ASCOT Legacy: Long-term Survival Benefit of BP, Lipid Lowering

Liam Davenport

August 27, 2018

MUNICH — Blood pressure (BP) and lipid-lowering medications continue to offer survival benefits to hypertensive patients more than a decade after they were taken, the results of a long-term follow-up of data from a landmark trial suggest.

Researchers conducted an analysis of more than 8500 UK patients almost 16 years after they were enrolled in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

They showed that patients treated with a regimen based on the calcium channel blocker amlodipine had a 29% reduction in stroke-related death vs those given a regimen based on the β-blocker atenolol, even after just 5.5 years of treatment.

Among patients who went on to be randomly assigned to atorvastatin or placebo, who were treated for 3.3 years, statin therapy was associated with a 15% reduction in rates of cardiovascular death.

Results of the ASCOT Legacy trial, given here at the European Society of Cardiology (ESC) Congress 2018 and published simultaneously in The Lancet, indicate that the benefits of BP- and lipid-lowering therapies accrue over time, even after patients have completed treatment.

Ajay Gupta, MD, PhD, William Harvey Research Institute, Queen Mary University of London, United Kingdom, who presented the study, told | Medscape Cardiology that the findings give "important messages" for both clinicians and patients.

For patients, the results "will give them encouragement to continue" with BP-  and lipid-lowering therapies, he said.

For physicians, they confirm the impact of treatment in the longer term. "Previously, we used to think that it will benefit; now we have proven that it's beneficial, especially the mortality benefits," Gupta said. "Mortality is the one hard outcome we have, so I think these are important things."

Gupta believes that the findings will also influence hypertension guidelines.

"There are hundreds of millions of patients with hypertension, and they were told that all medications are similar," he explained. "There is no doubt that blood pressure control is important but, given the same blood pressure control, are all drugs the same?"

"We have proven that it may not be the case," he said.

Long-term Benefits

Gupta began his presentation by noting that long-term cardiovascular benefits have been reported for hypertension trials comparing active drug treatment with placebo, in which substantial in-trial BP differences were observed.

However, there have been few instances of long-term cardiovascular event and mortality outcomes being examined in more recent trials with two active treatments.

Noting that some placebo-controlled statin trials have hinted at ongoing legacy benefits associated with the drugs, the team decided to look at mortality outcomes in patients who took part in ASCOT.

The original study involved 19,257 hypertensive patients aged 40 to 79 years with at least three other cardiovascular risk factors, who were recruited between 1998 and 2000.

They were randomly assigned to amlodipine, 5 to 10 mg, with the angiotensin-converting enzyme inhibitor perindopril, 4 to 8 mg as required, or atenolol, 50 to 100 mg, with the diuretic bendroflumethiazide, 1.25 to 2.50 mg, and potassium as required.

As per the study design, this BP-lowering arm (BPLA) of the trial was stopped after a median of 5.5 years because the newer amlodipine therapy prevented more strokes and deaths than the older β-blocker–based regimen.

In the subsequent lipid-lowering arm (LLA) of the trial, 10,305 patients from the original cohort who had nonfasting total cholesterol concentrations of 6.5 mmol/L or less were randomly assigned to additional atorvastatin, 10 mg, or placebo.

Again, the study was stopped after a median of 3.3 years after atorvastatin was shown to be associated with a significantly lower rate of nonfatal myocardial infarction and fatal coronary heart disease (CHD).

For the current ASCOT Legacy study, the researchers identified 8580 UK patients who took part in the original ASCOT study. All had taken part in the BPLA and 4605 had gone on to the LLA.

The team gathered post-trial mortality data from the Office for National Statistics and the General Register Office of Scotland, and all deaths were independently adjudicated.

The two treatment groups of both the BPLA and LLA were well balanced in terms of their baseline characteristics; the mean age was 64 years, and 81% to 87% of the patients were male.

The mean BP was 162/92 mm Hg, and the average total cholesterol level was 5.5 to 5.9 mmol/L.

During a median follow-up of 15.7 years, 38.1% of patients assigned to amlodipine-based treatment and 38.4% of those assigned to atenolol-based therapy in the BPLA died.

In addition, 37.3% of patients assigned to atorvastatin and 39.5% of those assigned to placebo died in the LLA during follow-up.

Overall, 36.9% of deaths were due to cardiovascular causes.

Analysis taking into account age, sex, ethnicity, socioeconomic status, body mass index, systolic BP, total cholesterol, diabetes, smoking history, and the other treatment comparison revealed no overall difference in all-cause mortality between treatments in the BPLA, at a hazard ratio (HR) of 0.97 (95% confidence interval [CI], 0.90 - 1.04; P = .34).

There was also no significant difference in rates of cardiovascular death, at an HR of 0.90 (95% CI, 0.81 - 1.01; P = .078), and in CHD death, at an HR of 0.88 (95% CI, 0.73 - 1.07; P = .22).

However, amlodipine-based treatment was associated with significantly fewer deaths from stroke than was atenolol-based therapy, at an adjusted HR of 0.71 (95% CI, 0.53 - 0.97; P = .030).

In the LLA, there were, again, no significant treatment differences in terms of all-cause mortality, at an HR of 0.92 (95% CI, 0.64 - 1.01; P = .091), and CHD death, at an HR of 0.78 (95% CI, 0.58 - 1.04; P = .088).

There were also no significant differences in stroke deaths between the two treatment groups in the LLA, at an HR  of 1.02 (95% CI, 0.67 - 1.55; P = .92).

However, there was a significant reduction in rates of cardiovascular death among patients assigned to atorvastatin vs those given placebo, at an HR of 0.85 (95% CI, 0.72 - 0.99; P = .039).

Looking specifically at BPLA patients who did not go on to take part in the LLA (non-LLA), the team found that patients who were assigned to amlodipine-based therapy had significantly fewer cardiovascular deaths than those given atenolol-based treatment, at an HR of 0.79 (95% CI, 0.67 - 0.93; P = .005).

Moreover, they found a significant interaction between the two BP treatments and whether or not patients were assigned to the LLA (P = .022 for interaction).

Gupta concluded that the findings "confirm the long-term benefits of statin therapy in reducing cardiovascular deaths…even after 13 years of trial closure."

He added that the findings from the non-LLA group, which had a higher baseline risk, underline "the long-term benefits of blood pressure lowering therapies in such patients."

Registries Needed

In a Comment accompanying the published results, Suzanne Oparil, University of Alabama at Birmingham, and Richard H. Fu, University of South Alabama, Mobile, say that a "major limitation" of the study is the lack of data on nonfatal outcomes or on post-trial antihypertensive or lipid-lowering medication use.

This, they write, makes it "impossible to attribute any beneficial effects solely to the treatments provided during the active treatment phase."

"Furthermore, the absence of information on post-trial patient use of ASCOT trial medications prevents the drawing of conclusions about so-called carry-over rather than legacy effects."

Consequently, Oparil and Fu argue that the study "points to the need to establish registries to permit long-term assessment of morbidity and mortality in participants involved in randomized controlled trials of interventions for cardiovascular disease."

They also call for the wider use of electronic medical records coupled with establishment of national regulations "to ensure that high-quality data are properly recorded and easily accessible."

"With such information, legacy studies could gather more meaningful findings by studying patients categorized into distinct groups based on post-trial or pre-follow-up variables."

Remarkable Accomplishment

Ann Marie Navar, MD, PhD, assistant professor of medicine, Duke University School of Medicine, Durham, North Carolina, who was not involved in the study, agreed with those points but emphasized the achievement of carrying out such a follow-up study.

She told | Medscape Cardiology: "We can criticize that they didn't have nonfatal outcomes, but the fact that they were able to pull off a long-term mortality study on that many thousands of patients is pretty remarkable."

She added that it is "a really good demonstration of how to use data collected for other purposes for research — it's a nice application of real-world evidence combined with a clinical trial to look at long-term outcomes."

Turning to the findings, Navar said that it is "no surprise that lipid-lowering therapy with statins works" and that the study "really argues for the need to identify people for treatment early."

"The part of it that it doesn't answer is: What would have happened if everybody had stayed on treatment over the long run?" she said.

"Where there's a gap still in the literature, we know there's a legacy effect of a few years of treatment, but what's the long-term effect of prolonged treatment?"

"I think the potential benefits on a population level are probably multiplied when you can treat populations for longer periods of time."

She pointed out that, rather than the 3 years of treatment that people received in ASCOT, patients in the real world are being treated for 30 years or more.

"So I think that what we're seeing in this study is a small glimpse into the benefit of statin treatment but we have yet to quantify the benefit of long-term treatment. We just know that short-term treatment has a benefit long term."

However, rather than focusing just on registries, as suggested in the editorial, Navar believes that there is space for a hybrid approach between clinical trials and registries, such as the current study.

Like the editorialists, Navar would like to see data on nonfatal endpoints and, to those ends, Gupta and colleagues are conducting an analysis that is due to report in 2019.

"That is going to be really interesting because, if you're seeing a difference in stroke mortality, what's happening for all stroke events?" Navar said. "Or if you're seeing a difference in cardiovascular mortality in the atorvastatin arm, what's happening for nonfatal cardiovascular events?"

She believes that the mortality differences seen in the study could be "just the tip of the iceberg" in terms of benefits.

Overall, Navar said that what the study tells clinicians "is that the benefits that patients accrue will last over the course of a lifetime, and so it reinforces the need to identify people for treatment early, and then maintain adherence, at least while they are being indicated for therapy."

She added that there is also a reminder that maybe β-blockers are not the first-line treatment for hypertension without comorbidities.

The novel aspect of the study is that "it allows clinicians to be able to maybe help motivate patients longer term that their treatments at an early age are banking for the future, to help keep them alive longer and hopefully healthier, if we can see those data," Navar concluded.

The original ASCOT study was investigator led with funding provided by Pfizer. The ASCOT Legacy program was investigator led and in part funded by research grants from Pfizer to Imperial College London and the Foundation for Circulatory Health. Gupta reports support from the Foundation for Circulatory Health, during the conduct of the study, and non-financial support from Servier, outside the submitted work. Gupta has been supported by the Barts Charity and William Harvey Research Institute. Other authors also declare several interests. Oparil reports grants and personal fees from Actelion Pharmaceuticals/George Clinical and ROX Medical; grants from Vascular Dynamics, Bayer, and Novartis; and personal fees from 98point6, Novo Nordisk, and Pfizer, all outside the area of work commented on here. Oparil has collaborated on a review with Neil Poulter, who is an author on the report of the ASCOT Legacy study. Fu declares no competing interests.

European Society of Cardiology (ESC) Congress 2018. Abstract 1327. Presented August 26, 2018.

Lancet. Published online August 26, 2018. Abstract, Comment

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