Cardiol Ther (2018) 7:79–87 https://doi.org/10.1007/s40119-018-0108-z ORIGINAL RESEARCH Dual Antithrombotic Therapy with Clopidogrel and Novel Oral Anticoagulants in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Real-world Study . . . . Julia Kebernik Martin Borlich Ralph Tolg Mohamed El-Mawardy Mohamed Abdel-Wahab Gert Richardt Received: January 29, 2018 / Published online: April 9, 2018 The Author(s) 2018 were bleeding events as deﬁned by Bleeding ABSTRACT Academic Consortium (BARC). Results: Baseline characteristics of our study Introduction: For patients with atrial ﬁbrilla- population were described by a CHA DS -VASc 2 2 tion (AF) undergoing percutaneous coronary score of greater than 4 and a HAS-BLED score of intervention (PCI), proper antithrombotic greater than 3. After a mean follow-up of therapy is equivocal. Current guidelines rec- 18.7 months, efﬁcacy events occurred in 12 ommend triple therapy, which carries a high patients (5.6%). We observed three (1.4%) car- risk of bleeding. Recent large trials suggest that diac deaths, two (0.9%) MIs, six (2.8%) strokes, dual therapy (DT) with novel oral anticoagulant and one (0.5%) deﬁnite ST. After switching from (NOAC) plus P2Y inhibitor can be an appro- DT to NOAC monotherapy after 6.3 ± priate alternative, but real-world data for this 1.7 months, there was no rebound of ischemic alternative are scarce and the optimal duration events. Bleeding events occurred in 34 patients of DT has not yet been established. (15.7%) mainly under DT, while bleeding was Methods: This analysis was performed in a less during NOAC monotherapy. single-center prospective cohort. We investi- Conclusions: In this long-term study of high- gated 216 PCI patients with indication for risk and real-world AF-patients with PCI, DT anticoagulation due to AF. After PCI patients with NOAC and P2Y inhibitor (6 months) received DT with reduced doses NOAC plus followed by NOAC monotherapy was safe and P2Y inhibitor for 6 months, which was fol- effective. lowed by standard dose NOAC monotherapy. Efﬁcacy endpoints were deﬁned as cardiac Keywords: Anticoagulant agents; Antiplatelet death, myocardial infarction (MI), stent agents; Atrial ﬁbrillation; NOAC; Percutaneous thrombosis (ST), and stroke. Safety endpoints coronary intervention Enhanced digital features To view enhanced digital INTRODUCTION features for this article go to https://doi.org/10.6084/ m9.ﬁgshare.6035594. Appropriate antithrombotic treatment in J. Kebernik (&) M. Borlich R. To ¨ lg patients with atrial ﬁbrillation (AF), who M. El-Mawardy M. Abdel-Wahab G. Richardt undergo OAC (PCI) is still unresolved. Dual Heart Center Segeberger Kliniken, Bad Segeberg, antiplatelet therapy (DAPT) appears to be Germany mandatory after PCI to reduce the risk of e-mail: email@example.com 80 Cardiol Ther (2018) 7:79–87 myocardial infarction (MI) and stent thrombo- Center Segeberger Kliniken, Bad Segeberg, Ger- sis (ST) , while long-term treatment with oral many. The current analysis includes 216 con- anticoagulation (OAC) is indicated in patients secutive AF patients who underwent PCI from with AF to prevent stroke or systemic embolism July 2013 to May 2016. Clinical follow-up was . Accordingly, current guidelines recommend performed at least 6 months after the proce- triple therapy (TT) with DAPT plus OAC for at dure. It was conducted by hospital visit or least 1 month after PCI [3, 4]. TT, however, phone contact. A clinical event committee substantially increases the risk of bleeding . reviewed patient medical records including Favorable results were reported for a treatment clinical events and hospital admissions in case strategy with dual therapy (DT) using single of any adverse event. antiplatelet therapy plus vitamin K antagonists (VKAs) after PCI [7–10]. Novel oral anticoagu- Interventional Procedure lants (NOACs) are suitable alternatives to VKAs for stroke prevention in non-valvular AF and The indications for PCI and procedures were their use in clinical practice is increasing rapidly performed in accordance with the current , also driven by guideline recommendation guidelines and included stable coronary artery as ﬁrst-line preference . DT using NOACs disease (CAD) as well as acute coronary syn- and P2Y inhibitors may replace TT in AF dromes (ACS). Procedural techniques were left patients with PCI, but so far, many questions to the operator’s discretion and generally did are still open regarding this new antithrombotic not differ from non AF patients. To provide a strategy. First, it is unclear which medications real-world case study, all clinical presentations are the best agents to combine. With several and procedural entities were included, as long P2Y inhibitors and four NOAC agents, multi- as NOACs were not contraindicated. All patients ple potential drug combinations exist. Second, received a loading dose of 500 mg acetylsalicylic the optimal duration of DT and the dosage of acid intravenously and 600 mg clopidogrel or NOAC is unclear. The recently published PIO- 60 mg prasugrel orally. Unfractionated heparin NEER AF-PCI trial  and REDUAL-PCI trial was given intra-arterially during PCI at a dose of  as well as the ongoing ENTRUST-AF-PCI 5000–7000 U with a target ACT time of [ 250 s. and the AUGUST studies aim to investigate the Patients did not take NOAC on the day of the value of NOACs in combination with P2Y procedure. inhibitors. PIONEER AF and REDUAL-PCI All procedures were performed trans- showed that DT using NOAC signiﬁcantly femorally and arterial closure devices were used reduced bleeding compared to TT using VKA. TM in all patients (FemoSeal , Terumo Europe Both trials, however, are underpowered for NV). In addition, access site was supplied with a other clinical endpoints and thus clinical data pressure bandage for 3 h after removal of the in this area are of current interest. As the opti- sheath as in-house standard after transfemoral mal antithrombotic treatment strategy for AF access. patients with PCI is still unresolved, the aim of this study was to assess safety and efﬁcacy of Endpoint Deﬁnition 6 months DT with NOAC and P2Y inhibitor. Pre-speciﬁed efﬁcacy endpoints of this study METHODS were cardiac death, MI, ST, and stroke as deﬁned by the Academic Research Consortium (ARC) Study Design . Safety endpoint was the occurrence of bleeding events, deﬁned by Bleeding Academic Consortium (BARC) . This retrospective analysis was performed in a single-center prospective cohort study aiming for consecutive enrolment of all AF patients with indication for PCI and OAC at the Heart Cardiol Ther (2018) 7:79–87 81 Antithrombotic Regimen Table 1 Baseline characteristics Age (years) mean ± SD 74.8 ± 1.3 All patients had indication for OAC due to non- valvular AF with risk factors. After PCI, patients Male, n (%) 174 (80.1) received reduced dosage NOAC plus a P2Y BMI (kg/m ), mean ± SD 28.4 ± 4.95 inhibitor for 6 months, followed by standard Comorbidity and cardiac risk factors dosage of NOAC monotherapy. Most patients were already on NOAC at the time of the pre- Diabetes mellitus, n (%) 65 (30.1) sentation and maintained the therapy, so the Hypertension, n (%) 201 (93.1) decision for a certain NOAC mainly depended on the referring physicians. Dyslipidemia, n (%) 112 (51.8) Current smoker, n (%) 27 (12.5) Statistical Analysis Previous MI, n (%) 29 (13.4) All data were processed using Excel 2016 (Mi- Previous CABG, n (%) 24 (11.1) crosoft) and Prism 7.0 (GraphPad). The Previous cerebral ischemia, n (%) 22 (10.2) descriptive statistical characteristics for quanti- tative parameters are listed as mean ± standard Peripheral vessel disease, n (%) 39 (18.1) deviation for normally distributed data and as Chronic renal failure (GFR \ 60), n (%) 49 (22.7) median with interquartile range for non-nor- Previous PCI, n (%) 85 (39.4) mally distributed data. Event-free survival for groups was constructed using Kaplan–Meier method. Table 2 Clinical characteristics Compliance with Ethics Guidelines Clinical presentation All procedures were in accordance with ethical Stable angina, n (%) 179 (82.9) standards of the responsible committee on Acute coronary artery disease, n (%) 37 (17.1) human experimentation (institutional and national) and with the Helsinki Declaration of Unstable angina, n (%) 21 (9.7) 1964, as revised in 2013. Informed written NSTEMI, n (%) 10 (4.6) consent for the procedure was obtained from all patients. STEMI, n (%) 6 (2.8) Left ventricular ejection fraction, 52.3 ± 11.59 RESULTS mean ± SD Left ventricular ejection fraction B 30%, 19 (8.8) A total of 220 patients with AF and need for n (%) OAC were consecutively treated with PCI from July 2013 until May 2016. Only four patients CHA DS -Vasc score, mean ± SD 4.3 ± 1.24 2 2 were lost to follow-up and excluded from ﬁnal CHA DS -Vasc score, median (range) 4 (2–8) 2 2 analysis. Detailed patients’ baseline and clinical Coronary artery disease characteristics are summarized in Table 1 and 2. Mean age of the study population was 1 VD, n (%) 58 (26.8) 74.8 ± 1.3 years, and 80.1% were males. The 2 VD, n (%) 74 (34.3) comorbidity index was high, with 30.1% of the patients being diabetics, 13.4% with previous 3 VD, n (%) 84 (38.9) MI, 10.2% with previous ischemic events, and 22.7% with impaired renal function (glomerular 82 Cardiol Ther (2018) 7:79–87 ﬁltration rate \ 60 ml/min). The mean dabigatran 110 mg twice-daily in 17 patients CHA DS -VASc score of our population was (7.9%), apixaban 2.5 mg twice-daily in 16 2 2 4.4 ± 1.2 with a mean HAS-BLED score of patients (7.4%), or edoxaban 30 mg once-daily 3.0 ± 0.2 representing a high-risk group for in one patient (0.5%), starting the day after thromboembolic as well as bleeding events. procedure in combination with either clopido- Three-quarters of the patients had multives- grel (n = 214; 99.1%) or prasugrel (n = 2; 0.9%). sel coronary disease; 37 patients (17.1%) pre- The duration of recommended DT was sented with ACS. Stents were implanted in 6 months but was reduced to 4 weeks in two 93.5% in of the patients. On average, two stents patients (0.9%) and extended up to one year in were implanted with a mean total stent length 14 patients (6.5%). The mean duration of rec- of 35 mm; 89.8% of the stents were new-gen- ommended DT treatment was 6.3 ± 1.7 months eration drug-eluting stents (DES). A drug-elut- (Fig. 1). DT was followed by a monotherapy of ing balloon PCI was performed in 5.5% of the the respective NOAC using the regular dose as patients, 0.9% were treated with thrombus indicated for non-valvular AF. aspiration. Further procedural details are given in Table 3. Outcomes Antithrombotic Regimen Clinical follow-up was available in 216 patients (98.2%) with a mean follow-up duration of After the procedure, patients were treated with 18.7 months. Bleeding was more frequently DT using reduced dosage NOAC, i.e., rivaroxa- reported on DT than on NOAC monotherapy. ban 15 mg once-daily in 182 patients (84.3%), During a mean DT of 6.3 months, bleeding events occurred in 11.5% of patients, while within the following NOAC monotherapy Table 3 Procedural characteristics (mean, 11.9 months) only 3.2% of the patients experienced bleeding. Target vessel, n (%) Bleeding events occurred in 34 of the Left main coronary artery 17 (6.2) patients (Table 4). Mild bleeding (BARC 1–2) was 6.5% on DT and 2.8% under NOAC Left anterior descending artery 109 (40.1) monotherapy. Moderate and severe bleeding Right coronary artery 83 (30.5) (BARC 3a–3c) was 4.6% on DT and 0.5% under NOAC monotherapy. There was only one fatal Left circumﬂex artery 53 (19.5) bleeding due to a hemorrhagic shock a few days Bypass graft, n (%) 10 (3.7) Number of target vessels, n (%) One target vessel 168 (77.8) Two target vessels 40 (18.5) Three target vessels 8 (3.7) Stents per patient, mean ± SD 2 ± 1 Total stent length (mm), mean ± SD 35.25 ± 25 Drug-eluting stents, n (%) 194 (89.8) Bare metal stents, n (%) 8 (3.7) Drug-eluting balloon, n (%) 12 (5.5) Other, n (%) 2 (0.9) Fig. 1 Study design and patient enrolment Cardiol Ther (2018) 7:79–87 83 Table 4 Bleeding events at follow-up cancer (n = 2), paralytic ileus (n = 1), and renal failure (n = 1). We observed two MIs (0.9%) and BARC type, n (%) one deﬁnite ST (0.5%). Six strokes were reported (2.8%), all were ischemic. Only two of these BARC 1 13 (6.0) occurred during DT period with reduced dose BARC 2 7 (3.2) NOAC, whereas four patients suffered stroke during the following period of NOAC BARC 3a 4 (1.8) monotherapy in standard dose. Efﬁcacy events BARC 3b 6 (2.8) occurred in 2.4% on DT (one cardiac death, one BARC 3c 3 (1.4) MI, one deﬁnite ST and two strokes), while 3.2% were seen on following NOAC monotherapy BARC 4 0 (two cardiac deaths, one MI, and four strokes; BARC 5a 0 Fig. 3). As shown in Fig. 3, ischemic events were equally distributed throughout the whole BARC 5b 1 (0.45) observation period. TIMI type, n (%) Major 7 (3.2) DISCUSSION Minor 5 (3.2) The principal ﬁnding of this study is that Minimal 9 (4.2) 6-month DT consisting of NOAC plus P2Y Bleeding requiring medical attention 13 (6.0) inhibitor is safe and effective in high-risk AF patients with PCI. Moreover, with the de-esca- Clinically signiﬁcant bleeding 25 (11.5) lation from DT to NOAC monotherapy, the risk of bleeding is further reduced. For patients with indication for long-term after the index PCI while the patient was on DT, OAC and PCI, guidelines recommend TT for at whereas no fatal bleeding happened during the least 1 month [3, 4]. TT, however, increases the following NOAC monotherapy. Two bleeding risk of fatal and non-fatal bleeding . Despite events (BARC 3a, 3c) occurred in patients who recommendations for TT, real-world data reveal had changed recommended treatment and were that discharge medication in most patients who on VKAs. The most common bleeding compli- had undergone PCI and require chronically cations were recurrent epistaxis (n = 10) and anticoagulation consists of DAPT or DT using access route related bleeding (n = 8). Further an OAC with single antiplatelet agent . Sev- bleeding sites were gastrointestinal in six, eral studies compared DT with TT. The WOEST intramuscular in two, trauma caused by collapse trial randomized 573 patients with need for in two, intracerebral in one, and of unknown long-term OAC to DT (warfarin plus clopido- origin in four. Bleeding according to TIMI clas- grel) or TT (warfarin plus clopidogrel plus siﬁcation was detailed in Table 4 (major in acetylsalicylic acid in an open-label design. The seven (3.2%), minor in ﬁve (2.3%) and minimal group receiving DT had signiﬁcantly lower rates in nine (4.2%)). Eighteen patients had changed of any bleeding and even less ischemic events the recommended treatment strategy mainly within 1 year after PCI than the group receiving because of recurrent epistaxis, renal dysfunc- TT . tion, valve replacement, and left ventricular Despite the widespread use of NOACs, their thrombus formation. Timing of all bleeding role in AF patients undergoing PCI is widely events is shown in Fig. 2. unknown. It is unclear which dose of a NOAC Efﬁcacy events occurred in 12 (5.6%) of the should be used in combination with antiplatelet patients (Table 5). All-cause mortality was 2.8% agents and which duration of DT is optimal. with a cardiac mortality of 1.4%. Non-cardio- Currently it is also unknown whether anti- vascular deaths were due to sepsis (n =2), platelet therapy with NOAC is superior to 84 Cardiol Ther (2018) 7:79–87 Fig. 2 Timing of all bleeding events. Bleeding events in patients with dual therapy (DT), NOAC monotherapy, and interruption of recommended antithrombotic treatment at some point before the occurrence of bleeding event Table 5 Efﬁcacy events at follow-up Death, n (%) 9 (4.2) Cardiac death 3 (1.4) Vascular death 0 (0) Non-cardiovascular death 6 (2.8) Spontaneous MI, n (%) 2 (0.9) Stent thrombosis, n (%) Deﬁnite 1 (0.5) Fig. 3 Timing of all efﬁcacy events. Efﬁcacy events in Probable 0 (0) patients with dual therapy (DT) and NOAC monotherapy Possible 0 (0) at some point before the occurrence of efﬁcacy event Stroke, n (%) 6 (2.8) versus DT with NOAC. Published in 2016, the Ischemic 6 (2.8) PIONEER AF-PCI trial included 2214 AF patients Hemorrhagic 0 (0) who had just undergone PCI to compare the safety of two rivaroxaban treatment strategies (15 mg rivaroxaban plus a P2Y inhibitor or 2.5 mg rivaroxaban twice daily plus DAPT) ver- antiplatelet therapy combined with VKA. sus a TT using VKA. At 12 months, the primary Because addition of any type of single or dual outcome of clinically signiﬁcant bleeding was antiplatelet therapy to VKA or NOAC antico- lower in the rivaroxaban group than in the VKA agulation signiﬁcantly increases the risk of group and lowest in the 15 mg rivaroxaban major bleeding, the European guidelines rec- group . In the recently published REDUAL- ommend maintaining the INR within 2–2.5 PCI trial, 2752 patients were either treated with during triple or DT with VKA and reducing DT or with TT. The TT group received VKA plus doses of NOAC . To date, only two trials have a P2Y inhibitor and acetylsalicylic acid, while randomly assigned patients requiring chronic the DT group received dabigatran (110 mg or anticoagulation and undergoing PCI to TT Cardiol Ther (2018) 7:79–87 85 150 mg twice daily) plus a P2Y inhibitor . The same applies with respect to deﬁnite and These results reassured the ﬁndings of PIO- probable stent thromboses of 0.5% compared to NEER-AF-PCI showing signiﬁcantly lower rates 0.8% in PIONEER-AF PCI and 1.5% in RE-DUAL of clinically relevant bleeding in the DT groups PCI. Of note, the triple therapy arms with receiving reduced-dosage NOAC than in the double antiplatelet agent in the large random- group receiving TT. While these trials have been ized trials demonstrated a rate of stent throm- designed and powered for the primary safety bosis in the range of 0.7 to 0.9%, which is not endpoint of bleeding events, the secondary lower than the rate in our patients only receiv- efﬁcacy endpoint of cardiovascular events has ing one antiplatelet agent. However, we found a not been adequately powered, even when somewhat higher rate of stroke with 2.8% enrolling several thousands of patients. This compared to 1.3% in PIONEER-A PCI and 1.7% illuminates the difﬁculty in conducting a ran- in RE-DUAL PCI of the respective treatment domized controlled trial with its need for even arms with DT. Of these six patients in our larger cohorts to address this question. Adding cohort with a stroke event, only two strokes more data supporting the efﬁcacy of DT should (0.9%) where noted during the phase of DT with therefore be of current interest and clinical a reduced NOAC dosage, whereas the majority importance. of strokes where seen in a phase where NOAC We mainly utilized the DT regime of PIO- was already administered in the approved NEER-AF but shortened DT from 12 to dosage. 6 months. This was justiﬁed by a higher bleed- As we had a 98% follow-up rate and always ing risk of DT than monotherapy and the full access to the patients’ charts, it is very declining risk of stent thrombosis within the unlikely that our analysis suffers from serious ﬁrst months after PCI. Furthermore, our patient underreporting of events. Our results rather cohort was mainly representative of stable CAD support the contention that we should further and high bleeding risk, so that 6 months of DT reduce the aggressiveness of our antithrombotic was an appropriate method. therapy in elderly high-risk post PCI patients With a mean age of nearly 75 years, a with AF. One might argue that 12 months of DT CHA DS -Vasc score of 4, and a HAS-BLED score would have been more beneﬁcial than 2 2 of 3, our population has a higher patient-related 6 months of DT in our patients. DT, however, risk for ischemic and bleeding events than did not prevent the progression of thrombotic patients in PIONEER-AF-PCI and in REDUAL- complications between month 6 and 12 in the PCI. Moreover, the number and total length of RCTs, while our strategy halted bleeding in the stents indicate a high procedure-related risk. same period after PCI. Nevertheless, the observed event rates are lower or at least similar to the two large RCTs. Clini- Study Limitations cally signiﬁcant bleeding of 11.5% in our cohort is slightly lower than 16.8% in the respective DT This study has all the limitations of a single- arm in PIONEER-AF PCI (13) or 15.4% in the DT center observational study. The sample size of arm with 110 mg dabigatran in RE-DUAL PCI the study was small and no inference about (14). Of note, the applied bleeding deﬁnitions comparative outcomes can be made due to lack differ slightly between both large trials, but may of a control group. Secondly, different from the allow a cautious estimation. With respect to the RCTs, our collective comprises mainly patients efﬁcacy endpoint events, we found a cardio- with stable CAD, which may compromise valid vascular death rate of 1.4%, which is lower than comparison to other published studies. 2.4% in the respective DT arm of PIONEER-AF PCI and 5.6% in the DT arm with 110 mg dabigatran in RE-DUAL PCI. The incidence of CONCLUSIONS 0.9% myocardial infarction in our patients is lower than 3.0% in PIONEER-A PCI and 4.5% in This single-center analysis suggests that RE-DUAL PCI of the respective treatment arms. 6 months of DT using a reduced dosage of 86 Cardiol Ther (2018) 7:79–87 NOAC plus P2Y inhibitor followed by stan- Open Access. This article is distributed dard dosage NOAC monotherapy is a safe and under the terms of the Creative Commons effective antithrombotic strategy for PCI Attribution-NonCommercial 4.0 International patients with AF and need of OAC. License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any non- commercial use, distribution, and reproduction in any medium, provided you give appropriate ACKNOWLEDGEMENTS credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Funding. No funding or sponsorship was received for this study or publication of this article. 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Cardiology and Therapy – Springer Journals
Published: Apr 9, 2018
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