LNSLNS

We would like to thank Prof. Dr. Meyer and Dr. Traut for their comments on our article (1). Both comments relate to the interpretation of the results of the IMPROVE-IT trial (2).

Both note that the combination therapy (statin plus ezetimibe) did not reduce the cardiovascular mortality or the all-cause mortality as compared to statin monotherapy, and that the benefits in terms of cardiovascular events are low. The clinical relevance of the combination therapy is therefore questioned.

Even though the cardiovascular mortality and all-cause mortality were not reduced by combination therapy in the IMPROVE-IT trial (2), the primary endpoint (a combination of cardiovascular events)—adjusted for the number of participants in the trial and for power calculations—showed that the combination therapy provided a statistically significant advantage, of an absolute risk reduction of 2 percentage points (number needed to treat [NNT], 50 over 7 years). This reduction is not great in absolute terms. Nonetheless, if we take into account the relevance of a myocardial infarction, a stroke, or a revascularization with hospitalization for the affected person, it is likely that even such low absolute risk reductions become important for these individuals. Still, we agree that routine administration of ezetimibe cannot be based on this evidence. In our view, however, it is also important to inform patients, as part of shared decision-making, about additional endpoints as well as the effectiveness of a drug, and not to only fixate on reduction of mortality. This is especially true considering that patient preferences are sometimes differently assessed by physicians than by the patients themselves (3).

Prof. Dr. Meyer points out that the number of enrolled patients was increased from 10 000 to 18 000 in the IMPROVE-IT trial. This protocol change was made transparent and was justified (4). Without this increase, the statistical power could not have been achieved. We see this action as positive, as it prevented the lack of statistical power that was problematic for the other trials in our systematic review. If statistical power cannot be obtained, it remains unclear whether a lack of statistical significance is due to the fact that there really is no significant difference or due to a sample size that is too small.

Dr. Traut notes that the composite endpoint has no patient-relevant significance, because some components of the composite endpoint considered individually did not show statistically significant differences. We agree that the use of composite endpoints can be problematic, especially when a composite endpoint was not defined a priori. However, the IMPROVE-IT trial defined the composite endpoint already in its initial description in the trials registry (5). We therefore do not believe that this endpoint was designed post-hoc to produce statistical significance.

DOI: 10.3238/arztebl.2017.0071

Barbara Nußbaumer, MSc BSc

Prof. Dr. med. Gerald Gartlehner, MPH

Department for Evidence-based Medicine and

Clinical Epidemiology– Danube University Krems

Austria

barbara.nussbaumer@donau-uni.ac.at

Conflict of interest statement

The authors of all contributions declare that no conflicts of interest exists.

1.
Nußbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G: Ezetimibe-statin combination therapy: efficacy and safety as compared with statin monotherapy—a systematic review. Dtsch Arztebl Int 2016; 113: 445–53 VOLLTEXT
2.
Cannon CP, Blazing MA, Giugliano RP, et al.: Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387–97 CrossRef MEDLINE
3.
Marshall DA, Johnson FR, Kulin NA, et al.: How do physician assessments of patient preferences for colorectal cancer screening tests differ from actual preferences? A comparison in Canada and the United States using a stated-choice survey. Health Econ 2009; 18: 1420–39 CrossRef MEDLINE PubMed Central
4.
Cannon CP, Giugliano RP, Blazing MA, et al.: Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008; 156: 826–32 CrossRef MEDLINE
5.
IMPROVE-IT, ClinicalTrials.gov registration identification number: NCT00202878, updated on 19 September 2005:
https://clinicaltrials.gov/archive/NCT00202878/2005_09_19 (last accessed on 18 August 2016).
1. Nußbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G: Ezetimibe-statin combination therapy: efficacy and safety as compared with statin monotherapy—a systematic review. Dtsch Arztebl Int 2016; 113: 445–53 VOLLTEXT
2.Cannon CP, Blazing MA, Giugliano RP, et al.: Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387–97 CrossRef MEDLINE
3. Marshall DA, Johnson FR, Kulin NA, et al.: How do physician assessments of patient preferences for colorectal cancer screening tests differ from actual preferences? A comparison in Canada and the United States using a stated-choice survey. Health Econ 2009; 18: 1420–39 CrossRef MEDLINE PubMed Central
4. Cannon CP, Giugliano RP, Blazing MA, et al.: Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008; 156: 826–32 CrossRef MEDLINE
5.IMPROVE-IT, ClinicalTrials.gov registration identification number: NCT00202878, updated on 19 September 2005:
https://clinicaltrials.gov/archive/NCT00202878/2005_09_19 (last accessed on 18 August 2016).

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