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CHICAGO -- Using a combination of a statin to lower LDL cholesterol and two blood-pressure lowering medications in a randomized trial reduced the risk of heart attacks, stroke, and death from cardiovascular disease in patients who are at risk for those events, but who have no evidence of heart disease.

But a close look at the results -- based on close to 13,000 patients followed for more than 5 years -- reveals an interesting twist: the real bang for the buck in this massive prevention study came from the statin therapy, not from lowering millimeters of mercury.

Intermediate risk patients given 10 mg of the rosuvastatin (Crestor), plus candesartan (16 mg/day) and hydrochlorothiazide (12.5 mg/day) had 44 fewer deaths, heart attacks, or strokes than those who assigned to placebo for 5.6 years (113 versus 157, P=0.005), and when statin therapy alone was compared with placebo the benefit was similar: 69 fewer events (235 versus 304, P=0.002).

Over the course of the study, the reduction in LDL was 33.7 mg/dL greater in the statin group than in the placebo arm; moreover, rosuvastatin was associated with a 24% reduction in relative risk, which worked out to an absolute difference of 1.1% in events.

Valentin Fuster, MD, who moderated the ACC press conference where the results were discussed, emphasized the need to avoid hype when reporting the findings.

The results "fulfill the concept of people who think lower LDL is better," he said, adding "we need to be clear about the absolute event rate ... we need to be very careful when talking to people about a relative risk reduction when the absolute event rate was maybe 1.2%. ... relative risk is a way to confuse people."

But when blood pressure meds alone were compared with placebo there was no significant benefit, although treatment with the angiotensin receptor blocker and the thiazide did reduce systolic blood pressure by an average of 6.0 mmHg and diastolic pressure by 3.0 mmHg over the 5.6-year study.

In an editorial also published by NEJM, and pointed out that the antihypertensive doses used in the study have never been shown to reduce cardiovascular events when used at such low doses.

Those are the primary results from the Heart Outcomes Prevention Evaluation (HOPE)-3 trial reported here at the and published -- in three papers, each devoted to one arm of the 2x2 factorial study -- online in The New England Journal of Medicine.

The double-blind, randomized, placebo-controlled trial recruited 12,705 patients who were free of heart disease but had a mix of factors that put them at intermediate risk for developing cardiovascular disease.

HOPE-3 follows earlier investigations -- like this one, led by MBBS, of McMaster University in Hamilton, Ontario -- each of which were prevention trials. In HOPE-2, Yusuf and colleagues investigated the role of homocysteine as a risk factor for cardiovascular disease and concluded that there was no evidence to support its prognostic value.

Yusuf said HOPE-3 was "the first formal testing of the polypill concept on clinical events. This was not a polypill, but the concept works."

He noted that blood-pressure lowering was effective among people who were hypertensive at baseline, which suggested that initiating statin preventive therapy without monitoring LDL levels -- the model used in HOPE-3 -- was safe and effective, but the same was not true for blood pressure, which when lowered too much caused symptomatic hypotension.

Asked if statins were the new polypill, Yusuf joked that, although many have suggested putting statins in the water, "it wouldn't work because they are not water soluable."

In HOPE-3, there was no excess risk of either diabetes or cancer among rosuvastatin-treated patients.

Rosuvastatin received FDA approval to be marketed for primary prevention based on the results of the JUPITER trial, which found a significant reduction in risk of cardiovascular events among patients who had elevated highly sensitive C-reactive protein -- a reduction of 44%, or 20 points more than the reduction seen in the HOPE-3 trial.

The HOPE-3 researchers suggest that the JUPITER results may reflect an inflated benefit due to the trial's early termination. Moreover, in this current study the observed benefit was same regardless of C-reactive protein level.

In the accompanying editorial Cushman and Goff write that the findings are a win for those who support the latest ACC/AHA guidelines, a flash-point for many since the guidelines moved away from the "lower is better" mantra and reinforce the primary prevention benefit for statins.

They wrote, "these results support a risk-based approach in statin use, which has been recommended in recent guidelines, rather than an approach based primarily on LDL cholesterol levels, and the results add to the evidence supporting statin use for primary prevention."