1130-0108/2015/107/5/289-306 REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS REV ESP ENFERM DIG (Madrid COPYRIGHT © 2015 ARÁN EDICIONES, S. L. Vol. 107, N.º 5, pp. 289-306, 2015 SPECIAL ARTICLE Management of antithrombotic drugs in association with endoscopic procedures* Fernando Alberca-de-las-Parras1, Francisco Marín2, Vanessa Roldán-Schilling3 and Fernando Carballo-Álvarez1 1Unit of Digestive Diseases and 2Department of Cardiology. Hospital Clínico Universitario Virgen de la Arrixaca. IMIB. Murcia, Spain. 3Department of Hematology and Oncology. Hospital Universitario Morales Meseguer. Murcia, Spain ABSTRACT benefits in terms of both financial savings and thrombosis incidence (9). The use of antithrombotic drugs (anticoagulants and antiplatelets) A first Spanish version of these guidelines was pub- has increased significantly with our understanding of cardiovascular risk. Encountering patients on these therapies who require an lished in 2010 (6). However, the emergence of new drugs endoscopic procedure is therefore increasingly common. At and of significant data in the literature has prompted a decision making the endoscopist must rely on other specialists revised and updated version, for which the consensus of (basically cardiologists and hematologists) as risk not only lies among the Working Group of Thrombosis of Spanish Cardiology increased bleeding odds but also in the possibility of thrombosis Society (GTCV-SEC) and the Spanish Society of Throm- following dose discontinuation or change. Understanding the pharmacology, indications, and risks of endoscopic procedures is bosis and Hemostasis. therefore essential if sound decisions are to be made. The efforts An analysis of the scarce adherence to guidelines and of four scientific societies have been brought together to provide of their applicability (10,11) suggests that less academic, clinical answers on the use of antiplatelets and anticoagulants, as more practical guidelines should be developed, since the well as action algorithms and a practical protocol proposal for endoscopy units. criteria for early drug re-introduction are approached by cardiologists (12), which conditions follow-up by gastro- Key words: Antithrombotic drugs. Antiplatelets. Anticoagulants. enterologists for fear of early bleeding. Endoscopic procedures. The goal of the present paper is to summarize the avail- able evidence, and to discuss newly marketed medications using a clinical questions and answers approach to help INTRODUCTION gastroenterologists in their decision-making. For many years single or dual anticoagulation and an- tiaggregation have become a therapeutic and preventive WHAT MANAGEMENT WOULD BE tool, particularly regarding highly prevalent cardiovascu- APPROPRIATE FOR ACUTE GI BLEEDING lar diseases. This, together with increased interventionism IN PATIENTS ON ANTICOAGULANTS OR among endoscopic techniques, represents a higher risk. ANTIPLATELETS? However, such risk is not only derived from potential bleeding but also from thrombotic risk (1), its obviation As is usual in medical practice, decision making de- by endoscopists being unacceptable. pends upon risk and severity. In patients with high throm- Scientific societies have issued a number of guidelines botic risk (for example, with mitral prosthesis) and mild and recommendations for such situations (2-8) and com- bleeding anticoagulation withdrawal is inappropriate pliance with them have even brought about secondary –pharmacological and endoscopic measures may be con- sidered while leaving reversal aside. *Guidelines endorsed by the Working Group of Thrombosis of Spanish Car- In general, anticoagulants must be discontinued imme- diology Society (GTCV-SEC), Spanish Society of Gastrointestinal Endos- diately for severe bleeding. In the absence of severity cri- copy (SEED), Spanish Society of Digestive Diseases (SEPD) and Spanish Society of Thrombosis and Hemostasis. teria the approach should hinge upon the patient’s throm- Received: 25-01-2015 Accepted: 16-02-2015 Correspondence: Fernando Alberca de las Parras. Unit of Digestive Dis- Alberca-de-las-Parras F, Marín F, Roldán-Schilling V, Carballo-Álvarez F. Man- eases. Hospital Clínico Universitario Virgen de la Arrixaca. Ctra. Madrid- agement of antithrombotic drugs in association with endoscopic procedures. Cartagena, s/n. 30120 El Palmar. Murcia, Spain Rev Esp Enferm Dig 2015;107:289-306. e-mail: [email protected] 290 F. ALBERCA-DE-LAS-PARRAS ET AL. REV ESP ENFERM DIG (MADRID) botic risk, and the following therapies may be initiated, 4. Recombinant activated factor VII (Novoseven®): whether sequentially or in parallel with the resolutive en- 90 µg/kg in slow bolus (2-ml ampoule = 1.2 mg). doscopic technique (3,13) (Fig. 1). Effects are seen at 10 to 30 minutes after dosing, 1. Vitamin K1, IV (phytomenadione), 10 mg (one am- and last 12 hours. It normalizes prothrombin time poule) in 100 ml of saline or 5% glucose solution: 10 ml and fixes platelet malfunction. It is highly thrombo- over 10 minutes (1 mg/10 min), the rest in 30 minutes. genic, and its use is currently indicated in hemophil- The effect begins within 6 hours and lasts for 12 hours. iacs with inhibitor, acquired hemophilia, and severe 2. Fresh plasma, 10 to 30 ml/kg; it may be repeated in congenital FVII deficiencies only. The latter two halved dose after 6 hours, as factors have a half-life drugs may not be administered together. of 5-8 hours. Currently, guidelines do not recom- These measures will be applied until the INR becomes mend the use of fresh plasma to reverse anticoagu- stable between 1.5 and 2.5, and bleeding stops. lation except when it is the only measure available, The bleeding risk of patients on anticoagulants is 6.5- nor is this therapy accepted for plasma expansion. fold higher than in those off these drugs (14). 3. Prothrombin complex concentrate containing fac- From a practical standpoint, and in the emergency set- tor IX ((BERIPLEX 500 IU®, OPTAPLEX®, PRO- ting, the right thing to do is to initially use a prothrom- THROMPLEX IMMUNO TIM 4 600 IU®): Equiv- bin complex concentrate, which is the fastest option to alent to 500 ml of plasma. Dosage is estimated achieve reversal. using the following formula: (Desired prothrombin The approach modestly changes with the new oral time - obtained prothrombin time) x kg weight x 0.6. anticoagulants (NOACs) as neither vitamin K nor fresh It may be thrombogenic. plasma have proven effective (15). Attitude will logically ACUTE GI BLEEDING IN AN ANTICOAGULATED PATIENT NOAC ACENOCOUMAROL/WARFARIN Mild Moderate Severe Mild bleeding Severe bleeding bleeding bleeding bleeding Thrombotic risk WITHDRAWAL + + Withdrawal Specific management Prothrombin (endoscopy) complex High Low Sequential therapy Platelets if < 60,000 if concentrate dabigatran, keep adequate urine Vitamin K output No withdrawal Prothrombin complex concentrate Achieve reversal of INR to 1.5-2.5 No risk of relapse Reinitiate anticoagulants (1-5 days) +/- use of IV heparin sodium if high thrombotic risk Fig. 1. Algorithm for acute bleeding in patients on anticoagulation. REV ESP ENFERM DIG 2015; 107 (5): 289-306 Vol. 107, N.º 5, 2015 MANAGEMENT OF ANTITHROMBOTIC DRUGS IN ASSOCIATION WITH ENDOSCOPIC PROCEDURES 291 depend on bleeding severity, paying particular attention erally speaking, only severe FVII and FX deficiencies to renal function especially in patients on dabigatran, as need correction (< 10%). it prolongs its anticoagulating action. This is also the case Activated partial prothrombin time (APTT) is mea- with apixaban and rivaroxaban in hepatocellular dysfunc- sured as an extension of PT. It may be seen in the (de- tion. creasing) use of heparin sodium i.v. and in some patients Antiplatelets and NSAID discontinuation will not al- with LMWH. As regards heparin sodium APTT becomes ter the natural history as effects on hemostasis will linger normal after discontinuation within 4 to 6 hours. How- for a few days; however, we should bear this in mind for ever, should faster reversal be desirable in an emergency lesions that predictably will not heal fast. The fact that as- setting, protamine sulphate is to be used. As for LMWH, pirin and NSAIDs may also be a cause of bleeding is not the effect usually clears within 12-24 h, and APTT nor- to be forgotten. Their effect may, nevertheless, be partly malization may take slightly longer. In the case of LMWH reversed with fresh platelet transfusions when advisable protamine is of limited help. APTT prolongation may also according to bleeding severity. be seen in factor deficiencies (hemophilia A/B/C), and in the presence of lupus anticoagulants. WHAT COAGULATION CHANGES SHOULD BE CONSIDERED BEFORE ENDOSCOPY AND HOW WHAT ENDOSCOPIC TECHNIQUES ARE CAN THEY BE CORRECTED? (TABLE I) CONSIDERED TO BE ASSOCIATED WITH A HIGHER BLEEDING RISK? In extreme situations (fewer than 10,000 platelets, INR higher than 6, etc.) with active bleeding, we must cor- Bleeding risk has been stratified by expert consensus, rect such changes before the endoscopic technique, as this as indicated in clinical guidelines (2) and manuals, into may stop the bleeding and render the technique –and its two risk levels (Table II). Basically agreeing with this potential complications– unnecessary. classification, we may importantly increase risk strat- In patients with thrombocytopenia our attitude will de- ification, as an endoscopic sphincterotomy in a patients pend on procedure type: for high-risk procedures platelet with multiple conditions is clearly unlike the excision of