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It's All About the Blood Pressure -- Trial Results, Guidelines, Journals, Risk Factors, and Drugs: Final Results of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) -- Implications for Beta-Blockers and Guidelines


Final Results of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) -- Implications for Beta-Blockers and Guidelines

The results of the ASCOT trial, presented at the European Society of Cardiology Congress 2005 in Stockholm, Sweden,[1] and published simultaneously in The Lancet,[2] have shown that compared with a standard antihypertensive regimen of a beta-blocker plus a thiazide-type diuretic, a combination of newer drugs -- a calcium channel blocker (CCB) and an angiotensin-converting enzyme (ACE) inhibitor, plus a statin -- can reduce coronary and stroke events by almost 50%.

In a population of hypertensive adults at moderate risk of developing cardiovascular disease, a regimen starting with amlodipine and adding perindopril as required reduced the risk for strokes by about 25%, total cardiovascular events by 15%, cardiovascular deaths by 25%, and new cases of diabetes by 30% compared with standard treatment of atenolol plus a diuretic. The addition of atorvastatin still further reduced the remaining risk, irrespective of the patient's original cholesterol level, which in ASCOT was average or below average at the outset of the study. The ASCOT investigators believe that the findings from their trial have implications for international guidelines for the management of hypertension. They also suggest that most patients with hypertension should also be considered for a cholesterol-lowering drug.

ASCOT was an independent, investigator-led study set up to compare different treatment strategies in the prevention of cardiovascular disease in hypertensive patients not considered conventionally dyslipidemic.[3] Patients entered into ASCOT had to be aged 40-79 years, have baseline blood pressure ≥ 160/100 mmHg untreated or ≥ 140/90 mmHg treated with 1 or more drugs, no previous myocardial infarction (MI) or current clinical coronary heart disease (CHD), and 3 or more risk factors for a future cardiovascular event. A total of 19,257 patients were enrolled in the United Kingdom, Ireland, and the Nordic countries and randomized to amlodipine or atenolol, to be combined with perindopril or bendroflumethiazide (BFZ), respectively. An alpha-blocker, doxazosin gastrointestinal therapeutic system (GITS), could be added as a third drug to either combination. The 2 regimens could be administered in 6 steps in order to reach blood pressure goal (< 140 mmHg SBP and < 90 mmHg DBP for nondiabetics for < 130 mmHg SBP and < 80 mmHg for diabetics).

Following a 2 X 2 factorial design, 10,305 of the 19,257 patients were also randomized to additional atorvastatin 10 mg or placebo. This lipid-lowering arm of the study (ASCOT-LLA) was stopped early after a significant benefit was seen in the reduction of cardiovascular events in the patients treated with atorvastatin, and the results were published in 2003.[5] The blood-pressure-lowering arm of the trial (ASCOT-BPLA) was also stopped early, in December 2004,[4] following the recommendation of its data safety monitoring board, due to significant differences in cardiovascular events and total mortality associated with the amlodipine-based regimen.

Median follow-up in ASCOT-BPLA was 5.5 years, during which blood pressure was well controlled on both treatment arms, but was on average 2.7/1.9 mmHg lower in the amlodipine-based regimen group. A nonsignificant risk reduction of 10% was seen in the primary endpoint (nonfatal MI plus fatal CHD) for amlodipine ± perindopril. The lack of significance was attributed to the early termination of the study, which resulted in an insufficient number of events. Significant reductions for the amlodipine-based regimen were seen in all the secondary endpoints except fatal and nonfatal heart failure and in the tertiary endpoints, including new-onset renal impairment and new-onset diabetes mellitus. No significant differences in adverse events were between the 2 regimens, but significantly more patients in the atenolol-based regimen group stopped therapy because of serious adverse events.

Effect of Blood Pressure on Differences in Cardiovascular Events

In a separate analysis, also published as a separate paper in The Lancet,[5] Neil Poulter, MD, MSc (Imperial College, London) and other ASCOT investigators studied the effect of blood pressure on the differences in cardiovascular events seen in the trial. No temporal association was observed between the sizes of the blood pressure differences between the 2 antihypertensive regimens and event rate differences. Application of serial mean matching, an adaptation of the serial median matching technique first applied to the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,[6] to SBP measurements and updated Cox regression analyses suggested that blood pressure accounted for 15% or more of the coronary differences and 30% of stroke differences. Multivariate adjustment accounted for only 50% of major cardiovascular event differences and for only 40% of the stroke differences. Prof. Poulter and his colleagues believe that blood pressure differences were unlikely to be the single explanation for the ASCOT-BPLA results and that some of the benefit associated with the amlodipine-based regimen may be due to other blood pressure-related or -unrelated variables not measured or considered in their analyses.

In an editorial accompanying the ASCOT results in The Lancet,[7] Jan A. Staessen, MD, PhD (University of Leuven, Belgium) and Willem H. Birkenhager, MD, PhD (Erasmus University, Rotterdam, The Netherlands) say that the analysis done by Prof. Poulter "weakens the key message that in hypertensive patients it is the lowering of blood pressure that produces most of the benefit." They charge that it "opens the door for possible misinterpretation, or even misuse of post-hoc results by drug marketers." The serial mean matching technique "violated the basic principles of randomization and intent-to-treat analysis," they say.

Profs. Staessen and Birkenhager caution that the results of ASCOT, which preferentially recruited older patients at high cardiovascular risk, might not be readily applicable to most hypertensive patients seen in daily practice, although they note that primary-care physicians enrolled over 50% of the ASCOT study population. They point out that at the end of the ASCOT trial, as in most other trials, only 32.2% of the diabetic and 60.0% of the nondiabetic population were properly controlled. "These dismal statistics underscore the need for use of multiple drug combinations spanning newer and older drug classes in a large group of hypertensive patients, and a need to up-titrate treatment more rapidly than is commonly done to capitalize on the massive benefits of early versus delayed blood pressure control," they say.

The Influence of ASCOT on Guidelines

As predicted by ASCOT co-chair Peter S. Sever, MD, PhD (Imperial College, London) at the presentation of the first data at the American College of Cardiology meeting in March,[8] the UK National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) announced August 25 that they will be jointly reviewing the new ASCOT data in the context of existing recommendations "to see whether any revision might be necessary."[9] No statement has (yet) been made about other guidelines such as the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),[10] which states that beta-blockers may be considered as first-line treatment alone or in combination for patients withor without compelling indications.[10] In addition, no statement has been made for the most recent hypertension guidelines issued by the World Health Organization (WHO), which state that there are no convincing differences between ACE inhibitors or CCBs and older drugs, although they do not exclude small differences on specific outcomes.[11] Current European guidelines refrain from recommending specific classes of drugs as initial treatment, although they list beta-blockers as one of the major classes of antihypertensive agents suitable for the initiation and maintenance of therapy.[12]