The Anglo-Scandinavian Cardiac Outcomes Trial
Aims The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial—8 years after closure of the lipid-lowering arm (LLA) of the trial (ASCOT-LLA) among the UK population.
Methods and results ASCOT-LLA was a factorially designed double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients enrolled into the ASCOT-Blood Pressure Lowering Arm (BPLA) of the trial and with total cholesterol concentrations, at baseline, of <6.5 mmol/L. ASCOT-LLA was stopped prematurely after a median 3.3-year follow-up because of a 36% relative risk reduction (RRR) in non-fatal myocardial infarction and fatal coronary heart disease (CHD) (the primary outcome) in favour of atorvastatin and a non-significant reduction in CV deaths (16%) and all-cause mortality (13%). After a further 2.2 years at the end of ASCOT-BPLA, despite extensive crossovers from and to statin usage, the RRR in all endpoints remained essentially unchanged. A median 11 years after initial randomization and ~8 years after closure of LLA, all-cause mortality (n= 520 and 460 in placebo and atorvastatin, respectively) remained significantly lower in those originally assigned atorvastatin (HR 0.86, CI 0.76–0.98, P= 0.02). CV deaths were fewer, but not significant (HR 0.89, CI 0.72–1.11, P= 0.32) and non-CV deaths were significantly lower (HR 0.85, CI 0.73–0.99, P= 0.03) in those formerly assigned atorvastatin attributed to a reduction in deaths due to infection and respiratory illness.
Conclusion Legacy effects of those originally assigned atorvastatin may contribute to long-term benefits on all-cause mortality. An explanation for long-term benefits on non-CV deaths has not been established.
In 2003, we reported the outcome of the lipid-lowering arm (LLA) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), a placebo-controlled randomized trial of the effects of atorvastatin 10 mg daily in the primary prevention of coronary heart disease (CHD) in hypertensive subjects who had a total cholesterol level of ≤6.5 mmol/L. The trial was stopped prematurely after a median 3.3-year follow-up due to substantial benefits of atorvastatin on the primary endpoint of non-fatal myocardial infarction and fatal CHD, together with significant reductions in several other cardiovascular (CV) endpoints. ASCOT-LLA was part of a factorially designed trial in which hypertensive patients with no prior history of CHD were initially randomized to one of the two antihypertensive treatment strategies [a beta-blocker adding a thiazide diuretic as required or a dihydropyridine calcium channel blocker (CCB), adding an angiotensin-converting enzyme inhibitor as required] (ASCOT-BPLA).
After the termination of LLA, subjects continued in BPLA for a further 2.2 years when the trial was stopped owing to substantial mortality benefits in favour of the CCB-based treatment strategy. At this time, the relative risk reductions (RRRs) in CV outcomes for those originally assigned atorvastatin were essentially unchanged despite extensive crossover to and from statin usage, and all-cause mortality was significantly reduced in those formerly assigned atorvastatin. At the end of BPLA, of those originally assigned atorvastatin, 69% were still taking atorvastatin or other statin compared with 63% of those formerlyy assigned placebo. The present report evaluates the mortality outcomes of those subjects originally assigned either atorvastatin or placebo in the LLA and followed-up for a median 11 years after initial randomization. The analyses are restricted to those subjects recruited to the trial in the UK as information on mortality and cause of death were not available for patients originally followed up in the Nordic countries.
Abstract and Introduction
Abstract
Aims The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial—8 years after closure of the lipid-lowering arm (LLA) of the trial (ASCOT-LLA) among the UK population.
Methods and results ASCOT-LLA was a factorially designed double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients enrolled into the ASCOT-Blood Pressure Lowering Arm (BPLA) of the trial and with total cholesterol concentrations, at baseline, of <6.5 mmol/L. ASCOT-LLA was stopped prematurely after a median 3.3-year follow-up because of a 36% relative risk reduction (RRR) in non-fatal myocardial infarction and fatal coronary heart disease (CHD) (the primary outcome) in favour of atorvastatin and a non-significant reduction in CV deaths (16%) and all-cause mortality (13%). After a further 2.2 years at the end of ASCOT-BPLA, despite extensive crossovers from and to statin usage, the RRR in all endpoints remained essentially unchanged. A median 11 years after initial randomization and ~8 years after closure of LLA, all-cause mortality (n= 520 and 460 in placebo and atorvastatin, respectively) remained significantly lower in those originally assigned atorvastatin (HR 0.86, CI 0.76–0.98, P= 0.02). CV deaths were fewer, but not significant (HR 0.89, CI 0.72–1.11, P= 0.32) and non-CV deaths were significantly lower (HR 0.85, CI 0.73–0.99, P= 0.03) in those formerly assigned atorvastatin attributed to a reduction in deaths due to infection and respiratory illness.
Conclusion Legacy effects of those originally assigned atorvastatin may contribute to long-term benefits on all-cause mortality. An explanation for long-term benefits on non-CV deaths has not been established.
Introduction
In 2003, we reported the outcome of the lipid-lowering arm (LLA) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), a placebo-controlled randomized trial of the effects of atorvastatin 10 mg daily in the primary prevention of coronary heart disease (CHD) in hypertensive subjects who had a total cholesterol level of ≤6.5 mmol/L. The trial was stopped prematurely after a median 3.3-year follow-up due to substantial benefits of atorvastatin on the primary endpoint of non-fatal myocardial infarction and fatal CHD, together with significant reductions in several other cardiovascular (CV) endpoints. ASCOT-LLA was part of a factorially designed trial in which hypertensive patients with no prior history of CHD were initially randomized to one of the two antihypertensive treatment strategies [a beta-blocker adding a thiazide diuretic as required or a dihydropyridine calcium channel blocker (CCB), adding an angiotensin-converting enzyme inhibitor as required] (ASCOT-BPLA).
After the termination of LLA, subjects continued in BPLA for a further 2.2 years when the trial was stopped owing to substantial mortality benefits in favour of the CCB-based treatment strategy. At this time, the relative risk reductions (RRRs) in CV outcomes for those originally assigned atorvastatin were essentially unchanged despite extensive crossover to and from statin usage, and all-cause mortality was significantly reduced in those formerly assigned atorvastatin. At the end of BPLA, of those originally assigned atorvastatin, 69% were still taking atorvastatin or other statin compared with 63% of those formerlyy assigned placebo. The present report evaluates the mortality outcomes of those subjects originally assigned either atorvastatin or placebo in the LLA and followed-up for a median 11 years after initial randomization. The analyses are restricted to those subjects recruited to the trial in the UK as information on mortality and cause of death were not available for patients originally followed up in the Nordic countries.