Amlodipine plus atorvastatin demonstrates potentially synergistic cardioprotective effects in ASCOT–LLA

In ASCOT, 19,257 hypertensive patients aged 40 to 79 years at moderate risk for myocardial infarction (MI) and strokes (≥3 additional cardiovascular risk factors corresponding to ~10% risk of an event over 10 years) were randomized to either an amlodipine-based or an atenolol-based antihypertensive treatment regimen. Initial antihypertensive agents were titrated and additional agents added (perindopril to amlodipine and bendroflumethiazide to atenolol) to achieve a target blood pressure of 140/90 mmHg in patients without diabetes or of 130/80 mmHg in patients with diabetes. In addition, patients from ASCOT who had a total cholesterol level of <250 mg/dL (n=10,305) were further randomized in a 2-by-2 factorial fashion to receive either atorvastatin 10 mg daily or placebo. The original ASCOT–LLA findings, published in Lancet in 2003, demonstrated that among all patients receiving antihypertensive therapy, atorvastatin significantly reduced patients' risk of nonfatal MI and fatal coronary heart disease (CHD) events by 36% (HR=0.64; 95% CI, 0.50–0.83; P=.0005), total cardiovascular events by 21% (HR=0.79; 95% CI, 0.69–0.90; P=.0005), and stroke by 27% (HR=0.73; 95% CI, 0.56–0.96; P=.024).

The more recent planned substudy, ASCOT–LLA, was designed to further compare the 4 treatment groups in the trial-amlodipine-based therapy plus placebo (n=2,554), amlodipine-based therapy plus atorvastatin (n=2,584), atenolol-based therapy plus placebo (n=2,583), and atenolol-based therapy plus atorvastatin (n=2,584)-to determine whether the beneficial effects of atorvastatin were different in patients who received different antihypertensive treatment regimens. After a median of 3.3 years of patient follow-up, the researchers observed that patients receiving amlodipine-based regimens experienced the primary end point (nonfatal MI and fatal CHD events) 53% less frequently when receiving atorvastatin 10 mg compared with placebo (HR=0.47; 95% CI, 0.32–0.69; P<.0001), but patients receiving atenolol-based regimens did not appear to benefit to the same degree (heterogeneity P=.025) when receiving atorvastatin compared with placebo, experiencing only a 16% reduction in their risk for the primary end point (HR=0.84; 95% CI, 0.60–1.17; P=.30). No significant differences in patients' risk of either fatal or nonfatal stroke (heterogeneity P=.73) or total cardiovascular events and procedures (heterogeneity P=.25) were observed with atorvastatin use between those randomized to the amlodipine-or atenolol-based regimens.

Although the authors said that these observations could represent "the play of chance," they also stated: "There are plausible explanations based upon molecular studies for such an interaction." One such explanation highlighted by the authors was the potential anti-atherosclerotic properties of calcium channel blockers.

The authors stressed that the results of this analysis should be viewed as hypothesis-generating, and they acknowledged the need to confirm these results with future studies.

SOURCES Sever P, Dahlöf B, Poulter N, et al; on behalf of the ASCOT Steering Committee Members. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006;27:2982–2988.

Sever PS, Dahlöf B, Poulter NR, et al; for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet. 2003;361:1149–1158.