ASCOT: Final results confirm better BP reduction, outcomes with amlodipine- vs atenolol-based regimen

Susan Jeffrey

September 04, 2005

Stockholm, Sweden - Final results of the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA) trial have confirmed preliminary findings showing that an antihypertensive strategy based on amlodipine, with perindopril added as required, significantly reduced all-cause mortality and other cardiovascular end points, including stroke, compared with an atenolol-based strategy, with the diuretic bendroflumethiazide added as required.

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. Preliminary results from ASCOT were presented at the American College of Cardiology Annual Scientific Session 2005.

Dr Peter S Sever

Co–principal investigator Dr Peter S Sever (Imperial College London, UK) told heartwire that on the basis of these findings it is "almost certain" that British and European guidelines will change. "My prediction would be that beta blockers should no longer be considered first-line treatment for the uncomplicated patient with hypertension," he said.

Beta blockers remain indicated for those hypertensive patients with coronary disease or a previous MI or those with heart failure, he added. But in the uncomplicated patient, particularly those over the age of 55, in whom beta blockers are less effective, more likely to cause new-onset diabetes, and less effective in preventing coronary events and stroke, Sever said, "I think they will be withdrawn as first-line drugs."

The results were presented here at the European Society of Cardiology Congress 2005, to coincide with online publication in the Lancet[1].

ASCOT-BPLA: A trial of combination regimens

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. 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.

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 to receive 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 design—the ASCOT-LLA population. The lipid-lowering arm of the trial was stopped for efficacy of atorvastatin over placebo and published in 2003[2].

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.

Dr Björn Dahlöf

Here in Stockholm, Sever presented the trial design, and Dr Bj ö rn Dahl ö f (Sahlgrenska University Hospital, Oslo, Norway) presented the final 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 groupsan 11% 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. Investigators 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 905 events.

However, highly significant reductions were seen in a variety of prespecified end points, including fatal and nonfatal stroke, cardiovascular mortality, and a post hoc analysis of total cardiovascular end point consisting of all events and proceduresto account for all the coronary events avoided by the recent trend to more aggressive revascularization strategies, Dahlöf noted.

ASCOT-BPLA: Primary and secondary end points

End point Amlodipine-based regimen Atenolol-based regimen Unadjusted hazard ratio (95% CI) p
Primary end point (n) 429 474 0.90 (0.79-1.02) 0.1052
Fatal and nonfatal stroke (n) 327 422 0.77 (0.66-0.89) 0.0003
Total CV events and procedures (n) 1362 1602 0.84 (0.78-0.90) <0.0001
All-cause mortality (n) 738 820 0.89 (0.81-0.99) 0.025

In addition, there was a 30% excess of new-onset diabetes in the beta-blocker-based treatment arm, which, while not a new finding, is a larger percentage difference between the arms than has been seen in other trials, Dahlöf said.

ASCOT-BPLA: Incidence of new-onset diabetes

End point Amlodipine-based regimen Atenolol-based regimen Unadjusted hazard ratio (95% CI) p
New-onset diabetes 567 799 0.70 (0.63-0.78) <0.0001

New-onset renal dysfunction was also significantly reduced by 15% (p=0.02).

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

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) and the Scandinavian Coordinating Center (Scandinavian CRI AB), Göteborg, Sweden.

Contribution of BP lowering?

One of the issues raised in this and several of the recent large comparative trials is that of blood-pressure differences seen between groups. As was seen in VALUE and in ALLHAT, there were also differences from the outset in blood-pressure control between groups in ASCOT. Although levels were virtually identical by the end of the trial, the mean difference was 2.7/1.9 mm Hg.

In a paper published separately at the same time in the Lancet[3], ASCOT investigators looked more closely at the initial difference in lowering BP and its effect on subsequent outcomes, as well as other factors that might help explain their findings. This analysis was presented here by Dr Neil R Poulter (Imperial College, London), who was also first author on this companion paper.

"As far as blood pressure is concerned, we addressed it three ways, acknowledging that none of these ways is perfect and all are potentially flawed," Poulter said. These were the temporal association between blood pressure at various points in the trial and events, serial mean matching (a technique used as well by the VALUE investigators), and updated Cox-regression modeling to take into account other factors.

They found that blood pressure was the biggest single contributor to stroke events, but differences in HDL cholesterol were more important for coronary events, the authors said. "Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in stroke events between the treatment regimens tested in ASCOT-BPLA, but residual differences were no longer significant," they sum up in their paper. "These residual differences could indicate inadequate statistical adjustment, but it remains possible that differential effects of the two treatment regimens on other variables also contributed to the different rates noted, particularly for stroke."

Poulter concluded by pointing out that combined with findings of the ASCOT-LLA trial, it is apparent that of all the combinations of therapyamlodipine + perindopril with and without a statin vs atenolol + bendroflumethiazide with or without a statinthe combination of amlodipine-based therapy with atorvastatin was the superior combination on all clinical end points studied, with, for example, a 48% relative risk reduction over the atenolol/diuretic combination without the statin on the primary end point.

If you start with the wrong drug and you don't do anything about it, that may explain why 90% of hypertensives don't get to goal.

Sever told heartwire that what seems clear from the VALUE, ALLHAT, and now ASCOT trials is that the initial choice of treatments appears to be a key issue. "What's very interesting is that if you start on the wrong drug, a drug that's less effective—it was lisinopril in ALLHAT, valsartan in VALUE, and atenolol in ASCOT—whether or not you increase the dose, or add second-, third-, or fourth-line drugs trying to get to goal, if your first choice was the wrong one, you never seem to actually get there."

One of the problems is that in clinical practice, doctors are not good at up-titrating doses or adding second- and third-line drugs. That is, "If you start with the wrong drug and you don't do anything about it, that may explain why 90% of hypertensives don't get to goal," Sever said.

And the debate does continue . . . 

However, in an accompanying editorial[4], Drs Jan A Staessen and Willem H Birkenhäger (Campus Gasthuisberg, University of Leuven, Belgium) point out that they predicted the relative risk reductions in ASCOT just by using the 2.7-mm-Hg difference in systolic BP and the overall event rates previously published in ASCOT-LLA. "Unfortunately, the companion article in today's Lancet by Neil Poulter and colleagues weakens the key message that in hypertensive patients it is the lowering of blood pressure that produces most of the benefit and thereby opens the door for possible misinterpretation or even misuse of post hoc results by drug marketers."

The ASCOT results suggest 220 to 650 patients must be treated for one year with newer rather than older drugs to prevent one CV event or death, respectively, Staessen and Birkenhager write. "This apparently small absolute benefit must be qualified because five years of treatment are not representative of a patient's lifetime treatment." Adverse events and new-onset diabetes were also more common with the older drugs.

Governments and healthcare insurers will have to accept that the use of antihypertensive drugs cannot be rationed.

The mean number of antihypertensive drugs used in ASCOT was 2.2, but at the end of trial, only 32.2% of diabetic and 60.0% of nondiabetic patients were controlled to BP goals, they point out. "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 the need to up-titrate treatment more rapidly than is commonly done to capitalize on the massive benefits of early vs delayed blood-pressure control," they note.

"Governments and healthcare insurers will have to accept that the use of antihypertensive drugs cannot be rationed," Staessen and Birkenhager conclude. "The pharmaceutical industry has to live with the idea that antihypertensive drugs, in particular the highly promoted angiotensin-converting-enzyme inhibitors and angiotensin 2 type-1 receptor blockers, work best if they excel in doing what they are supposed to do: lowering blood pressure without side effects."

The consistency of evidence

Dr Salim Yusuf

Invited discussant for the ASCOT findings here was Dr Salim Yusuf (McMaster University, Hamilton, ON). Yusuf pointed out two of the major limitations of the study. First, the ASCOT trial did not reach its primary end point with a 10% reduction in the primary end point of nonfatal MI and fatal CHD, "technically" compromises the other end points, he said, "but that's technically and doesn't make sense," he noted.

In addition, the study was stopped early but well in advance of reaching the prespecified stopping boundary, so the effects seen are probably real but possibly exaggerated. He also pointed to the early differences in blood pressure but went along with the ASCOT investigators that this difference may have accounted for some part of the difference seen between treatments, but some part was probably due to other factors.

"However," he said of the findings, "I believe it. I believe it despite the points I've made, and the reason for it is the consistency of results with outside data," including results from ALLHAT, LIFE, and ANBP. "Overall, the newer drugs, especially the renin-angiotensin blockers and perhaps amlodipine have a moderate additional benefit over and above" other agents, Yusuf said. But even this small difference could translate into prevention of hundreds of thousands of events in the large population of those with hypertension.

Most patients will need more than one drug to get to BP targets, and the concept is now to use several drugs at lower doses. "Do I believe that drugs that block the [renin-angiotensin-aldosterone system] RAAS have a role? Definitely. Do I believe amlodipine might have a role? Probably. Do I believe thiazides have a role? I would say definitely. And I think what seems to be happening today is maybe, despite my own biases and my own previous work in beta blockers, perhaps beta blockers need not be number one out of these four drugs," he said, although they still have a role.


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