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1 August 2009
Beyond statin titration: Additional treatment approaches are needed to further reduce the risk of coronary events – The CALIPSO study

A predictive analysis suggests that following statin titration to maximum dose, 28.2-62.7% of high CAD-risk individuals, depending on the statin used, would not attain the LDL cholesterol goal of <2 mmol/L (78 mg/dL) recommended by Canadian guidelines.

Senecal M, Fodor G, Gagne C, Genest J, Lavoie MA, McPherson R, Marentette M, Sebaldt RJ.
Comments & References

The Canadian Lipid Study – Observational (CALIPSO) is a cross-sectional study of statin treatment patterns and goal attainment in 3721 patients from Quebec and Ontario treated with statins for at least 8 weeks.1
A predictive analysis was based on a subset of the CALIPSO study population (n=1795). High-risk patients on statin monotherapy for whom LDL cholesterol (LDL-C) value prior to pharmacotherapy initiation was available were included.
A predictive model exploring the potential limits of statin monotherapy in getting patients at high coronary artery disease (CAD) risk to the currently recommended Canadian LDL-C target of <2.0 mmol/L (78 mg/dL)2 was developed. The additional LDL-C reduction patients might achieve with maximal titration of their statin was estimated based on a meta-analysis of clinical trials evaluating LDL-C responses to various statin regimens,3 and applied to patients’ current LDL-C levels.

The proportion of patients reaching the recommended LDL-C level was compared according to the statin used, as well as between users of low and high statin doses.
Main results
  • At study visit, 69.8% had their LDL-C level above the currently recommended treatment target (2 mmol/L).
  • Patients had been prescribed atorvastatin (59.3%), simvastatin (23.3%), rosuvastatin (4%) or another statin (13.4%).
  • The predictive model projected that the majority of these patients (54.4%) would remain above the recommended LDL-C target if all had their statin titrated up to the maximum dose.
  • The estimated proportion of patients who would fail to reach a LDL-C level of <2.0 mmol/L was 30% for atorvastatin, 45.7% for simvastatin, 28.2% for rosuvastatin, and 62.7% for all other statins combined.


Patients are considered to be in a high-risk category if their 10-year CAD risk is ≥20%, as calculated by the Framingham risk equation.4 This high-risk category also includes patients with established CAD, peripheral artery disease, cerebrovascular disease, and most patients with diabetes or chronic kidney disease. Recent results from a number of randomized controlled trials have confirmed that LDL-C concentrations <2.0 mmol/L (78 mg/dL) are associated with improved clinical outcomes in high-risk statin-treated patients.5-7
Previously reported results from the CALIPSO study demonstrated that 67.9% of patients taking statins were either at high risk for CAD or had established CAD.1 In all, 91% of patients not reaching LDL-C targets belonged to the high-risk category, thus showing that not attaining recommended LDL-C treatment targets is an issue for high-risk patients. Despite statin therapy, 34.7% of these high-risk patients had LDL-C levels above the previously recommended 2003 target (2.5 mmol/L, or 97.5 mg/dL), highlighting an important unaddressed medical need in the management of LDL-C in high-risk patients.
The present study was a predictive analysis achieved by applying clinical trials data (obtained from a meta-analysis of 164 short-term randomized controlled trials of LDL-C reduction with statins)3 to a subset of the CALIPSO study population. In this predictive analysis, patients using atorvastatin, simvastatin, rosuvastatin or other statins achieved an average LDL-C reduction of 42%, 39.4%, 47.9%, and 34.1%, respectively (p<0.0001). Of note, comparisons were not adjusted for potential confounding factors.

Additional treatment approaches are needed for the population of high CAD risk patients currently treated with statin monotherapy

The projection suggests that statin titration would bring around 62% of high-risk patients to the LDL-C target currently recommended in Canada; thus, in approximately 38% of patients at high CAD risk, titration of statin monotherapy to maximum dose would not achieve the LDL-C target. Depending on the statin used, 28.2% to 62.7% of high CAD-risk patients would not attain a LDL-C of <2 mmol/L following statin titration to maximum dose.
Several reasons might explain why many high-risk patients are projected not to attain the currently recommended LDL-C goal despite titration of statin monotherapy to maximal doses. Firstly, some patients do not strictly adhere to their recommended treatment and thus, do not get the full benefits of statins. Adherence in the clinical trial setting is likely to be greater than in the wider population. Secondly, baseline LDL-C levels can be too high for statin monotherapy to be adequate. Lastly, some patients may not respond well to statin therapy due to inter-individual variation between statin dose and LDL-C reduction and/or as a result of post-statin inter-individual variation in intestinal cholesterol handling.
A limitation of this predictive analysis is the accuracy of projections obtained by the application of clinical trials data to an external sample of patients. In this present analysis, the effect of maximal statin titration on LDL-C levels was projected based on the results of short-term randomized control trials.
Nevertheless, this study highlights that for patients at high CAD risk, and for whom titration of statin monotherapy is not sufficient to achieve a LDL-C target of <2 mmol/L, additional treatment approaches are needed to further reduce the risk of coronary events associated with LDL-C levels.

    1.Bourgault C, Davignon J, Fodor G, et al. Statin therapy in Canadian patients with hypercholesterolemia: the Canadian Lipid Study – Observational (CALIPSO). Can J Cardiol 2005; 21:1187-93.
    2. McPherson R, Frohlich J, Fodor G, et al. Canadian Cardiovascular Society position statement: recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006; 22:913-27.
    3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423.
    4. Grundy SM, Pasternak R, Greenland P, et al. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999;100:1481-92.
    5. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
    6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
    7. 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;294:2437-45