Abstract & Commentary
The lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was initially reported at the American College of Cardiology meeting in Chicago in March and subsequently in Lancet. The study is somewhat similar to the recently reported ALLHAT trial, in that both were very large trials that enrolled individuals with hypertension randomized to 2 antihypertensive therapy arms, with a large subset of individuals treated with a statin or placebo. The ALLHAT lipid strategy failed to show a significant difference between pravastatin and placebo. In ASCOT, atorvastatin was used; this is the first large, randomized, controlled trial involving this statin to be reported.
ASCOT enrolled 19,342 patients, aged 40-79, with hypertension as well as 3 additional cardiovascular risk factors. The subjects were recruited from family practice physicians in Scandinavia, the United Kingdom, and Ireland. Eligibility was an untreated blood pressure of > 160/100 mm Hg or treated hypertension with a blood pressure of > 140/90 mm Hg. Either an elevated systolic or diastolic blood pressure meeting criteria allowed eligibility. Three additional risk factors were required: left ventricular hypertrophy, diabetes, peripheral vascular disease, prior stroke or TIA, male gender, age 55 or older, proteinuria, smoking, premature CAD, or a total cholesterol/HDL ratio of > 6. Patients were recruited between 1998 and 2000. The blood pressure arm (BP) of ASCOT is ongoing. The lipid substudy consisted of 10,305 individuals randomized to atorvastatin 10 mg daily or placebo. This population was 95% Caucasian, 81% male, with a mean age of 63. Additional risk factors averaged 3.7. The study was designed to last 5 years but was stopped by the Data Safety Monitoring Board in September 2002, because the lipid arm achieved "a highly significant reduction in the primary end point," and risk reduction was 36% (P = .0005). The average follow-up was 3.3 years. The primary end point (the same used in all major statin trials) was fatal CAD and nonfatal myocardial infarction. Secondary end points that were positive included total cardiovascular events and procedures and total coronary events. However, all-cause mortality was not lowered by atorvastatin. Of interest, fatal and nonfatal stroke were reduced by atorvastatin. Baseline lipid levels in these high-risk individuals were a total cholesterol (TC) of 209 mg/dL, and an LDL cholesterol of 131. At the end of the follow-up, TC had fallen to 160 and LDL-C was lowered to a mean of 87 mg/dL. There were no safety problems; cancer and abnormal liver enzymes were not different between placebo and atorvastatin. A subgroup analysis indicatedthat the hazard ratios were identical for all strata of baseline lipids. There was 27% reduction in all stroke (P =.02). Of interest, there was no benefit of atorvastatin in women (19% of cohort) although there were only 36 total end points in this group. ASCOT achieved much better maintenance of randomized lipid-lowering therapy compared to ALLHAT; only 15% of atorvastatin patients had dropped out at 3 years, and only 9% of placebo subjects were started on open-label statin. The drop in and drop out rates in ALLHAT were very large and are believed to have strongly contributed to the failure of that study to show a difference between pravastatin and placebo. Overall BP control in ASCOT was excellent in both groups, with a reduction of 25/14 mm Hg and an average BP of 130/80 mm Hg. The ASCOT investigators, as well as an editorial by Lindholm and Samuelsson,1 suggest that guidelines for use of lipid-lowering agents need to be modified based on these results; they also suggest that ASCOT supports a global risk strategy to reduce cardiovascular disease rather than relying on individual lipid or BP levels. A cost effectiveness assessment is not available and hopefully will be forthcoming. Finally, in terms of absolute risk reduction, there was a decrease in absolute coronary events of only 3.4 per 1000 patient-years. The ASCOT authors agree that "there are clearly financial implications of statin use among all hypertensive patients with absolute levels of cardiovascular risk as low as those included in ASCOT" (Sever PS, et al. Lancet. 2003;361:1149-1158).
Comment by Jonathan Abrams, MD
This study is important, although not particularly surprising. This was a primary prevention cohort, predominately an older male population with a relatively modest event rate. The ASCOT placebo group experienced a 9.4% estimated 10-year coronary event rate and a 7.4% 10-year total stroke rate. When both CAD and stroke are combined, the reduction in vascular risk is considerably more robust. Nevertheless, this study population was almost as low risk as the AfCAPS/TexCAPS study that had a primary event rate for CAD events of approximately 0.6% per year. The major objective of the main ASCOT trial arm is to compare 2 hypertension regimens; data supplied in the editorial indicate that excellent blood pressure control has been achieved in both active treatment groups. Thus, the lipid-lowering effects in ASCOT are in addition to a substantial reduction in blood pressure in this relatively high-risk population. It is conceivable, and perhaps even likely, that without BP control, there may have been a greater absolute reduction in risk in atorvastatin patients. Ideally, all CAD risk factors should be aggressively managed; both ASCOT and ALLHAT have demonstrated that this type of strategy can be easily applied. As mentioned above, the failure of ALLHAT to demonstrate a reduction in cardiovascular events in the pravastatin arm has been attributed to its open-label design with the substantial placebo individuals who received open-label statin, as well as the large drop out of prava statin patients, resulting in an LDL gradient at the end of ALLHAT that was rather modest. Finally, it should be stressed that ASCOT echoes and amplifies the results of the Heart Protection Study (HPS), which demonstrated that individuals at vascular risk obtained a comparable benefit from a statin irrespective of baseline lipid levels. Thus, there was an approximately 35% risk reduction in all lipid cohorts in ASCOT, including those who started with a TC of < 190 mg/dL and (an estimated) baseline LDL-C level of < 115. The actual data are not available.
In conclusion, a strategy of using overall vascular risk to qualify for a statin, even with relatively unremarkable or even low baseline total cholesterol and LDL-C levels, is confirmed by both in HPS and ASCOT. The now rather old Texas trial is confirmative, enrolling individuals with only modest elevation of LDL-C and who also had depression of HDL-C, showing CV event reductions. The problem with all 3 of these studies is the large number needed to treat. In spite of unequivocal favorable cholesterol reductions, a very large number of individuals need to receive a statin in order to prevent few cardiovascular events. Thus, cost effectiveness analyses and lipid-lowering guidelines must be modified in line with what society will accept. The ASCOT investigators and the editorialists stress that current guidelines and use of statins are widely variable around the world. Nevertheless, the concept that global risk should drive preventive measures is sound. The level of total and LDL cholesterol that may benefit with active pharmacologic therapy, as well as the target end point for lipid levels, is decreasing, particularly in those individuals who have multiple CV risk factors.
Dr. Abrams is Professor of Medicine Division of Cardiology University of New Mexico, Albuquerque.
1. Lindholm LH, Samuelsson O. Lancet. 2003;361: 1144-1145.