Physicians' Academy for Cardiovascular Education

Treatment effect of high-dose statin therapy estimated by prediction model

Literature - Dorresteijn JA, Boekholdt SM, Van der Graaf Y, et al. - Circulation May 14, 2013, doi: 10.1161/CIRCULATIONAHA.112.000712

High-Dose Statin Therapy in Patients with Stable Coronary Artery Disease: Treating the Right Patients Based on Individualized Prediction of Treatment Effect

Dorresteijn JA, Boekholdt SM, Van der Graaf Y, et al.
Circulation May 14, 2013, doi: 10.1161/​CIRCULATIONAHA.112.000712


Intensive lipid lowering results in reduction of vascular events in patients with coronary artery disease (CAD) [1-6]. Reluctance may exist about high-dose statin therapy for all patients with stable CAD, caused by concerns about side-effects, costs and need for closer follow-up. Patients most likely to benefit from high-dose statin therapy should be identified. Currently, guidelines recommend dose titration in patients whose LDL-cholesterol is not at target [7,8]. Meta-analyses however show that the reduction of vascular events by statin treatment is independent of pre-treatment LDL-C [6]; the absolute CV risk reduction by high-dose statin therapy is only proportional to the absolute baseline risk. The aim of this study was to develop and validate a model, based on multiple clinical patient characteristics, for prediction of treatment effect of high-dose versus usual-dose statin therapy in patients with stable CAD. Data from the Treating to New Targets (TNT, n=10,001) trial and the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL, n=8,888) trial were analyzed [1,2]. Net benefit of strategies to select high-risk patients with stable CAD for high-dose statin therapy were compared.

Main results

  • Based on data from the TNT, a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, HDL-C, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (i.e. atorvastatin 80mg or 10mg).
  • The model C-statistic was 0.67 (95%CI 0.65-0.68) in the derivation sample (TNT), and 0.63 (95%CI 0.62-0.65) in the validation sample (IDEAL). The calibration plots of 5-year predicted versus observed event-free survival (i.e. 1-risk) in the derivation and validation sample show that model calibration was excellent. The p-values of the Gronnesby and Borgan tests were 0.65 in the derivation sample and 0.30 in the validation sample, thus confirming satisfactory goodness-of-fit.
  • The median absolute reduction of 5-year risk of major cardiovascular events (MCVE) was 2.2% [IQR 1.6-3.1%; 5-year number needed to treat, NNT 45]. However, 41.9% of patients had <2% predicted treatment effect (5-year NNT>50) and 46.4% of patients had 2 to 4% predicted treatment effect (5-year NNT between 25 and 50). A total of 11.7% of patients had >4% predicted reduction of absolute 5-year MCVE risk (5-year NNT <25).
  • If treatment of patients with <6% 5-year MCVE-risk with atorvastatin 80mg instead of usual-dose statin is acceptable, the strategy that leads to optimal net benefit is to simply prescribe atorvastatin 80 mg to all. The median treatment effect will then be 2.0% reduction of absolute MCVE risk (effective NNT=49). If a threshold between ~6% and ~23% is considered appropriate, more selective prediction-based treatment can reduce the treatment rate and average NNT.


The incremental treatment effect of high-dose statin therapy over usual-dose statin therapy in individual CAD-patients can be estimated by a prediction model, containing 13 easy-to-measure clinical predictors that are readily available in clinical practice. Predicted treatment effect can be used to guide treatment decisions in clinical practice, which may improve net benefit of therapy.


1. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
2. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.
3. Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658-1669.
4. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
5. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-1316.
6. Baigent C, Blackwell L, Emberson J, et al. 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;376:1670-1681.
7. Smith SC, Jr., Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372.
8. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) * Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635-1701.

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