were consistent in subgroup analyses regardless of baseline cholesterol level, C-reactive protein level, blood pressure, and race or ethnic group.
The rate of the first co-primary outcome was not different with candesartan/hydrochlorothiazide than with placebo (4.1% vs. 4.4%; HR 0.93; 95% CI 0.79 to 1.10; P=0.40). In a pre-specified subgroup analysis, blood pressure treatment when compared to placebo did lower the incidence of the co-primary outcome of CV death, nonfatal stroke, and nonfatal MI in the tertile of study participants with systolic BP > 143.5 mm Hg (4.8% vs. 6.5%) but did not have a significant effect in either of the two lower tertiles (P for trend =0.02) .
So should everyone receive combination therapy of statin and anti-hypertensives?
The addition of anti-hypertensive regime with fixed doses of candesartan/hydrochlorothiazide to fixed rosuvastatin did not differ significantly than rosuvastatin therapy alone in reducing the incidence of CV death, nonfatal stroke, and nonfatal MI (3.6% vs. 3.8%).
How do I reconcile the blood-pressure intervention results with the SPRINT trial?
In an accompanying editorial, William Cushman (Veterans Affairs Medical Center, Memphis) and David Goff (University of Colorado Anschutz Medical Campus) caution that the overall negative results of the blood-pressure–lowering component of HOPE-3 could be due to the treatment of a lower-risk group in HOPE-3 than the SPRINT trial, where participants had subclinical CV disease or a ten-year Framingham CV risk score > 15%. Further more, “the difference in systolic blood pressure between the active-treatment and control groups that was seen in SPRINT was twice the difference seen in HOPE-3 because the treatment regimen was more intensive.” Therefore, the low doses of the anti-hypertensive agents used in HOPE-3 may help explain the result.
What is my take-away?
For patients at intermediate risks for cardiovascular events, irrespective of the cholesterol level or hypertension status, taking a fixed dose of statin reduced this risk. The addition of fixed doses of anti-hypertensives to the statin therapy did not reduce this risk unless the patient was hypertensive.
Don’t miss the NEJM Quick Take video summary of the SPRINT trial:
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James was a 2015-2016 NEJM Editorial Fellow. He recently completed fellowship in General Internal Medicine at Brigham and Women’s Hospital. He is interested in evidence-based medicine, medical education, knowledge translation, and pharmacoepidemiology.