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NIHR Signal The benefits of commonly used blood pressure and cholesterol lowering treatment can last 16 years

Published on 15 January 2019

doi: 10.3310/signal-000710

Fewer deaths from stroke had occurred in people who had high blood pressure treated with amlodipine, a calcium-channel blocker, compared to atenolol, 10 years after the end of a large trial. People with high blood pressure who took statins were less likely to die from cardiovascular diseases, such as heart disease or stroke than those taking a placebo.

This study followed over 7,000 UK patients who had taken part in a clinical trial of blood pressure and cholesterol-lowering treatments between 1998 and 2005. It compared those who had been allocated to amlodipine with those who took atenolol. Those in either blood pressure group who had not already received a statin were also randomised to either atorvastatin (a cholesterol-lowering drug) or placebo.

Some caution is needed in interpreting these findings because no details were available on what treatments were taken after the trial ended. Both arms of the original trial were stopped early because of the superiority of amlodipine-based treatment over atenolol-based treatment and atorvastatin over placebo. But it is likely that all groups received similar post-trial management according to best practice at the time. The results add important information for clinicians and patients considering the long-term implications of taking these medications.

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Why was this study needed?

High blood pressure affects around 12.5 million people in the UK. Treatment guidelines for lowering blood pressure and cholesterol are based on clinical trials where patients are followed for around five years. Longer follow-up is needed to understand whether the benefits of these medicines are sustained.

This study aimed to describe further outcomes 10 years after the trial had ended.

What did this study do?

The ASCOT Legacy study tracked the long-term health of 7,302 UK patients who had taken part in the original ASCOT trial which started in 1998. It analysed the cause of all deaths within the groups up until December 2015. The average age at entry to the trial was 64.1 years, 81% were men, and 24% were current smokers.

There were two arms to the original study, blood pressure and cholesterol lowering. Participants with high blood pressure were randomised to amlodipine, with perindopril added as required, or to atenolol, with thiazide diuretic added as required. After 5.5 years the trial was stopped because fewer people had died on the amlodipine-based treatment.

About 10,000 of the recruits, with a total cholesterol of 6.5mmol/L or less, were also randomised to either atorvastatin or placebo. This arm of the trial also was stopped early, after 3.3 years, because atorvastatin showed a clear benefit. Two-thirds of both groups then chose to be on atorvastatin for the next 2.2 years of the trial.

A strength of this study is its long follow-up. However, a limitation is the lack of information on the use of blood pressure and cholesterol lowering medicines after the trial finished, and the lack of recording of any harmful events, such as the side effects of treatment.

What did it find?

  • During almost 16 years of total follow-up, people treated with amlodipine were less likely to die from stroke than those treated with atenolol. In the amlodipine group 1.7% died compared with 2.3% on atenolol (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.53 to 0.97).
  • There was no difference in the number of deaths from all causes between the groups, with 38% dying in the amlodipine group and 38% dying in the atenolol group (HR 0.97, 95% CI 0.90 to 1.04).
  • There was no difference in overall number of deaths from cardiovascular causes which occurred in 13.6% of the amlodipine group compared with 14.6% in the atenolol group (HR 0.90, 95% CI 0.81 to 1.01). In the subgroup not on lipid-lowering therapy, there were fewer cardiovascular deaths in the amlodipine group, 13.7% versus 16.5% on atenolol (HR 0.79, 95% CI 0.67 to 0.93) and fewer coronary heart disease deaths, 5% on amlodipine versus 6% on atenolol (HR 0.76, 95% CI 0.59 to 0.99).
  • Fewer people died from cardiovascular-related causes in the group taking atorvastatin, 12% compared with 14% in the placebo group (HR 0.85, 95% CI 0.72 to 0.99).
  • There were no differences in numbers of deaths from any cause, deaths from coronary heart disease or stroke between the statin and placebo treatment groups.

What does current guidance say on this issue?

NICE hypertension guidance updated in 2016 recommends the use of a calcium-channel blocker (such as amlodipine) in people over 55 years or in black people of African or Caribbean family origin of any age with high blood pressure. Angiotensin-converting enzyme (ACE) inhibitors or low-cost angiotensin-II receptor blockers are recommended for people younger than 55. Beta-blockers (such as atenolol) are not a preferred initial therapy for hypertension but may be considered in younger people.

NICE guidance on cardiovascular disease risk assessment and reduction updated in 2016 recommends atorvastatin for primary prevention after optimal lifestyle management of modifiable cardiovascular risk factors. Atorvastatin is then suggested for primary prevention for people who have a 10% or greater 10‑year risk of developing cardiovascular disease, estimated using the QRISK2 assessment tool. Atorvastatin is also the recommended treatment for secondary prevention after a patient has had a cardiovascular event.

What are the implications?

This study provides further evidence that blood-pressure and lipid-lowering treatment with a statin may have long-term benefits in terms of reducing cardiovascular outcomes. The choice of which regimen and sequence of drugs is best remains unclear.

All four groups are likely to have continued to require various blood pressure lowering medications after the trial finished and so it is not possible to confidently attribute the benefits to one drug alone. However, the current practice of controlling increased cardiovascular risk with blood pressure and statin treatments is confirmed by these observations over 16 years.

Why was this study needed?

High blood pressure affects around 12.5 million people in the UK. Treatment guidelines for lowering blood pressure and cholesterol are based on clinical trials where patients are followed for around five years. Longer follow-up is needed to understand whether the benefits of these medicines are sustained.

This study aimed to describe further outcomes 10 years after the trial had ended.

What did this study do?

The ASCOT Legacy study tracked the long-term health of 7,302 UK patients who had taken part in the original ASCOT trial which started in 1998. It analysed the cause of all deaths within the groups up until December 2015. The average age at entry to the trial was 64.1 years, 81% were men, and 24% were current smokers.

There were two arms to the original study, blood pressure and cholesterol lowering. Participants with high blood pressure were randomised to amlodipine, with perindopril added as required, or to atenolol, with thiazide diuretic added as required. After 5.5 years the trial was stopped because fewer people had died on the amlodipine-based treatment.

About 10,000 of the recruits, with a total cholesterol of 6.5mmol/L or less, were also randomised to either atorvastatin or placebo. This arm of the trial also was stopped early, after 3.3 years, because atorvastatin showed a clear benefit. Two-thirds of both groups then chose to be on atorvastatin for the next 2.2 years of the trial.

A strength of this study is its long follow-up. However, a limitation is the lack of information on the use of blood pressure and cholesterol lowering medicines after the trial finished, and the lack of recording of any harmful events, such as the side effects of treatment.

What did it find?

  • During almost 16 years of total follow-up, people treated with amlodipine were less likely to die from stroke than those treated with atenolol. In the amlodipine group 1.7% died compared with 2.3% on atenolol (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.53 to 0.97).
  • There was no difference in the number of deaths from all causes between the groups, with 38% dying in the amlodipine group and 38% dying in the atenolol group (HR 0.97, 95% CI 0.90 to 1.04).
  • There was no difference in overall number of deaths from cardiovascular causes which occurred in 13.6% of the amlodipine group compared with 14.6% in the atenolol group (HR 0.90, 95% CI 0.81 to 1.01). In the subgroup not on lipid-lowering therapy, there were fewer cardiovascular deaths in the amlodipine group, 13.7% versus 16.5% on atenolol (HR 0.79, 95% CI 0.67 to 0.93) and fewer coronary heart disease deaths, 5% on amlodipine versus 6% on atenolol (HR 0.76, 95% CI 0.59 to 0.99).
  • Fewer people died from cardiovascular-related causes in the group taking atorvastatin, 12% compared with 14% in the placebo group (HR 0.85, 95% CI 0.72 to 0.99).
  • There were no differences in numbers of deaths from any cause, deaths from coronary heart disease or stroke between the statin and placebo treatment groups.

What does current guidance say on this issue?

NICE hypertension guidance updated in 2016 recommends the use of a calcium-channel blocker (such as amlodipine) in people over 55 years or in black people of African or Caribbean family origin of any age with high blood pressure. Angiotensin-converting enzyme (ACE) inhibitors or low-cost angiotensin-II receptor blockers are recommended for people younger than 55. Beta-blockers (such as atenolol) are not a preferred initial therapy for hypertension but may be considered in younger people.

NICE guidance on cardiovascular disease risk assessment and reduction updated in 2016 recommends atorvastatin for primary prevention after optimal lifestyle management of modifiable cardiovascular risk factors. Atorvastatin is then suggested for primary prevention for people who have a 10% or greater 10‑year risk of developing cardiovascular disease, estimated using the QRISK2 assessment tool. Atorvastatin is also the recommended treatment for secondary prevention after a patient has had a cardiovascular event.

What are the implications?

This study provides further evidence that blood-pressure and lipid-lowering treatment with a statin may have long-term benefits in terms of reducing cardiovascular outcomes. The choice of which regimen and sequence of drugs is best remains unclear.

All four groups are likely to have continued to require various blood pressure lowering medications after the trial finished and so it is not possible to confidently attribute the benefits to one drug alone. However, the current practice of controlling increased cardiovascular risk with blood pressure and statin treatments is confirmed by these observations over 16 years.

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

Published on 31 August 2018

Gupta, A.,Mackay, J.,Whitehouse, A.,Godec, T.,Collier, T.,Pocock, S.,Poulter, N.,Sever, P.

Lancet , 2018

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 x 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.

Expert commentary

Most cardiovascular clinical trials report defined outcomes at study end, with little follow-up information about the lifetime impact of the study intervention. However, there is growing interest in understanding how short-term primary prevention strategies influence trajectories of disease and long-term outcomes, with recent studies assessing the ‘legacy’ effect many years after trial end.

This study showed that 10 years after trial termination, patients treated with calcium-channel blocker-based therapy versus atenolol-based therapy had less stroke and that statins reduced cardiovascular deaths.

Clearly, these findings show that cardiovascular risk reduction from short-term treatment persists for many years. While underlying mechanisms for this legacy effect remain elusive, it is clear that calcium-channel-based antihypertensive therapy and cholesterol-lowering with statins are associated with long-term cardiovascular benefits.

Dr Rhian M Touyz, British Heart Foundation Chair of Cardiovascular Medicine; Director of the Institute of Cardiovascular and Medical Sciences, University of Glasgow; Honorary Consultant, Queen Elizabeth University Hospital, Glasgow

The commentator receives funding from the British Heart Foundation to support his personal research programme