Risk Evaluation Tools for Prediction and Possible Guidance of DAPT: Is Scoring a Hit in East Asians Patients undergoing PCI?
07 May 2019
07 May 2019
10 June 2019 (eFirst)
The benefit of dual antiplatelet therapy (DAPT) in the acute and chronic phase after percutaneous coronary intervention (PCI) for acute coronary syndromes (ACSs) or stable coronary artery disease (SCAD) has been thoroughly validated in a large number of clinical trials.  While potent ischemic event protection is essential in the acute phase after PCI but also thereafter, bleeding events are an accumulative issue during the maintenance phase. Counterbalancing hazards from stent thrombosis and recurrent myocardial infarction versus a pharmacologically aggravated bleeding disposition remains an ongoing challenge for the cardiologist. Not only the choice of drugs for DAPT and their dosage, but also the duration of DAPT is at discussion.  Previous scientific statements on DAPT duration and intensity have summarized a multitude of factors affecting ischemic and bleeding risk after PCI for ACS or SCAD.   Most notably, the DAPT, PRECISE-DAPT, and PARIS risk scores were introduced as valuable risk prediction tools integrating and correlating the ischemic benefit and bleeding risk for guidance of DAPT. However, the vaizast majority of clinical trials in the field of DAPT as well as the above-mentioned risk scores were evaluated in the Western population and study cohorts included little to no East Asian patients. In consequence, there is a large gap of knowledge for this patient population, including choice and dosage of drugs as well as dedicated scoring systems.
In this issue of Thrombosis and Haemostasis, Kang et al take efforts to establish a risk-adjusted dichotomous DAPT score, specifically adapted to East Asian patients undergoing PCI. Five different registries were pooled and data from 13,172 patients receiving second-generation drug-eluting stents (DESs) and clopidogrel treatment were used for this important, innovative, and novel analysis. Of note, patients who received a first-generation DES were excluded from the analysis. Ischemic and bleeding endpoints were assessed up to 3 years after index PCI. A net Asian dual antiplatelet treatment score (ADAPT score) was derived by subtraction of an estimated bleeding score (B-ADAPT) from an estimated ischemic score (I-ADAPT). External validation was conducted in the HOST-ASSURE and NIPPON trials and a comparison of the discriminative ability between the ADAPT and the PARIS risk score models was presented.
Key findings of this study were that the discriminative power of both, the I-ADAPT (c-statistics 0.649, 95% confidence interval [CI], 0.610 − 0.688, p < 0.001, goodness of fit p = 0.898) and the B-ADAPT (c-statistics 0.664, 95% CI, 0.620 − 0.708, p < 0.001, goodness of fit p = 0.880) scores were moderate but significant—as was the discriminative performance of other previous score models.   Further, best cut-off values were calculated for the I-ADAPT and B-ADAPT scores. Values above 3.0 were highly predictive of an increased ischemic and bleeding risk (1.0% vs. 2.3%, p < 0.001 for I-ADAPT, 0.9% vs. 2.8%, p < 0.001 for B-ADAPT). The net-ADAPT score was correlated with the net clinical risk and a higher ischemic risk compared with the bleeding risk was suggested when the score was ≥ 1, whereas a higher bleeding risk compared with ischemic risk was suggested when the score was ≤ –1. External validation of the ADAPT scores by the HOST-ASSURE and NIPPON cohorts showed reliable and consistent results compared with the derivation cohort. Of note, patient characteristics clearly reflect the overall lower body mass index in East Asian patients compared with Western populations and indicate a high rate (around one-third) of patients under DAPT after 3 years of follow-up. The authors conclude that their novel ADAPT scores predict ischemic and bleeding events in East Asian patients and that those scores could be used to determine DAPT duration.
Kang et al are to be commended for this study and for trying to establish a scoring system that could be unique for risk prediction and possible guidance of DAPT in the East Asian population. Besides a large sample size, the exclusive use of second-generation DES and integration of clinical and procedural variables is certainly a strength of the study along with a sound statistical processing. However, several limitations must be acknowledged when examining the data.
First, the risk prediction of the scoring systems under investigation was found to be significant but the discriminatory power of the models was only modest (as expected for clinical risk scores). Thus, while the ADAPT scores could be used for predicting ischemic and bleeding risk in East Asian patients, their role for a guidance of DAPT including determination of DAPT duration definitely requires the conduction of further dedicated clinical studies. At best, a randomized parallel-group clinical trial could be conducted that includes a fixed duration in the control arm (along with guideline recommendations) versus a determination of variable DAPT durations based on the ADAPT score in an experimental arm of such a study. Such data seems mandatory for providing robust evidence to include this specific scoring system into clinical routine practice.
Second, the overall bleeding risk is low in this cohort with major bleeds (classified according to the Thrombolysis In Myocardial Infarction [TIMI] definition) below 2%. This may also relate to the lack of data on ACS patients treated with the potent P2Y12 adenosine diphosphate receptor blockers ticagrelor or prasugrel. In consequence, it remains unclear in how far these findings could be extrapolated to current clinical practice where treatment with potent antiplatelet drugs should be standard of care in ACS patients undergoing PCI. Further investigations are mandatory to test the predictive value of the ADAPT score in ACS patients receiving ticagrelor or prasugrel.
Finally, the bleeding complications captured in this study included major bleeds only and were defined according to the TIMI bleeding classification. For a more in-depth investigation on bleeding events and how they relate to the scoring systems, it seems mandatory to include minor bleeds as well and to possibly expand bleeding event classifications to modern definitions like the Bleeding Academic Research Consortium bleeding classification.
In summary, bleeding and ischemic risk prediction in patients undergoing PCI is complex and this holds also true for the inclusion of scoring systems when trying to find the best predictors of patient's risk ([Fig. 1]). Bleeding risk is also a highly dynamic process, and its variation over time is often a better determinant of bleeding events; indeed, a bleeding score should help identify the modifiable bleeding risk factors and, subsequently, to facilitate the identification of “high-risk” subjects for more frequent review and follow-up. All prior risk scores including the DAPT and PRECISE-DAPT scores were not established in dedicated randomized trials but were designed and calculated in a post hoc fashion from the data of preceding clinical trials. This also explains the relatively “weak” class IIb (“may be considered”) recommendations in current European guidelines  for the use of scores for guidance of DAPT. For both Western and East Asian patients undergoing PCI with DAPT much more data are urgently needed before those scores could find their way into clinical routine. The study by Kang et al is a first and important step into this direction for a better and more individualized treatment of East Asian patients undergoing PCI.
- 1 Neumann FJ, Sousa-Uva M, Ahlsson A. , et al; ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
- 2 Sibbing D, Angiolillo DJ, Huber K. Antithrombotic therapy for acute coronary syndrome: past, present and future. Thromb Haemost 2017; 117 (07) 1240-1248
- 3 Capodanno D, Greco A. Risk stratification for bleeding in the elderly with acute coronary syndrome: not so simple. Thromb Haemost 2018; 118 (06) 949-952
- 4 Levine GN, Bates ER, Bittl JA. , et al. 2016 ACC/AHA Guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
- 5 Valgimigli M, Bueno H, Byrne RA. , et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
- 6 Gallone G, Baldetti L, Pagnesi M. , et al. Medical therapy for long-term prevention of atherothrombosis following an acute coronary syndrome: JACC state-of-the-art review. J Am Coll Cardiol 2018; 72 (23 Pt A): 2886-2903
- 7 Yeh RW, Secemsky EA, Kereiakes DJ. , et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315 (16) 1735-1749
- 8 Costa F, van Klaveren D, James S. , et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017; 389 (10073): 1025-1034
- 9 Baber U, Mehran R, Giustino G. , et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016; 67 (19) 2224-2234
- 10 Kang J, Ki Y, Park J. , et al. Development and validation of an ischemic and bleeding risk evaluation tool in East Asian patients receiving percutaneous coronary intervention. Thromb Haemost 2019; DOI: 10.1055/s-0039-1688792.
- 11 Park KW, Kang SH, Kang HJ. , et al; HOST–ASSURE Investigators. A randomized comparison of platinum chromium-based everolimus-eluting stents versus cobalt chromium-based Zotarolimus-Eluting stents in all-comers receiving percutaneous coronary intervention: HOST-ASSURE (harmonizing optimal strategy for treatment of coronary artery stenosis-safety & effectiveness of drug-eluting stents & anti-platelet regimen), a randomized, controlled, noninferiority trial. J Am Coll Cardiol 2014; 63 (25 Pt A): 2805-2816
- 12 Nakamura M, Iijima R, Ako J. , et al; NIPPON Investigators. Dual antiplatelet therapy for 6 versus 18 months after biodegradable polymer drug-eluting stent implantation. JACC Cardiovasc Interv 2017; 10 (12) 1189-1198
- 13 Mehran R, Rao SV, Bhatt DL. , et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
- 14 Chao TF, Lip GYH, Lin YJ. , et al. Incident risk factors and major bleeding in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost 2018; 118 (04) 768-777