Intern Emerg Med DOI 10.1007/s11739-013-1037-4

CE - LETTER TO THE EDITOR

Primary PCI in dabigatran-treated patient: is transradial approach and bivalirudin infusion a safe and effective therapeutic option? Francesco Summaria • Enrico Romagnoli • Marina Mustilli • Roberto Patrizi • Adolfo Pagnanelli

Received: 27 October 2013 / Accepted: 13 December 2013 Ó SIMI 2014

To the Editor, Novel oral anticoagulants (NOAs) provide an effective and convenient alternative to warfarin for stroke prevention in patients with non-valvular atrial fibrillation. However, in emergency situations such as an acute coronary syndrome (ACS), NOAs also present new challenges related to timing of introduction, measurement of anticoagulant efficacy and, concomitant use of antiplatelet agents. Moreover, due to the frequent association of atrial fibrillation (AF) and coronary artery disease (CAD), the widespread use of NOAs may raise several questions in terms of optimal treatment, especially in patients with ACS undergoing interventional procedure during the acute phase. We report the case of a 67-year-old man with diabetes, hypertension, hypercholesterolemia, and previously diagnosed persistent non-valvular AF shifted from warfarin to dabigatran (150 mg twice daily) 4 months prior, referred to our ED for an acute inferior–posterior–lateral STEMI. Due to the ongoing treatment with dabigatran, only an oral loading dose of ASA (300 mg) was administered in the ED, and the patient was promptly transferred to the catheterization laboratory for an emergent primari PCI. According to the catheterization laboratory protocol, a transradial left approach was performed, and after F. Summaria (&)  E. Romagnoli  R. Patrizi Interventional Cardiology, Cath Lab Policlinico Casilino, Via Casilina, 1049, 00168 Rome, Italy e-mail: [email protected] M. Mustilli CCU S. Pertini Hospital, Rome, Italy A. Pagnanelli Emergency Department Policlinico Casilino, Rome, Italy

documentation of aPTT of 46 s, an intra arterial 4,000 IU bolus dose of unfractioned heparin (60 IU/Kg) was directly administered through the 6 French radial introducer. The coronary angiography showed a normal right coronary artery and left descending artery with a thrombotic occlusion in the mid segment of a large left circumflex artery (Fig. 1a). Considering the evidence of a high intracoronary thrombotic burden, an i.v. bolus of bivalirudin (0.5 mg/kg) followed by infusion (1.75 mg/kg/h) was started and a manual thrombus aspiration was performed (Fig. 1b). The coronary manual dethrombosis resulted in a macroscopic aspiration of white thrombus (Fig. 1c) with important reduction of the thrombotic burden. Subsequently a 3.5 9 28 mm everolimus eluting stent was implanted (Fig. 1d), and overexpanded with a 3.75 9 15 mm non-compliant balloon up to 20 atm (Fig. 1e). The final angiographic result was excellent (nonresidual stenosis, TIMI 3 flow, blush grade 3, and residual thrombus score 0) (Fig. 1f). At the end of the procedure, a loading dose of 300 mg of clopidogrel was administered, and warfarin was started within 24 h after PCI aiming to 2–3 INR target. The subsequent clinical stay was uncomplicated, and the patient was discharged on day 4 on triple therapy: ASA 100 mg ? clopidogrel 75 mg ? warfarin with indication to stop only the ASA 3 months after the procedure. Recently, NOAs have been approved for several indications including non-valvular AF. Although head-to-head comparisons between different NOAs are lacking, they show favorable cost–benefit relations overcoming some limitations of traditional anticoagulants. In particular, NOAs do not require INR monitoring, require dose adjustment only in patients with renal and hepatic impairment, and are actually more patient-friendly for chronic use.

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Fig. 1 a The coronary angiography shows a thrombotic occlusion in the mid segment of a large circumflex artery (white arrow). b Result after manual thrombus aspiration. c Large white thrombus in the

basket. d Implantation of a 3.5 9 28 mm DES on mid segment of circumflex artery. e Post-dilation at 20 atm with a 3.75 9 15 mm non-compliant balloon. f The final angiographic result

No definitive indications are available in case of concomitant use of anticoagulant (heparin or direct thrombin inhibitor) and antiplatelet (ASA and thienopyridine) drugs in the context of ACS. A recent meta-analysis [1] has raised questions about a possible increase of acute myocardial infarction (MI) occurrence in patients treated with dabigatran compared either to warfarin or other NOAs. Conversely, another analysis shows only a more protective effect of well-controlled warfarin regimen compared to dabigatran in preventing MI, suggesting that myocardial infarction is not an adverse drug reaction associated with the use of dabigatran [2]. Although the pathophysiology of MI in dabigatran treated patients is unclear, a possible explanation seems to

be related to the univalent thrombin inhibition causing an enhancement of thrombin generation and platelet activation, both promoting the coagulation cascade. Hence, in our report, we used bivalirudin as the procedural anticoagulant for the following reasons: bivalirudin is a direct bivalent inhibitor of both circulating and clotbound thrombin, the ‘‘visual’’ documentation of a white thrombus removed from the coronary artery requires an aggressive antithrombotic therapy and, the use of bivalirudin is associated with a significantly lower bleeding risk reduction during ACS, ultimately resulting in an optimal net adverse clinical events (combined ischemic plus hemorrhagic). A recent report describes the acute treatment with fibrinolysis for ST elevation MI in patient taking chronic

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dabigatran [3], but no data are available about the pharmacological and interventional management during primary PCI. Despite no definitive indication about the optimal test to measure the anticoagulant activity in patients treated with NOAs during ACS, general advice and local consensus documents indicate the aPTT test as an approximate semiqualitative evaluation of the anticoagulant intensity achieved with dabigatran. In case of unavailability of the quantitative diluted thrombin time (dTT) measure with the calibrated HemoclotÒ assay, the utility of aPTT assessment is primarily due to its negative predictive value; in other words, a normal aPTT value suggests a weak anticoagulant activity. In our case, we decided to use aPTT to discriminate real dabigatran anticoagulant efficacy due to the urgent clinical setting, the necessity to switch to another anticoagulant agent, the large amount of intracoronary thrombus and the unavailability of a dTT assay. Furthermore, the procedure was performed 7 h after the last 150 mg dabigatran dose intake with an expected high pharmacological anticoagulant drug-related activity. In this case, the aPTT value provided a safer bridging peri-procedural use of UFH and bivalirudin. Indeed, as recently confirmed [4], dabigatran treatment may not provide sufficient anticoagulation during PCI requiring adjunctive antithrombotic treatment (i.e., loading dose of UFH and bivalirudin) to perform the procedure safely. Finally, the choice of combined dual antiplatelet therapy (DAPT) with standard anticoagulant treatment at discharge is strongly colored by the choice of drug eluting stent implantation and the persistent uncertainty regarding the net clinical benefit of combined therapy of dabigatran and DAPT, principally related to excessive bleeding. Indeed, newer antiplatelet agents in combination with NOAs have demonstrated an excess in intracranial bleeding; thus, at the present, clopidogrel appears to be safer than ticagrelor or prasugrel in patient with a concomitant ACS and chronic AF. When patients with AF undergo percutaneous coronary intervention, the need to combine dual antiplatelet therapy (DAPT) and warfarin considerably raises the risk of major bleeding complications. The WOEST trial [5] has explored the option of omitting aspirin with promising results. Moreover, in the PCI-CURE trial [6], the DAPT prevented 22 CV events/1,000 pts during the 12-month study period: 50 % of the CV events are prevented in the first 30 days and 50 % from 1 to 12 months. More specifically, 9 of the 11 prevented CV events occurred between 1 and 3 months. The randomized PRODIGY trial [7] broke the psychological barrier of 12 months in terms of safety and efficacy, suggesting that optimal duration of DAPT may be stent-

specific, and does not support a clear association between stent potency and vulnerability to shorter DAPT therapy. In particular, the everolimus eluting stent implanted, given the diabetic status of the patient, is a thin-strut, fluoropolymercoated cobalt–chromium second generation DES associated with lower rates of definite stent thrombosis than other DES and, unexpectedly, even lower than BMS also during ACS, having received the CE Mark in Europe for a DAPT length of only 3 months. According to all the above considerations, in this specific patient, considering the non-negligible bleeding risk score (CRUSADE = 43; HAS-BLED = 4), the proposed customized antiplatelet therapy seems to be a reasonable option to achieve a break even point between safety and efficacy. Although patients with non-valvular AF and high CHA2DS2-VASc score are the more favorable candidates for dabigatran treatment, they also frequently have a high risk for CAD. Indeed, these patients share the same risk factors either for thromboembolic complications or for ischemic heart disease. Therefore, in the absence of definitive clinical evidence, when myocardial ischemia is suspected or highly probable, an oral anticoagulant other than dabigatran would be preferred in combination with standard antiplatelet agents notwithstanding the higher risks of major bleeding [2]. In conclusion, in patients with ACS and concomitant dabigatran treatment undergoing early invasive revascularization, a customized strategy based on a transradial approach and bivalirudin use to minimize peri-procedural bleeding risk seems to be safe and effective.

Conflict of interest

None.

References 1. Artang R, Rome E, Nielsen JD, Vidaillet HJ (2013) Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol 112(12):1973–1979. doi:10.1016/j.amjcard.2013.08.027 2. Clemens A, Fraessdorf M, Friedman J (2013) Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag 9:599–615. doi:10.2147/VHRM.S49830 3. Shavadia J, Welsh RC (2013) Acute management of ST-elevation myocardial infarction patients taking dabigatran. Can J Cardiol 29(11):1531.e13–1531.e14. doi:10.1016/j.cjca.2013.06.008 4. Vranckx P, Verheugt F, de Maat MP, Ulmans V, Regar E, Smits P, ten Berg JM, Lindeboom W, Jones R, Friedman J, Reilly P, Leebeek F (2013) A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients. EuroIntervention 8:1052–1060 5. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis

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Intern Emerg Med MM, Tijsen JG, van ‘t Hof AW, ten Berg JM, WOEST study investigators (2013) Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 381(9872):1107–1115 6. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA, Clopidogrel in unstable angina to prevent recurrent events trial (CURE) investigators (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in

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patients undergoing percutaneous coronary intervention: the PCICURE study. Lancet 358(9281):527–533 7. Valgimigli M, Borghesi M, Tebaldi M, Vranckx P, Parrinello G, Ferrari R, PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY Investigators (2013) Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stentinduced Intimal hyperplasia studY (PRODIGY). Eur Heart J 34(12):909–919

Primary PCI in dabigatran-treated patient: is transradial approach and bivalirudin infusion a safe and effective therapeutic option?

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