W e thank Bolland and colleagues for engaging in a dialog on an important issue. In essence, their letter raises two important and contentious issues in clinical trialing, the selection of safety endpoints and the power of the study.
Endpoint selection: As noted by a recent BMJ review of the topic of endpoint selection, the approach adopted by Bolland and colleagues risks the accusation of ''cherry picking.'' (1) Their response was as follows. ''In fact, no cherry picking took place. In 1996-1997 the protocol was finalized. . . . The specified composite endpoint was the combination of angina, chest pain, myocardial infarction, or sudden death. . . . In 2005 the trial statistician reported an adverse effect of calcium supplements on self-reported cardiovascular events. . . . We adopted the composite endpoint of myocardial infarction, stroke, or sudden death for the adjudicated events.'' (2) Interestingly, in their 2008 article, (3) when they applied the original composite criteria, there was no adverse effect [relative risk (RR) ¼ 0.94, 95% confidence interval (CI) 0.72-1.24], and even after application of the second set of criteria, there was no effect (RR ¼ 1.47, 95% CI 0.97-2.23). However, that article contained the highlighted statement, ''What this study adds: Healthy older women randomised to calcium supplementation showed increased rates of myocardial infarction'' based on a reported RR of 2.12 (95% CI 1.01-4.47, p ¼ .047). In our view, in light of the four separate endpoints eventually tested, myocardial infarction, stroke, sudden death, and the composite, the p value for statistical significance should have been .00625. We leave it to the reader's judgment as to whether the removal of angina and chest pain, the inclusion of stroke including hemorrhagic stroke, and the final highlighted selection of myocardial infarction without adjustment of the p value constitute cherry picking.
Next, the question arises as to why angina and chest pain were excluded from the 2005 analysis when in such epidemiologic studies it is usual to explore the effects of supplementary endpoints related to the main effect. The authors state that these endpoints were excluded because ''adjudication of episodes of angina or chest pain was not possible.'' However, in other studies, including our own, there was no particular difficulty in