Adherence-adjusted efficacy with intensive versus standard statin therapy in patients with acute myocardial
Ingar Holme1, Michael Szarek, Nilo B Cater
1Center of Preventive Medicine, Oslo University Hospital, Sector Ullevål, Oslo, Norway. ingar.holme@uus.no
Insights
Aggressive lipid lowering with atorvastatin showed a greater reduction in major coronary events than simvastatin, especially when adherence was considered. This highlights the importance of patient adherence in clinical trials.
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Background:
- The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEO) trial compared atorvastatin 80 mg to simvastatin 20-40 mg in coronary heart disease patients.
- The primary endpoint, major coronary events, showed an 11% reduction with atorvastatin (P=0.07), with higher adherence observed in the simvastatin group.
Purpose of the Study:
- To re-evaluate the efficacy of atorvastatin versus simvastatin in reducing major coronary events, considering patient adherence as a potential confounder.
- To assess the impact of adherence on the observed treatment effect in lipid-lowering therapy.
Main Methods:
- A prospective, randomized, open-label trial with endpoint evaluation was conducted.
- Adherence was calculated as drug exposure time relative to total follow-up time.
- Statistical adjustments were made for adherence levels (below or above 80%) and censoring methods.
Main Results:
- Adjusting for adherence, the relative risk reduction for major coronary events increased to 15% (P=0.02) and further to 17% (P=0.02) when censoring at the first event rather than death.
- Atorvastatin treatment led to a 21% reduction in noncardiovascular mortality after adherence adjustment (P=0.02).
Conclusions:
- Differences in patient adherence may have led to an underestimation of atorvastatin's true treatment effect.
- The study design (prospective randomized open-label endpoint evaluation) requires careful consideration, particularly when comparing established and novel treatments.
- Patients with low adherence in clinical trials may face elevated risks for fatal and nonfatal endpoints and warrant close monitoring.
Background:
The Incremental Decrease in End Points through Aggressive Lipid Lowering trial showed that the primary endpoint major coronary event was reduced by 11% (0.78-1.01) using atorvastatin 80 mg versus simvastatin 20-40 mg in patients with coronary heart disease (P=0.07). Adherence was high in both treatment groups but significantly higher in patients treated with simvastatin.
Design:
The Incremental Decrease in End Points through Aggressive Lipid Lowering was a prescription trial with a prospective randomized open label endpoint evaluation.
Methods And Results:
Adherence was calculated as exposure time on prescribed drugs divided by total follow-up time until death or end of follow-up and was a potential confounder. Adjusting for categorical adherence below or above 80% by two methods revealed that the relative risk reduction of the primary endpoint was more in the region of 15% (P=0.02) than 11% as found unadjusted. Censoring at the first occurrence of a cardiovascular event rather than at death increased this estimate to 17% (P=0.02). Noncardiovascular mortality was reduced on atorvastatin treatment by 21% (1-37%) after adjustment for adherence, whereas such reduction was not observed for cardiovascular mortality.
Conclusion:
This study found that the difference in adherence between treatment groups may have underestimated the true effect of the treatment differential. Usage of prospective randomized open label endpoint evaluation design should be carefully considered when well-known treatments are compared with rather new ones and especially in segments where patients could be more vulnerable, as in the elderly. Nonadherers in a clinical trial may be at especially high risk of fatal and nonfatal endpoints from various diseases and should be carefully monitored.
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