COVID-19 and heart injury: Appropriate methodology is crucial for assessing the emerging evidence

To the Editor:

We read with interest the article by Li et al. in the Prog Cardiovasc Dis journal regarding the evidence on the association between COVID-19 and cardiac injury.¹ The authors performed a systematic review and subsequent meta-analyses showing that: (i) cardiac biomarkers are higher in COVID-19 patients with severe disease compared to those without, and (ii) cardiac injury was associated with a pooled risk ratio 3.9 (95% confidence intervals [CI] 2.1, 7.0) for mortality.¹ The authors concluded that physicians need to effectively monitor cardiac function to prevent myocarditis in patients infected with COVID-19.¹

The prompt publication of emerging evidence is crucial for our understanding of the natural course of COVID-19 and most importantly for the risk stratification of these patients. In this context, rapid analyses and review processes are needed. Cardiac injury appears to be common in patients with severe COVID-19 and influences their prognosis. Multiple mechanisms including both ischemic and non-ischemic ones have been implicated in its aetiology.

Although the clinical relevance of the observations by Li et al. is indisputable, several methodological issues should be taken into account before reaching definite conclusions. The authors have listed several potential limitations of their work, including the retrospective design of the studies, the heterogeneity in key aspects, and the potential confounding factors for which adjustment was not possible. However, additional important methodological issues need to be considered in interpreting these results, which are listed below.

• (i)One third of the studies included in the meta-analysis reporting data on the prognostic relevance of cardiac injury in terms of mortality have not been subjected to peer-review.2., 3., 4.
• (ii)There seems to be overlapping in the populations of the included studies since there was overlapping in the recruitment hospitals and investigation periods.5., 6., 7., 8.
• (iii)Meta-analysis of the risk ratios for mortality included unadjusted ratios, which considerably influence the key findings. For example, in the study of Shi et al. which was the largest one, the unadjusted risk ratio for death was 11.4 (95% CI: 6.7, 19.5) whereas the adjusted hazard ratio was 3.4 (95% CI: 1.6, 7.2) during the time from admission to study endpoint.⁹

The abovementioned methodological deficiencies do not undermine the importance and usefulness of the authors' observations and analyses,¹ but are crucial for the accurate quantification of clinical issues related to the natural course of this disease.