ASCOT-BPLA: Preliminary results favor strategy with newer agents

Susan Jeffrey

March 08, 2005

Orlando, FLA - Preliminary data from the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) show that an amlodipine/perindopril-based strategy significantly reduced all-cause mortality and other cardiovascular end points, including stroke, compared with an atenolol/ bendroflumethiazide-based regimen in patients with hypertension.

A 10% reduction in nonfatal MI and fatal coronary heart disease (CHD), the primary end point of the trial, did not reach statistical significance, a finding that the researchers attribute to the early stop of the trial. A reduction in all-cause mortality seen with the amlodipine/perindopril strategy caused the trial to be stopped in November 2004.

Dr Peter S Sever

The data were presented here at a late-breaking clinical-trial session at the American College of Cardiology 2005 Scientific Sessions.

"What we expect, at least in the UK, is a meeting of the guideline committee to reevaluate the future place of beta blockers as first-line treatment in hypertension," Dr Peter S Sever (Imperial College London, UK) told a press conference here. "We recognize that there are clearly subgroups of patients in whom beta blockers are indicatedthose with a prior myocardial infarction or symptomatic coronary heart diseasebut in uncomplicated hypertension, I think the ASCOT data seriously raise questions about the future position of beta blockers in the management of hypertension."

ASCOT

The ASCOT trial was designed to provide further data on outcomes with newer agents over standard therapy with beta blockers and diuretics and begin to provide some information on combinations of agents. Dr Bj ö rn Dahl ö f (Sahlgrenska University Hospital, Oslo, Norway), coprincipal investigator of the trial, presented the trial design. The trial enrolled 19 257 hypertensive patients with at least three other cardiovascular risk factors from 650 general practices in the UK, Ireland, Sweden, Finland, Denmark, Norway, and Iceland.

Dr Bjorn Dahlof

Patients were randomized to one of two antihypertensive regimens: amlodipine (5/10 mg) (Norvasc®, Pfizer) with or without perindopril (4/8 mg) (ACEON®, CV Therapeutics/Solvay Pharmaceuticals; Coversyl®, Servier) or atenolol (50/100 mg) (Tenormin®, AstraZeneca) with or without the thiazide diuretic bendroflumethiazide (1.25-2.5 mg), as well as further treatment as required to reach a target BP of 140/90 mm Hg or less.

To be eligible, patients had to have a baseline BP of >160 mm Hg systolic or >100 mm Hg diastolic untreated or >140 mm Hg systolic or >90 mm Hg diastolic despite being on treatment.

Of the overall population, 10 305 patients with total cholesterol levels of 6.5 mmol/L or less were further randomized to receive atorvastatin 10 mg/day or placebo in a 2x2 factorial designthe ASCOT-LLA population. The lipid-lowering arm of the trial was stopped for efficacy of atorvastatin over placebo and published in 2003.[1]

The primary outcome measure for the BP-lowering trial was nonfatal myocardial infarction and fatal coronary heart disease. This part of the trial was also stopped by the ASCOT steering committee in November 2004 on the recommendation of the trial's data and safety monitoring board.

 
I think the ASCOT data seriously raise questions about the future position of beta blockers in the management of hypertension.
 

The data presented today are preliminary, Dahlöf noted, since the last patient visits will not be completed until May of this year. Sever noted, though, that these represent about 95% of the data and results are not expected to change materially. Final results will be presented in September at the European Society of Cardiology meeting in Stockholm, he said.

Blood-pressure control was better early on with amlodipine/perindopril, Dahlöf said. Although levels were virtually identical by the end of the trial, the mean difference was 2.9/1.8 mm Hg through the course of the study. The difference, he said, "according to epidemiology, will mean something. But we can also say at the same time that it cannot explain the whole result. The mortality difference is coming after three or four years, where we have virtually no difference left in blood pressure."

He speculated after the presentation that the increase in diabetes over time with the beta-blocker/diuretic strategy may have had some impact on the all-cause mortality end point and they intend to look at this relationship further.

Patients were begun on one drug, amlodipine or atenolol, and the other drugs added as needed, but Dahlöf noted that only 14.3% of patients in the amlodipine group and 8.6% in the beta-blocker group remained on monotherapy at the end of the study, making this a trial of combination regimens.

All-cause mortality reduction

Sever presented the ASCOT results, with follow-up to about 5.4 years. The major reason for stopping this arm was a significant difference in all-cause mortality between groupsa 14% risk reduction in the amlodipine/perindopril group vs the atenolol/bendroflumethiazide group, he said.

There was a reduction of about 10% in the primary end point of nonfatal MI or fatal CHD, but this did not reach statistical significance. Sever and Dahlöf both pointed out that the power calculation for this end point had been based on 1150 events, and when the study was stopped, they had reached only 869 events.

However, highly significant reductions were seen in a variety of prespecified end points, including a 24% reduction in a total coronary end point consisting of the primary end point plus new-onset angina and heart failure, a 23% reduction in fatal and nonfatal stroke, and a 24% reduction in cardiovascular mortality.

ASCOT: Primary and secondary end points for amlodipine and perindopril vs atenolol and bendroflumethiazide

End point Hazard ratio 95% CI p
All-cause mortality 0.86 0.78-0.96 0.005
Primary end point: nonfatal MI and fatal CHD 0.90 0.78-1.03 0.12
Total coronary end point: primary end point + new-onset angina + fatal and nonfatal heart failure 0.86 0.78-0.96 0.0048
Fatal and nonfatal stroke 0.77 0.66-0.90 0.0007
All CV events and revascularization procedures 0.84 0.77-0.90 <0.0001
CV mortality 0.76 0.65-0.91 0.0017

"In keeping with several other blood-pressure trials involving comparisons of newer agents against beta-blocker/thiazide regimens, we again saw an excess of new-onset diabetes in the beta-blocker/diuretic limb," Sever said.

ASCOT: New-onset diabetes with amlodipine/perindopril vs atenolol/ bendroflumethiazide

End point Hazard ratio 95% CI p
New diabetes mellitus 0.68 0.60-0.77 <0.0001

Secondary and tertiary end points also suggested a nonsignificant reduction in fatal and nonfatal heart failure and a significant reduction in newly diagnosed peripheral arterial disease and new-onset renal impairment in the amlodipine/perindopril group. They saw no heterogeneity in outcomes in subgroup analyses, he added, and there were no significant differences in the occurrence of adverse events.

Sever showed a time-dependent analysis of the hazard ratios as a series of time points meant to address any issues in interpretation of the data given the differences seen in blood pressure between groups. "What is clear from this is that there is complete consistency in the risk reduction throughout the whole trial period, despite the fact that blood pressures were different particularly in the first six months but were identical for the last part of the trial," he said. "We put this forward as at least one piece of evidence against the fact that the differences we've seen overall in the trial can be explained by blood pressure."

Sever also speculated on other explanations for the differences they'd seen in outcomes beyond blood-pressure lowering. "We have reason to believe there may well be an adverse interaction between atenolol, thiazides, and statins and also a potential for beneficial interaction between amlodipine, perindopril, and statins," he said. Non-blood-pressure-lowering benefits of the newer agents remain a possibility, as do the possibility of non-blood-pressure-related disadvantages of the beta-blocker/thiazide combination, he added.

Asked how these findings should affect how patients currently on treatment should be managed, Dahlöf said that patients currently controlled on existing treatment should probably not be switched away from these drugs, but that, given the diabetes result, the combination of a beta blocker and diuretic should probably be avoided. "Maybe switch the beta blocker to something that blocks the renin angiotensin system, or switch the diuretic to a calcium channel blocker," he said.

Reaction to ASCOT data

Invited discussant for the ASCOT trial was Dr Richard Devereux (New York-Presbyterian Hospital, New York, NY), who concluded his remarks by discussing what he thought the ASCOT results mean.

"The blockade of calcium channels and the renin angiotensin system lowers blood pressure a bit better than the traditional regimen [beta blockers and diuretics] until attenuated by add-on therapy, and this is a benefit of the newer regimen," he said.

Therapy with neither the beta blocker nor diuretic resulted in about one third less diabetes, he said, and there were substantial effects on HDL and triglycerides with the newer combination. Cardiovascular end points were reduced by 10% to 24% vs the traditional regimen, a clear benefit of the newer strategy, he added.

 
The difference in outcomes cannot be solely attributed to the initial drug in either arm. I think the differences should be interpreted as being between regimens rather than between classes of drugs.
 

"In view of nearly as high usage of diuretics as beta blocker and of ACE inhibitors as calcium blockers in the two treatment arms of ASCOT, the difference in outcomes cannot be solely attributed to the initial drug in either arm," Devereux said. "I think the differences should be interpreted as being between regimens rather than between classes of drugs."

"I believe the ASCOT trial, particularly when the results are final, will help us to move forward in our understanding of the treatment of hypertension for our patients," he concluded.

Dr Thomas Giles (Louisiana State University Medical School, New Orleans), president of the American Society of Hypertension, told heart wire that the ASCOT results are "good news." It's no surprise that the combination of the so-called "newer" agents did well, since ACE inhibitors and calcium channel blockers are pretty well established in this setting, he said. "It doesn't mean that there aren't good uses still for beta blockers and diuretics," he said, but it does mean that that there are now a wide variety of useful agents for physicians to choose from. "It's still a matter of individual physicians tailoring a regimen to the specific needs of their patient."

"I think it will change medical practice," Dr Phillip Poole-Wilson (Imperial College London, UK) told heart wire . "If I were going on treatment of high blood pressure, I don't think I would go on the old regime."

Dr Franz H Messerli (St Luke's-Roosevelt Hospital, New York, NY) said the ASCOT results reinforce an earlier lesson from the VALUE study, that in complex patients such as those in ASCOT, a calcium antagonist should be part of the antihypertensive cocktail. In VALUE, as in ASCOT, blood-pressure control was achieved more promptly with amlodipine.

 
ALLHAT notwithstanding, ASCOT clearly makes beta blockers and diuretics OLDHAT.
 

A calcium antagonist, Messerli said, "together with an ACE inhibitor if needed, allows for better blood-pressure control, fewer side effects such as new-onset diabetes, less add-on medication for better persistence with antihypertensive therapy, and last but not least, a greater reduction in morbidity and mortality than with beta blockers and diuretics.

"ALLHAT notwithstanding, ASCOT clearly makes beta blockers and diuretics OLDHAT."

The principal sponsor of ASCOT is Pfizer Inc, New York, with support provided by Servier Research Group, Paris, France, and Leo Laboratories, Copenhagen, Denmark.

The trial was jointly coordinated by the Imperial College London (International Center for Circulatory Health, National Heart and Lung Institute at St Mary's Hospital, London, UK) and the Scandinavian Coordinating Center (Scandinavian CRI AB), Göteborg, Sweden.

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