ASCOT Legacy: Calcium Channel Blockers, Statins Confer Long-term Survival Benefits in Hypertensive Patients

More than a decade after they were treated in the trial, patients continued to have lower rates of stroke and cardiovascular death

ASCOT Legacy: Calcium Channel Blockers, Statins Confer Long-term Survival Benefits in Hypertensive Patients

Lowering cholesterol along with blood pressure in patients with hypertension has a lasting impact on survival years after medications have been stopped, new long-term data from the ASCOT Legacy study suggest.

The findings are the latest from the 19,257-patient randomized ASCOT trial, which began in 1998. Both the lipid-lowering and the BP-lowering arms of the trial were prematurely stopped due to an overwhelming benefit of atorvastatin over placebo and of the calcium channel blocker amlodipine over the beta-blocker atenolol. The 16-year data on UK patients in the cohort, presented this week at the European Society of Cardiology Congress 2018 and simultaneously published in the Lancet, show that those benefits continued to accrue long after the study was completed.

“The really novel finding is the long-term benefit of a calcium-channel-blocker regimen on stroke outcome,” the study’s senior author Peter Sever, MD (Imperial College London, United Kingdom), told TCTMD.

Those initially randomized to amlodipine for the 5.5 years before the study was stopped were 29% less likely to have died from a stroke 10 years later than those randomized to atenolol. In the lipid-lowering arm, there were 15% fewer cardiovascular deaths among patients with average (6.5 mmol/L) or below-average cholesterol at baseline who were assigned to atorvastatin compared with placebo, and 21% fewer cardiovascular deaths in those with above average cholesterol at baseline assigned to the statin. Patients had only been on the statin for 3.3 to 5.5 years a decade earlier.

To TCTMD, Sever said while other trials have also shown similar statin benefits, the benefits of the BP-lowering are novel. “To show now that there are two completely independent risk factors that if treated appropriately can have long-term benefit is a really important finding,” he commented.

ASCOT Legacy, led by Ajay Gupta, MD (Queen Mary University of London, England), involved long-term follow up of the 8,580 patients from the original trial who were from the United Kingdom. All had high blood pressure and three or more additional risk factors for cardiovascular disease but no previous history of a coronary event.

Over median follow up of 15.7 years, all-cause mortality rates were similar between the atorvastatin and placebo groups, and between the amlodipine and atenolol groups. While there were fewer all-cause and coronary heart disease deaths with atorvastatin in addition to less cardiovascular deaths, the difference was not significant.

To TCTMD, Sever said his group only looked at the UK cohort due to data-access issues and speculated that if they had been able to do long-term assessment of the entire study group they may have seen more of an impact on all-cause mortality and coronary heart disease deaths.

The $64,000 Question

But in an accompanying editorial, Suzanne Oparil, MD, and Richard H. Fu (University of Alabama at Birmingham), say a major limitation of the study is that when the trial ended the researchers no longer had access to nonfatal cardiovascular disease outcomes or to antihypertensive and lipid-lowering medications being taken by the participants. Therefore, it is hard to say for certain that the short period of being on the medications translated to legacy effects so many years later.

“That’s the $64,000 question,” Sever acknowledged. “We do have a substudy, which was finished a few months ago, in which we sent out questionnaires to about 3,000 patients. Included in those questions was what were their contemporary medications, both for blood pressure treatment and for lipid lowering. We’re just beginning to start the analyses of these data, so hopefully within the next few months we will have some new information on that.”

Operil and Fu say among other things, the study raises the issue of the need for properly recording and allowing access to long-term data on patients enrolled in clinical trials. “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,” they write.

Sever noted that in the UK the national registries are being opened to include not only mortality but also hospitalization records.

“So for the first time we’re going to be able to go back and look at the hospital records for patients admitted during the last 16 years and we’ll get information on nonfatal events, and from our own questionnaires we’ll have information on contemporary treatment,” he said, adding that it is unlikely that the findings can be explained by a change in treatment once the study ended.

Ultimately, Sever said, the main message of ASCOT is in line with contemporary hypertension guidelines and shows that “the earlier you treat people, you are likely to confer not only short-term benefits but long-term benefits, and it’s very reassuring to see that in this study.”

Commenting on the study for TCTMD, Erin Michos, MD (Johns Hopkins University School of Medicine, Baltimore, MD), said that while these legacy types of observational studies are not without limitation, “this is an overall very reassuring message that I can give to my patients when I am initiating these medications for BP and lipid treatment, that there is likely long-term benefit.”

Questioning the Legacy

In an email, Michos added that the legacy effect of statins makes sense from a biological standpoint since LDL cholesterol is causally related to atherosclerotic CVD. “I think it is not only the magnitude of LDL cholesterol elevation but also duration of exposure,” she said. “Thus, if you can reduce the duration of exposure even for a little bit (ie, reduce LDL ‘pack-years’), particularly if you start earlier in life, then that is likely to confer long-term effects from plaque regression and stabilization.”

As for a legacy effect of BP medications, however, Michos was more circumspect. “I would certainly anticipate that therapeutic reductions in BP, whether it be through lifestyle changes or pharmacotherapy, would have long-lasting vascular effects,” she noted. “And I would have anticipated that reductions in BP would have more of an impact for stroke than coronary heart disease. But the confusing thing for the ASCOT-BPLA legacy was that the long-term benefits of amlodipine for stroke mortality were out of proportion to differences in BP levels. Thus, this means the lingering effect on stroke mortality from amlodipine-based treatment appears independent of BP, suggesting there might be other mechanisms than BP that explains the legacy.”

Sever said one mechanism may be related to a prior observation that calcium channel blockers exert a more profound reduction on blood pressure variability than do beta-blockers.

“Another possibility is that amlodipine might have direct benefit on endothelial function or other metabolic parameters outside of BP control,” Michos suggested. There also may be subtle differences in other cardiometabolic variables, such as an adverse effect of hyperglycemia with atenolol-based therapy, she noted.

“I think, at this point, we can only speculate about mechanisms,” she added. “While we have consistency of data of legacy among the statin trials, this is the first study I am aware of that showed a legacy with amlodipine, so I think we still need more confirmation about long-term benefits for specific classes of BP medications versus just long-term benefits of BP control itself.”

  • Gupta reports support from the Foundation for Circulatory Health, during the conduct of the study, and non-financial support from Servier.
  • Sever reports grants and personal fees from Pfizer and Servier during the conduct of the study, and grants and personal fees from Pfizer, Servier, and Amgen outside the submitted work.
  • 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 submitted work.
  • Fu and Michos report no relevant conflicts of interest.