Hypertension: Long-term CV benefits with intervention for BP and cholesterol

Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomized factorial trial

Literature - Gupta A, Mackay J, Whitehouse A et al. - The Lancet 2018; published online ahead of print DOI: http://dx.doi.org/10.1016/S0140-6736(18)31776-8

Introduction and methods

Long-term cardiovascular (CV) benefits have been reported for hypertension trials comparing active drug treatment with placebo, in which substantial in-trial blood pressure (BP) differences were observed [1]. However, only few long-term CV event and mortality follow-up data are available from more recent trials with two active treatments [2]. Although long-term follow-up studies of placebo-controlled statin trials with persistent benefits have been reported [3-5], none involved patients with hypertension who were also assigned interventions with different antihypertensive strategies. This sub-analysis of the Anglo-Scandinavian Cardiac Outcomes (ASCOT) trial therefore evaluated the long-term effect of original BP-lowering (BPL) regimens and lipid-lowering (LL) treatment on all-cause and cause-specific mortality outcomes in hypertensive patients.

ASCOT Legacy involved long-term follow up of the 8,580 UK-based patients from the original ASCOT trial [6]. The ASCOT trial study was a multicenter randomized trial with a 2x2 factorial design comparing amlodipine-based (n=4,305) versus atenolol-based (n=4,275) BPL therapy in 8,580 hypertensive patients aged 40-79 year. Of these patients, those with total cholesterol levels of ≤6.5 mmol/L, no previous lipid treatment with statins or fibrates and at least three additional risk factors for CVD were further randomized to receive either atorvastatin-based LL therapy (n=2,317) or placebo (n=2,288). The remaining patients formed the non-LL (NLL) treatment arm. Subjects with history of coronary heart disease (CHD) events, currently treated angina, or a cerebrovascular event within three months of randomization were excluded.

The primary outcome was non-fatal myocardial infarction and fatal CHD, which was adjudicated independently by two physicians.

Main results

  • In the BPL-arm, there was no significant difference in all-cause mortality between the two treatments (HRadj: 0.97, 95%CI: 0.90–1.04, P=0.3411).
  • The effect of amlodipine-based versus atenolol-based treatment on CV mortality decreased between the in-trial period (HRadj: 0.74, 95%CI:0.58–0.95, P=0.0177) and total follow-up (HRadj: 0.90, 95%CI:0.81–1.01, P=0.0776). However, the effect on stroke mortality was similar during the in-trial period (HRadj: 0.69, 95%CI: 0.40–1.21, P=0.2013) to that at the end of the follow-up (HRadj: 0.71, 0.53–0.97, P=0.0305).
  • The effect of the two BPL therapies differed, depending on whether a patient was treated with LL therapy or not (P-interaction=0.0220).
  • In the NLL-arm, patients treated with amlodipine had significantly fewer CV deaths (HRadj: 0.79, 95%CI: 0.67–0.93, P=0.0046), CHD deaths (HRadj: 0.76, 95%CI: 0.59–0.93, P=0.0439) and non-significantly fewer stroke deaths (HRadj: 0.67, 95%CI: 0.43–1.04, P=0.0751), compared to those treated with atenolol.
  • In the LL-arm, significantly fewer patients treated with atorvastatin died from CV causes (HRadj: 0.85, 95%CI: 0.72–0.99, P=0.0395), compared to those treated with placebo. Non-significantly fewer all-cause and CHD deaths occurred in the atorvastatin-arm (HRadj: 0.92, 95%CI: 0.84–1.01, P=0.0913 and HRadj: 0.78, 95%CI: 0.58–1.04, P=0.0884, respectively), compared to the placebo-arm.


The legacy outcomes from the ASCOT trial show the long-term benefits of antihypertensive treatment with a calcium channel blocker-based regimen and cholesterol-lowering treatment with a statin for reducing CV mortality, 16 years after entry into the trial and more than 10 years after its closure. The fact that interventions for BP and cholesterol are associated with long-term benefits on CV outcomes is supported by these data.

Editorial comment

In an editorial comment [7], Suzanne Oparil, MD, and Richard H. Fu 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. They say 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.


1. Kostis WJ, Thijs L, Richart T, et al. Persistence of mortality reduction after the end of randomized therapy in clinical trials of blood pressure-lowering medications. Hypertension 2010;56: 1060–68.

2. Chowdhury EK, Owen A, Ademi Z, et al. Short- and long-term survival in treated elderly hypertensive patients with or without diabetes: findings from the Second Australian National Blood Pressure study. Am J Hypertens 2014; 27: 199–206.

3. Kostis WJ, Moreyra AE, Cheng JQ, Dobrzynski JM, Kostis JB. Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy. J Clin Lipidol 2011; 5: 97–104.

4. Ford I, Murray H, McCowan C, Packard CJ. Long term safety and efficacy of lowering LDL cholesterol with statin therapy: 20-year follow up of West of Scotland Coronary Prevention Study. Circulation. 2016; 133: 1073–80

5. Hague WE, Simes J, Kirby A et al. Long-term effectiveness and safety of pravastatin in patients with coronary heart disease: 16 years of follow-up of the LIPID Study. Circulation 2016: 133: 1851–60.

6. Sever PS, Dahlöf B, Poulter NR, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators. J Hypertens 2001; 19: 1139–47.

7. Oparil S, Fu RH. Revisiting ASCOT 16 years later. Lancet. 2018;Epub ahead of print.

Find this article online at The Lancet

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