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Gupta A, Mackay J, Whitehouse A, et al. 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 randomised factorial trial. Lancet. 2018 Aug 24. pii: S0140-6736(18)31776-8. doi: 10.1016/S0140-6736(18)31776-8.
Area Score
Internal Medicine
Public Health
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)

BACKGROUND: In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial.

METHODS: ASCOT was a multicentre randomised trial with a 2?×?2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7-16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death.

FINDINGS: Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81-1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53-0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67-0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72-0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo.

INTERPRETATION: Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes.

FUNDING: Pfizer.

Comments from MORE raters

Cardiology rater

Nothing new in the finding. We already know the benefit of statin therapy. Calcium channel blockers for decreased stroke risk is probably associated with its anti-hypertensive effect.

Cardiology rater

This is a wonderful study with surprising results that amlodipine outperforms Atenolol for CAD reduction.

Family Medicine (FM)/General Practice (GP) rater

This shows both blood pressure-lowering and lipid-lowering treatments confer long-term benefits. The difference between Ca channel blockers and beta blockers is less important (for example the absolute difference in stroke is 27 out of ~8,500 randomised in 15 years).

General Internal Medicine-Primary Care(US) rater

Overall mortality was not reduced differently between amlodipine and atenolol, but stroke mortality was reduced with amlodipine. More patients taking amlodipine must have died from something else in order to account for the lack of difference in all-cause mortality. The statin lowered mortality by an amount similar to that shown in other studies.

General Internal Medicine-Primary Care(US) rater

Most internists know that atenolol is worse than worthless for hypertension; although, they still inherit many patients who have been on it for years. What is new information, if I am interpreting the information correctly, is a statistically significant benefit in cardiovascular primary risk in patients with normal, or low, lipid profile when placed on a statin. I will need to learn more about that before being able to convince the statin phobic patient population to go on the drug.

Internal Medicine rater

This is a very important and groundbreaking article, particularly with regard to the superiority of amlodipine-based versus atenolol-based blood pressure lowering regimens in reducing overall cardiovascular mortality.

Public Health rater

The very modest effect sizes and multiple testing limits the strength of the positive conclusions which appear overly supportive of the sponsor's products to this reader.

Public Health rater

While the use of anti-hypertensive and statin for primary ASCVD prevention reduces these risks, it is not new information to most clinicians. Some of the details in this long term follow-up (there are only 2 > 15 yr longer f/u trials on this; this one and the ALL-HAT) are likely new to most clinicians. Specifically, stroke death appears to be lower with amlodipine than atenolol in the blood pressure lowering arm.