CAFE-LLA: Statin Therapy Does Not Influence Central Aortic Pressure or Hemodynamics

December 31, 2008 (Leicester, United Kingdom) — The use of statin therapy in hypertensive patients has no impact on central aortic pressures, pulse-wave augmentation, the augmentation index, pressure amplification, or any other central hemodynamic parameter [1].

These are the findings of the Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) study, a large-scale, placebo-controlled substudy of the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) designed to prospectively evaluate the effect of statin therapy on the relationship between brachial and central aortic pressures.

Publishing their findings online December 22, 2008 in Circulation, lead investigator Dr Bryan Williams (University of Leicester, UK) and colleagues state that the "favorable effects of statins in cardiovascular outcomes in hypertensive patients are via mechanisms that are independent of important effects on large-artery function and central pressure."

Looking at Large-Artery Function in ASCOT

Because statins reduce the risk of cardiovascular events in individuals with hypertension, there has been interest in the hypothesis that the lipid-lowering drugs modulate large-artery function and central aortic pressures independent of cholesterol lowering. With this in mind, the researchers assessed the effects of atorvastatin 10 mg daily in 891 patients enrolled in ASCOT-LLA.

Patients were, on average, 63 years old and enrolled in ASCOT if they had untreated hypertension or treated hypertension >140/90 mm Hg and three cardiovascular risk factors but no history of coronary heart disease. To be eligible for ASCOT-LLA, patients had to have total cholesterol concentrations <250 mg/dL and be untreated with any lipid-lowering medication.

After six months, treatment with atorvastatin reduced LDL cholesterol by 32 mg/dL and total cholesterol by 35 mg/dL from baseline, a relative reduction of approximately 33% and 25%, respectively, compared with placebo.

Despite the reductions in LDL- and total-cholesterol levels, atorvastatin did not have any effect on central aortic blood pressure or various hemodynamic measurements. Time-averaged brachial blood pressure was similar in the placebo and atorvastatin-treatment arms, as was the change in aortic-pulse pressure. The augmentation index and heart rate were also unaltered with statin therapy compared with placebo.

"The results of CAFE-LLA are unequivocal," write Williams and colleagues. The clinical-outcome benefits of atorvastatin in treated hypertensive patients are not mediated by direct effects on central aortic pressure and hemodynamics, they write.

Too Little, Too Late, and Too Short

In an editorial accompanying the published study [2], Drs Michel Safar, Athanase Protogerou, and Jacque Blacher (Hotel-Dieu Centre de Diagnostique et Thérapeutique, Paris, France) suggest that the results of the study are surprising, "because arterial stiffening and atherosclerosis, although different diseases, have overlapping processes due to common cardiovascular risk factors and complications."

The editorialists note that several studies have shown, although the results are not entirely consistent, that statins have a beneficial effect on central aortic stiffness, possibly because of pleiotropic effects on atherosclerotic plaques, such as improved endothelial function and increased nitric-oxide bioavailability. The negative results of CAFE-LLA might be partly attributed to a lack of power to evaluate hemodynamic outcomes, but for the most part, they say the findings are a case of "too little, too late, too short."

For example, the 10-mg statin dose used in CAFE-LLA might be too low. Although the dose was chosen because baseline cholesterol levels were only modestly elevated, previous studies have shown reductions of aortic stiffness with higher doses of statins, up to 80 mg of atorvastatin. Regarding too late, vascular damage might have already been established in these patients, given that their age was 63 years upon study entry. And finally, too short, in that longer follow-up is needed to observe significant pressure-independent effects on central hemodynamics.

In their paper, Williams and colleagues echo many of these possible explanations in reconciling the differences between large-artery function, hemodynamics, and plasma cholesterol reductions.

Although CAFE-LLA was not powered to assess statin-mediated differences in central pressures and hemodynamics relative to clinical outcomes, the researchers note that atorvastatin in ASCOT-LLA was associated with significant reductions in cardiovascular events compared with placebo.

Williams B, Lacy PS, Cruickshank JK, et al. Impact of statin therapy on central aortic pressures and hemodynamics. Circulation 2009; 119:53-61. Abstract
Safar ME, Protogerou AD, Blacher J. Statins, central blood pressure, and blood pressure amplification. Circulation 2009; 119:9-12. Abstract

The complete contents of Heartwire, a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.

Source: Heartwire/Medscape


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