Can we proceed with physical activity recommendations if (almost) no clinical trial data exist on mortality?

Observational studies consistently show reduced mortality rates among participants with higher physical activity levels compared with participants with less activity.1 2 However, as Kujala eloquently points out,3 there are sparse data from randomised trials leading some argue that a causal relationship of physical activity with mortality cannot be confirmed. As current physical activity guidelines were developed primarily based on observational studies of physical activity and clinical outcomes,4 one might question how despite the lack of trial data—the gold standard for causality inference—policy and medical advice for physical activity can be made. This opinion piece aims to highlight some of the challenges and implications of examining physical activity and mortality solely through a lens which sees causality only when randomised trial data are available. To our knowledge, there are currently no completed randomised trials of physical activity where mortality is a prespecified primary outcome, and where analyses are adequately powered to examine the effects of physical activity on mortality. While several large trials, such as LIFE5 and Look AHEAD,6 were able to provide a secondary look at mortality, they were not designed with mortality as a primary outcome. (And, further, Look AHEAD was not designed to exclusively target physical activity, but rather both diet and physical activity in order to achieve and maintain weight loss.) Thus, null findings for mortality or other clinical outcomes should be interpreted cautiously due to a lack of statistical power. For example, the LIFE study comprised 1635 adults between the ages of 70 and 89 years who were followed for an average duration of 2.6 years.5 Using the average probability of death, and the estimated reduction in mortality from a large observational study2 comparing those who participated in at least 150 min of moderate-to-vigorous activity with those who did no …