Author + information
- Davide Capodanno, MD, PhD∗ (, )
- Giuseppe Gargiulo, MD,
- Sergio Buccheri, MD,
- Daniele Giacoppo, MD,
- Piera Capranzano, MD and
- Corrado Tamburino, MD, PhD
- ↵∗Division of Cardiology, Ferrarotto Hospital, University of Catania, Italy, Citelli 1, Catania 95124, Italy
We read with interest the meta-analyses of Giustino et al. (1) and Palmerini et al. (2) recently published in the Journal. These studies add meaningfully to the ongoing debate on dual antiplatelet therapy (DAPT) duration, but their conclusions on mortality are conflicting, with Giustino et al. (1) concluding that prolonging DAPT increases all-cause mortality and Palmerini et al. (2) demonstrating no significant effect on this endpoint. Indeed, addressing the net benefit of extended DAPT requires preliminary clarification of the relative weights of stent thrombosis (ST) and bleeding on mortality, an issue that has not been explored by any trial or meta-analysis of DAPT duration. We hypothesized that in the contemporary era of drug-eluting stents, ST and bleeding have a different impact on mortality. To explore this hypothesis, we performed a meta-regression of the effects sizes of ST and bleeding on mortality in trials of DAPT duration, including the recently presented I-LOVE-IT (Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary) 2 randomized substudy (China Interventional Therapeutics, March 19, 2015, Beijing, China). Trials were excluded if the outcomes of interest were not available. Risk ratios for treatment effects in individual trials were log-transformed before being used as independent variables in linear meta-regression analyses. Statistical analyses were performed using the open-source R Software (R Foundation for Statistical Computing, Vienna, Austria). We found a significant association between all bleeding and noncardiovascular mortality across individual studies (8 trials; intercept value [IV]: -0.15; slope estimate [SE]: 0.61; p = 0.01) (Figure 1, top graph), while there was no evidence of a significant correlation of all bleeding with both cardiovascular (8 trials; IV: -0.46; SE: -0.17; p = 0.69) and all-cause mortality (10 trials; IV: -0.33; SE: 0.75; p = 0.18). On the other hand, no significant associations were found between ST and both cardiovascular (9 trials; IV: 0.75; SE: 0.71; p = 0.31) (Figure 1, bottom graph) and all-cause mortality (11 trials; IV: 0.52; SE: -0.86; p = 0.42).
The observed significant link between bleeding and noncardiovascular mortality is consistent with a pattern already noted in the DAPT trial, where bleeding-related, trauma-related, and cancer-related causes primarily contributed to the observed higher risk of all-cause mortality with prolonged DAPT (3). Conversely, we did not find the risk of ST across DAPT trials to be significantly associated with cardiovascular mortality. Indeed, it has been suggested that the association between ST and mortality depends on timing, with late ST less likely to present with fatal outcomes (4).
The observational nature of meta-regressions carries major unavoidable limitations, including the risk of incorrect conclusions caused by ecological fallacy (i.e., when inferences about individuals are made on the basis of aggregate statistics). To account for 2 other potential limitations of this regression approach: 1) effect size in the analysis is treated as a fixed regressor ignoring the degree of variance of the variable entered in the model; and 2) the unknown covariance among effect sizes determined by the presence of a within-study correlation among different reported outcomes—we also used a multivariate meta-analytic approach (5) to explore the consistency of our findings and confirmed a moderate-to-strong relationship between the log odds ratios for all bleeding and noncardiovascular mortality (rho coefficient = 0.52), whereas only a weak association was demonstrated between the log odds ratio for ST and cardiovascular mortality (rho coefficient = 0.24).
In conclusion, in drug-eluting stent trials of DAPT duration, bleeding seems to be significantly associated with noncardiovascular mortality, whereas ST does not seem to be significantly associated with cardiovascular mortality. Therefore, DAPT prolongation over current recommendations should only be undertaken after careful consideration of the benefit-risk balance.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sanjay Kaul, MD, served as Guest Editor for this paper.
- American College of Cardiology Foundation
- Giustino G.,
- Baber U.,
- Sartori S.,
- et al.
- Palmerini T.,
- Sangiorgi D.,
- Valgimigli M.,
- et al.