Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI

Abstract

Aims

Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT.

Methods and results

A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31–0.57] and HBR (HR 0.70, 95% CI 0.52–0.94), with a greater magnitude of benefit among non-HBR (P_int = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45–0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63–1.34; P_int = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (P_int = 0.45 and P_int = 0.56, respectively).

Conclusions

PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit–risk ratio in an individual patient.

Introduction

Coronary stenting in patients with the need for long-term oral anticoagulation (OAC) poses special challenges regarding the best antithrombotic strategy.¹ Coronary stenting requires an initial period of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor to prevent stent thrombosis and other coronary thrombotic events.² Yet, high-risk patients with atrial fibrillation (AF) need OAC to mitigate the risk of stroke or systemic embolism, further amplifying the bleeding risk of DAPT.³ In fact, this combination, also called triple antithrombotic therapy, has been associated to a greater than three-fold increased risk of major bleeding.⁴ Considering that indefinite OAC therapy is mandatory in this setting, reducing DAPT duration has been widely explored in multiple clinical trials to enhance safety, testing the hypothesis of removing one antiplatelet agent early after stenting, hence downgrading TAT to dual antithrombotic therapy (DAT).⁵ The latter has ultimately proved useful to limit the risk of major bleeding and has been endorsed by clinical guidelines, which now suggest adjusting antiplatelet therapy duration, and eventually OAC dosage, based on the preponderant ischaemic or bleeding risk.⁶ Given that bleeding risk is a major determinant for DAPT duration after stenting, standardized bleeding risk scores such as the PRECISE-DAPT may be useful to identify patients at high bleeding risk (HBR) whom may be indicated for shorter courses of treatment; however, this score has never been tested in the context of AF-PCI.⁷ For this reason, we aimed to explore the impact of treatment with dabigatran DAT vs. warfarin TAT, among patients included in the RE-DUAL PCI trial at different baseline bleeding risk based on the PRECISE-DAPT score.

Methods

This is a post hoc analysis of the RE-DUAL PCI trial, a randomized, open-label study. Study design and main results have been previously reported.^8,9 A total of 2725 AF-PCI patients were randomly assigned to DAT comprising dabigatran 110 mg or 150 mg b.i.d. and a P2Y12 inhibitor (either clopidogrel or ticagrelor) or TAT with warfarin, adjusted to achieve an international normalized ratio of 2.0–3.0, in association with aspirin and a P2Y12 inhibitor. According to the study protocol, patients in the USA or younger patients in the rest of the world could be randomized to both doses of dabigatran (i.e. 110 and 150 mg b.i.d) or to warfarin plus aspirin in a 1:1:1 ratio. Whereas elderly patients outside the USA (i.e. ≥80 years of age worldwide, ≥70 years of age in Japan) were randomized only to the 110-mg dabigatran dose vs. warfarin plus aspirin comparison in a 1:1 ratio. All patients were to receive clopidogrel (75 mg daily) or ticagrelor (90 mg b.i.d.) for at least 12 months after randomization. Aspirin in the triple therapy arm was prescribed for 1 or 3 months after PCI in case of bare-metal or drug-eluting stent implantation respectively, whereas in the dual therapy arm was maintained during the periprocedural phase in all patients and discontinued at the time of randomization which occurred after PCI.

In the current analysis, the baseline bleeding risk was estimated by the PRECISE-DAPT score as previously reported.⁷ The PRECISE-DAPT score is calculated through five clinical and laboratory variables: age, creatinine clearance, haemoglobin, white blood cell count, and a history of prior bleeding (Supplementary material online, Figure S1). Patients with a score ≥25 points were deemed HBR. Patients in which the PRECISE-DAPT score was not available owing to missing values were excluded (N = 389/2725). Details regarding excluded patients and the distribution of score missing variables are presented in the Appendix (Supplementary material online, Tables S1 and S2). The modified Hypertension, Abnormal renal and liver function, Stroke, Bleeding tendency/predisposition, Elderly, Drugs, or alcohol excess (HAS-BLED), omitting the labile International Normalized Ratio (INR) component, was also computed.^10,11

The primary safety endpoint of the study was the International Society of Thrombosis and Haemostasis (ISTH) major bleeding events or clinically relevant non-major bleeding events (CRNMBE). The main efficacy endpoint was a composite of death or thrombo-embolic events (DTE: death for all causes, myocardial infarction, stroke, or systemic embolism) or unplanned revascularization. A list of other safety and efficacy endpoints have also been explored as pre-specified in the study protocol.⁸

Statistical analysis

Baseline patients’ characteristics were presented by HBR status. Categorical variables were reported as frequencies and percentages, and continuous variables as means and standard deviations. Discrimination and calibration of the PRECISE-DAPT score and the modified HAS-BLED score were calculated in the RE-DUAL PCI population based on C-statistics and Hosmer–Lemeshow goodness-of-fit test. For the comparison of dabigatran, 110 mg DAT vs. warfarin Cox proportional hazard regression models stratified by age (elderly vs. non-elderly) were computed, whereas unstratified Cox proportional hazard regression models were computed for the comparison of dabigatran 150 mg DAT vs. warfarin, among HBR and non-HBR patients. Treatment by subgroup interaction P-values for dabigatran 110 mg DAT vs. warfarin TAT and dabigatran 150 mg DAT vs. warfarin TAT were provided. Additionally, Cox proportional hazard regression models including the score as a continuous variable, the treatment, and the interaction between the treatment and the score were also computed. Treatment-independent Cox proportional hazard regression models were computed to evaluate the impact of HBR vs. non-HBR at baseline on the efficacy and safety outcomes.

Results

Population

PRECISE-DAPT score was available in 2336 of 2725 patients in the RE-DUAL PCI trial. Median PRECISE-DAPT score was 21 (IQR 13–29) and 37.9% (N = 885) were deemed at HBR. Patients at HBR were older, more frequently women, with a higher prevalence of prior TIA or stroke and major bleeding (Table 1). These patients had a worse renal function and higher CHA₂DS₂-VASc and HAS-BLED scores. Drug-eluting stents have been used in a similar proportion irrespectively of bleeding risk status. Patients assigned to DAT with dabigatran 110 mg therapy were 842 (502 non-HBR and 340 HBR), those assigned to DAT with dabigatran 150 mg were 659 (474 non-HBR and 185 HBR), whereas patients assigned to warfarin TAT were 835 (475 non-HBR and 360 HBR). Details regarding baseline characteristics for HBR status and randomized treatment are presented in Supplementary material online, Tables S3 and S4.

Score performance

PRECISE-DAPT score distribution in the RE-DUAL PCI population is presented in Supplementary material online, Figure S1. Discrimination and calibration of the bleeding risk scores are presented in Table 2. PRECISE-DAPT score and HAS-BLED score showed modest discrimination in the RE-DUAL PCI population except for TIMI major bleed and ICH. PRECISE-DAPT showed numerically higher discrimination compared to the HAS-BLED score for the primary safety endpoint and higher discrimination for ISTH major bleeding. Similar results were observed with multiple definitions for bleeding. At a difference with HAS-BLED score, PRECISE-DAPT appeared well calibrated for the primary safety endpoint and for multiple definitions of bleeding explored (Table 2).

Impact of bleeding risk status on clinical events

Compared to non-HBR, HBR patients were associated with higher risks of bleeding (Table 3). This was confirmed irrespective of the bleeding definition used (Supplementary material online, Table S5) except for TIMI major bleed and ICH. High bleeding risk status was also associated with a higher risk of ischaemic events and death for all causes (Table 3).

Safety of the randomized treatment on bleeding risk subgroups

The impact of DAT vs. TAT on the primary safety endpoint by PRECISE-DAPT score as a continuous variable is presented in Figure 1. There was no statistically significant interaction between the continuous PRECISE-DAPT score and the treatment comparing DAT with dabigatran 110 mg vs. TAT for the primary safety endpoint (P_int = 0.10). Yet, a trend could be observed for a greater magnitude of the benefit of DAT compared to TAT with decreasing PRECISE-DAPT scores (Figure 1A). For the comparison of DAT with dabigatran 150 mg vs. TAT, a statistically significant interaction in the treatment effect for varying PRECISE-DAPT scores was observed (P_int = <0.01), suggesting a benefit of DAT vs. TAT in patients with lower PRECISE-DAPT values (Figure 1B). However, due to a low number of patients with a very high PRECISE-DAPT scores, the confidence intervals remain wide.

When the study population was stratified into two groups according to the HBR status (i.e. HBR and non-HBR according to the standard bleeding risk cut-off ≥25 points of the PRECISE-DAPT score), DAT with dabigatran 110 mg compared to TAT with warfarin was associated with lower bleeding risks in non-HBR patients (HR 0.42, 95% CI 0.31–0.57) and in HBR patients (HR 0.70, 95% CI 0.52–0.94), with a statistically significant interaction (P_int = 0.02), suggesting a similar direction, but a greater magnitude of the benefit, among non-HBR patients (Central Figure and Table 3). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT was associated with reduced bleeding risk among non-HBR patients (HR 0.60, 95% CI 0.45–0.80), but no clear benefit among HBR patients (HR 0.92, 95% CI 0.63–1.34) with a borderline interaction P-value suggesting a trend towards less benefit among HBR patients (P_int = 0.08) (Central Figure and Figure 3). Results remained largely consistent when other definitions for bleeding were explored (Figure 3 and Supplementary material online, Table S6).

At sensitivity analysis using an alternative score cut-off for HBR (i.e. ≥30 points) (Supplementary material online, Figure S2) and higher vs. lower haemoglobin values (Supplementary material online, Appendix) consistent results were obtained.

Efficacy of the treatment on bleeding risk subgroups

For the main secondary composite endpoint of DTE or unplanned revascularization, DAT with dabigatran (at both dosages of 110 and 150 mg b.i.d.) showed similar risks of events compared to TAT in non-HBR and HBR patients’ (P_int = 0.45 and P_int = 0.56, respectively) (Figure 2). The impact of DAT vs. TAT according to the bleeding risk of the PRECISE-DAPT score managed as a continuous variable is presented in Supplementary material online, Figure S3. Stent thrombosis rates are presented in Supplementary material online, Table S7. Dual antithrombotic therapy with dabigatran showed similar risks for definite stent thrombosis compared to TAT in non-HBR and HBR patients’ at both dosages of 110 and 150 mg b.i.d. (P_int = 0.55 and P_int = 0.99, respectively) (Supplementary material online, Table S7).

No interaction between baseline bleeding risk subgroup and the treatment was observed for other secondary ischaemic endpoints (Figure 3).

Discussion

The main findings of the current analysis of the RE-DUAL PCI trial can be summarized as follows: first, HBR patients selected according to the PRECISE-DAPT score had a 38% higher risk of major or clinically relevant non-major bleeding and 71% higher risk of ISTH major bleeding; second, DAT with dabigatran 110 mg reduced bleeding among both non-HBR and HBR patients compared to warfarin TAT and the magnitude of the benefit conferred by DAT with dabigatran 110 mg appeared higher among non-HBR than HBR patients; third, DAT with dabigatran 150 mg, compared to warfarin TAT, reduced bleeding among non-HBR patients, while a trend towards less benefit among HBR patients was observed.

European and North American guidelines suggest that bleeding risk should be taken into account to select the optimal antithrombotic strategy in AF-PCI patients.^1,2,6 Hence, decisions for DAT or TAT, and eventually OAC dose, should be based on individual patients’ risk. Given the higher prevalence of bleeding complications in this setting, DAT or very short courses of TAT should be the primary choice in most of the cases.⁵ In fact, DAT appeared safer across multiple strata of bleeding risk, especially when dabigatran 110 mg was selected.

Importantly, OAC dose selection in AF-PCI patients should be based on the approved dose effective for stroke prevention, tested in adequately powered clinical trials. Pivotal trials demonstrated that both approved doses of dabigatran (i.e. 110 and 150 mg b.i.d.) proved effective for stroke prevention,¹² and real-world data confirmed that also among patients with no formal elements for dose reduction according to drug labelling, dabigatran at lower dose remains effective.^13,14 Hence, international guidelines suggest to select dabigatran 150-mg for AF-PCI patients considered at higher thrombotic risk, while the 110-mg dose should be considered in elderly patients and those with higher bleeding risk.⁶ Our study is the first to give support to guidelines for treatment selection according to patients baseline bleeding risk in AF-PCI patients. We found that the PRECISE-DAPT score, assessed by age, prior bleeding history, creatinine clearance, haemoglobin, and white blood cell count, could identify a higher risk of bleeding among AF-PCI patients.

Recently, a risk model was generated from AF patients included in the RELY trial, to highlight ischaemic and bleeding risk factors and guide optimal dose selection of dabigatran.¹⁵ Also in this report, older age, lower haemoglobin, and creatinine clearance, together with the additional use of antiplatelet therapy were found to be major predictors for bleeding, and higher bleeding risk patients had better safety with dabigatran 110 mg dose, whereas those not qualifying as HBR could get additional ischaemic advantage from dabigatran 150 mg without an excessive bleeding liability. DAT with dabigatran 110 mg, showed the most favourable net outcome among patients with the expected higher clinical impact from bleeding, and appeared to be the best choice when bleeding risk was a concern.¹⁶ Our results align with current international drug labelling, as many patients with higher bleeding risk according to PRECISE-DAPT score would already qualify for dose reduction owing to age or renal function. Yet, at the difference with single elements, the use of a score, taking into account multiple features with different weights at the same time, is more effective in estimating risk and taking decisions.

An interesting observation from the current study was that the relative benefit for DAT compared to TAT was actually greater in those at lower bleeding risk than among those at higher bleeding risk at baseline. This is unexpected, as one would predict that a reduction of the number of antithrombotic agents would lower bleeding especially among individuals with a higher risk at baseline. While this result is counterintuitive several possible explanations could be proposed. HBR patients are often older and with a worse renal function. Direct oral anticoagulants are excreted through renal clearance, and dabigatran has 80% renal elimination. Higher blood concentrations and accumulation of dabigatran are expected in this subgroup, justifying the smaller advantage of a dabigatran DAT strategy, especially when higher doses of the drug are used.¹⁷ In fact, as observed in the current analysis, a relatively lower benefit of DAT compared to TAT was also observed among elderly patients, whereas the benefit of DAT in terms of reduction of bleeding appeared larger among young patients.¹⁸ Yet, the renal function alone does not appear to fully justify our findings. Hohnloser et al.¹⁹ showed that DAT reduced bleeding compared to TAT irrespective of baseline renal function. In addition, in the current study, when in a sensitivity analysis bleeding risk was gauged by levels of haemoglobin alone, a similar pattern arose as when analysed by bleeding risk groups. Hence, HBR status might broadly represent a marker of frailty, and in the context of AF-PCI, the exaggerated bleeding risk conveyed by baseline clinical features added to the multiple antithrombotic therapies might plateau the risk of bleeding and mask the benefit of aspirin withdrawal. Nevertheless, among HBR patients with AF-PCI, the association of dabigatran 110 mg DAT was safer than warfarin TAT and appear the best choice to limit the risk of bleeding while maintaining adequate stroke protection.⁶ Plus, the availability of a reversing agent might be convenient in case of overt major bleeding would occur in this high-risk population.²⁰

Limitations

This is a post hoc analysis of the RE-DUAL PCI trial and as such, results should be considered hypothesis generating. Nevertheless, this is the first study exploring the role of baseline bleeding risk according to the PRECISE-DAPT score and its implications towards treatment decision-making within AF patients undergoing coronary interventions. Further validation of this tool in other cohorts of patients with AF-PCI is warranted. RE-DUAL PCI trial was neither powered to explore the effect of treatment with respect to ischaemic endpoints in the overall population nor to explore any safety or efficacy endpoint in subgroups. Hence, the interaction P-values presented can only be regarded as exploratory. In particular, the group of patients at HBR assigned to DAT with dabigatran 150 mg was very small, hence more data are needed to inform the nuances of treatment with various dosages of oral anticoagulation in the PCI population. Nonetheless, sensitivity analysis and prior subanalysis from the same population support the findings of the current study. Recent studies reported an excess of stent thrombosis with DAT compared to TAT,²¹ especially during the first 30 days after PCI.²² In RE-DUAL PCI rates of stent thrombosis were very low, and while the occurrence of these events was similar in the subgroups explored, the study was not powered to evaluate treatment impact with respect to this rare event. Further studies in larger populations are needed to explore factors associated with an increased risk of stent thrombosis favouring a prolonged use of aspirin. The use of potent P2Y12 inhibitors such as ticagrelor in combination with oral anticoagulation was reported elsewhere.²³ Since this treatment was not randomized and administered in a relatively small group of patients, the potential to draw conclusions regarding its impact among bleeding risk categories is limited.

Conclusions

The PRECISE-DAPT score appeared useful for risk stratification in patients with AF receiving anticoagulation in addition to antiplatelet therapy post-PCI, helping to identify patients with an additional higher risk for bleeding complications. In this setting, DAT with dabigatran 110 mg, compared to warfarin TAT, reduced bleeding among non-HBR and HBR patients, with a higher magnitude of the benefit among non-HBR patients. Dual antithrombotic therapy with dabigatran 150 mg, compared to warfarin TAT, reduced bleeding among non-HBR patients, with a trend towards less benefit among HBR patients. In line with guideline recommendations, bleeding risk evaluation may be useful to inform the intensity of the antithrombotic treatment (DAT and dabigatran dose) and select the combination with the best benefit–risk ratio in an individual patient.

Supplementary material

Supplementary material is available at European Heart Journal – Cardiovascular Pharmacotherapy online.

Funding

The trial was funded by Boehringer Ingelheim. No additional external funding was used for this analysis.

Conflict of interest: F.C. reports no conflicts of interest. M.V. reports grants and personal fees from Abbott, Terumo, AstraZeneca, personal fees from Chiesi, Bayer, Daiichi Sankyo, Amgen, Alvimedica, Biosensors, Idorsia, grants from Medicure outside the submitted work. reports grants and personal fees from Abbott, Terumo, and AstraZeneca, and personal fees from Chiesi, Bayer, Daiichi Sankyo, Amgen, Alvimedica, Medicure, Biosensors, and Idorsia, outside the submitted work. P.G.S. reports research grants from Amarin, Bayer, Sanofi, and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Servier. D.L.B. Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. S.H.H. has received personal fees from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, SJM, and ZOLL. C.M. is an employee of mainanalytics GmbH, contracted by Boehringer Ingelheim International GmbH. M.N. is an employee of Boehringer Ingelheim International GmbH. G.Y.H.L. has served as a consultant for Bayer/Janssen, Bristol-Meyers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi Sankyo. He has been a speaker for Bayer, Bristol-Meyers Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Medtronic. No fees are personally received. J.O. has received fees to his institution from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Portola, Roche Diagnostics, and Sanofi. C.P.C. reports in calendar years 2018 to 2020: Research Grants from Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer; consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Sanofi, and Rhoshan.

Data availability

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References