The Long-Term Legacy of Atorvastatin: Insights from the 20-Year ASCOT-Legacy Follow-Up

Highlight

• Atorvastatin administration in hypertensive patients with moderately elevated cholesterol confers sustained reduction in non-fatal myocardial infarction and fatal coronary heart disease events over 20 years.
• Long-term follow-up reveals a 14% reduction in cardiovascular deaths and significant decreases in total coronary events, underscoring statin legacy effects beyond trial duration.
• Lipid profiles between original treatment groups equilibrated after trial completion, yet early LDL-cholesterol lowering strongly associates with improved long-term cardiovascular outcomes.
• Findings reinforce the clinical benefit of early statin initiation to prevent fatal and non-fatal cardiovascular outcomes in at-risk populations.

Study Background and Disease Burden

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide. Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable risk factor driving atherosclerosis and CV events such as myocardial infarction (MI), stroke, and coronary heart disease (CHD). Statins are the cornerstone lipid-lowering therapy recommended to reduce CV risk. Yet despite strong clinical trial evidence of statins’ efficacy over relatively short treatment durations, questions remain regarding the durability of benefit and “legacy effects” after trial completion.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was designed to evaluate the effects of atorvastatin in hypertensive patients with controlled cholesterol levels (<6.5 mmol/L). Prior reports demonstrated atorvastatin’s benefit in reducing CV mortality and events over a median 3.3-year intervention period and subsequent 16 years of follow-up. The ASCOT-Legacy study extends this observation to 20 years, addressing long-term benefits on both fatal and non-fatal CV outcomes, thereby filling an important knowledge gap in primary prevention of CV disease.

Study Design

This extended follow-up cohort study included 4605 UK hypertensive participants enrolled in ASCOT’s lipid-lowering arm with baseline total cholesterol <6.5 mmol/L. Participants were randomly assigned to atorvastatin 10 mg daily (n=2317) or placebo (n=2288) for a median treatment period of 3.3 years. After completion of the blinded trial phase, atorvastatin was offered to all participants, reflecting contemporary clinical practice.

Lipid profiles were measured at trial end, 2 years post-trial in the entire cohort, and in subgroups approximately 9 years after trial completion. The primary endpoints were fatal and non-fatal CV events including MI, CHD death, heart failure (HF), stroke, and total cardiovascular events. Cox proportional hazard models were applied to estimate hazard ratios (HRs) for these outcomes over up to 21 years (interquartile range 9.1–19.3 years).

Key Findings

Allocation to atorvastatin resulted in significant long-term reductions in several key cardiovascular outcomes. The hazard ratio for non-fatal MI and fatal CHD events was 0.81 (95% CI 0.69 to 0.94, p=0.006), representing a 19% risk reduction over 20 years. Similarly, total coronary events decreased by 12% (HR 0.88; 95% CI 0.80 to 0.98, p=0.017), and CV deaths were reduced by 14% (HR 0.86; 95% CI 0.74 to 0.99, p=0.048).

Notably, no significant reductions were observed for heart failure, stroke, total cardiovascular events, or all-cause mortality in the primary analysis. However, detailed exploration of 3-year mean LDL-cholesterol demonstrated a robust relationship between LDL-C levels and a broad spectrum of long-term CV outcomes:

– For each 1 mmol/L decrease in LDL-C, significant risk reductions were noted for non-fatal MI and fatal CHD (HR 0.69, p<0.001), total coronary events (HR 0.70, p<0.001), non-fatal and fatal HF (HR 0.68, p<0.001), strokes (HR 0.74, p=0.006), total CV events and procedures (HR 0.74, p<0.001), CV mortality (HR 0.66, p<0.001), and all-cause mortality (HR 0.81, p<0.001).

Two years after the trial, approximately two-thirds of participants in both original arms were taking atorvastatin, and lipid profiles between previously randomized groups were comparable both at 2 and 9 years post-trial, indicating widespread adoption of atorvastatin influenced observed long-term outcomes.

These findings clearly demonstrate that early LDL-C reduction with atorvastatin has durable protective effects against fatal and non-fatal coronary events extending two decades beyond the original intervention period.

Expert Commentary

The ASCOT-Legacy 20-year follow-up provides compelling evidence for statins’ legacy effects, affirming that early initiation of lipid-lowering therapy yields measurable lifelong cardiovascular benefits. This aligns with prior studies like WOSCOPS and the HOPE-3 trial, underscoring LDL-C as a causal and modifiable factor for atherosclerosis progression.

While statin therapy did not significantly reduce heart failure or stroke incidence in this cohort, the strong association of LDL-C levels with broad CV outcomes supports the mechanistic plausibility that prolonged LDL-C control mitigates plaque instability and ischemic events. The absence of all-cause mortality benefit in primary analysis may reflect competing risks or longer follow-up needed.

Limitations include crossover post-trial, potentially diluting between-group differences, and the UK hypertensive population may limit generalizability to other ethnicities or risk profiles. Nonetheless, the large sample size, duration of follow-up, and rigor of endpoint adjudication enhance confidence in findings.

Current guidelines increasingly emphasize early and sustained statin use in individuals with elevated CV risk, regardless of baseline cholesterol levels. The ASCOT-Legacy data bolster this strategy, advocating for proactive lipid management to harness long-term mortality and morbidity reductions.

Conclusion

The ASCOT-Legacy study conclusively demonstrates that early atorvastatin therapy in hypertensive patients with modestly elevated cholesterol confers sustained, significant reductions in key cardiovascular events and mortality over a 20-year horizon. These findings highlight a powerful legacy effect of statins and reinforce the imperative for early initiation and maintenance of lipid-lowering therapy to prevent cardiovascular disease and death.

Future research should explore tailored approaches to maximize statin benefits across diverse populations and determine strategies to extend benefits beyond traditional atherosclerotic endpoints. Clinicians should integrate these insights into cardiovascular risk management paradigms to optimize long-term patient outcomes.

References

Sever PS, Rostamian S, Whiteley W, Ariti C, Godec T, Gupta A, Mackay J, Whitehouse A, Poulter NR; ASCOT Investigators; ASCOT investigators. Long-term benefits of atorvastatin on the incidence of cardiovascular events: the ASCOT-Legacy 20-year follow-up. Heart. 2025 Jul 28;111(16):769-775. doi: 10.1136/heartjnl-2024-325104. PMID: 40139683; PMCID: PMC12322408.

Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.