management of antithrombotic drugs in association with

SPECIAL ARTICLE

Rev esp enfeRm Dig (MadridVol. 107, N.º 5, pp. 289-306, 2015

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

1130-0108/2015/107/5/289-306Revista española De enfeRmeDaDes DigestivasCopyRight © 2015 aRán eDiCiones, s. l.

ABSTRACT

The use of antithrombotic drugs (anticoagulants and antiplatelets) has increased significantly with our understanding of cardiovascular risk. Encountering patients on these therapies who require an endoscopic procedure is therefore increasingly common. At decision making the endoscopist must rely on other specialists (basically cardiologists and hematologists) as risk not only lies among increased bleeding odds but also in the possibility of thrombosis following dose discontinuation or change. Understanding the pharmacology, indications, and risks of endoscopic procedures is therefore essential if sound decisions are to be made. The efforts of four scientific societies have been brought together to provide clinical answers on the use of antiplatelets and anticoagulants, as well as action algorithms and a practical protocol proposal for endoscopy units.

Key words: Antithrombotic drugs. Antiplatelets. Anticoagulants. Endoscopic procedures.

INTRODUCTION

For many years single or dual anticoagulation and an-tiaggregation have become a therapeutic and preventive tool, particularly regarding highly prevalent cardiovascu-lar diseases. This, together with increased interventionism among endoscopic techniques, represents a higher risk. However, such risk is not only derived from potential bleeding but also from thrombotic risk (1), its obviation by endoscopists being unacceptable.

Scientific societies have issued a number of guidelines and recommendations for such situations (2-8) and com-pliance with them have even brought about secondary

benefits in terms of both financial savings and thrombosis incidence (9).

A first Spanish version of these guidelines was pub-lished in 2010 (6). However, the emergence of new drugs and of significant data in the literature has prompted a revised and updated version, for which the consensus of the Working Group of Thrombosis of Spanish Cardiology Society (GTCV-SEC) and the Spanish Society of Throm-bosis and Hemostasis.

An analysis of the scarce adherence to guidelines and of their applicability (10,11) suggests that less academic, more practical guidelines should be developed, since the criteria for early drug re-introduction are approached by cardiologists (12), which conditions follow-up by gastro-enterologists for fear of early bleeding.

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 gastroenterologists in their decision-making.

WHAT MANAGEMENT WOULD BE APPROPRIATE FOR ACUTE GI BLEEDING IN PATIENTS ON ANTICOAGULANTS OR ANTIPLATELETS?

As is usual in medical practice, decision making de-pends upon risk and severity. In patients with high throm-botic risk (for example, with mitral prosthesis) and mild bleeding anticoagulation withdrawal is inappropriate –pharmacological and endoscopic measures may be con-sidered while leaving reversal aside.

In general, anticoagulants must be discontinued imme-diately for severe bleeding. In the absence of severity cri-teria the approach should hinge upon the patient’s throm-

Alberca-de-las-Parras F, Marín F, Roldán-Schilling V, Carballo-Álvarez F. Man-agement of antithrombotic drugs in association with endoscopic procedures. Rev Esp Enferm Dig 2015;107:289-306.

Received: 25-01-2015Accepted: 16-02-2015

Correspondence: Fernando Alberca de las Parras. Unit of Digestive Dis-eases. Hospital Clínico Universitario Virgen de la Arrixaca. Ctra. Madrid-Cartagena, s/n. 30120 El Palmar. Murcia, Spaine-mail: [email protected]

*Guidelines endorsed by the Working Group of Thrombosis of Spanish Car-diology Society (GTCV-SEC), Spanish Society of Gastrointestinal Endos-copy (SEED), Spanish Society of Digestive Diseases (SEPD) and Spanish Society of Thrombosis and Hemostasis.

290 F. ALBERCA-DE-LAS-PARRAS ET AL. Rev esp enfeRm Dig (maDRiD)

Rev esp enfeRm Dig 2015; 107 (5): 289-306

botic risk, and the following therapies may be initiated, whether sequentially or in parallel with the resolutive en-doscopic technique (3,13) (Fig. 1).

1. Vitamin K1, IV (phytomenadione), 10 mg (one am-poule) in 100 ml of saline or 5% glucose solution: 10 ml over 10 minutes (1 mg/10 min), the rest in 30 minutes. The effect begins within 6 hours and lasts for 12 hours.

2. Fresh plasma, 10 to 30 ml/kg; it may be repeated in halved dose after 6 hours, as factors have a half-life of 5-8 hours. Currently, guidelines do not recom-mend the use of fresh plasma to reverse anticoagu-lation except when it is the only measure available, nor is this therapy accepted for plasma expansion.

3. Prothrombin complex concentrate containing fac-tor IX ((BERIPLEX 500 IU®, OPTAPLEX®, PRO-THROMPLEX IMMUNO TIM 4 600 IU®): Equiv-alent to 500 ml of plasma. Dosage is estimated using the following formula: (Desired prothrombin time - obtained prothrombin time) x kg weight x 0.6. It may be thrombogenic.

4. Recombinant activated factor VII (Novoseven®): 90 µg/kg in slow bolus (2-ml ampoule = 1.2 mg). Effects are seen at 10 to 30 minutes after dosing, and last 12 hours. It normalizes prothrombin time and fixes platelet malfunction. It is highly thrombo-genic, and its use is currently indicated in hemophil-iacs with inhibitor, acquired hemophilia, and severe congenital FVII deficiencies only. The latter two drugs may not be administered together.

These measures will be applied until the INR becomes stable between 1.5 and 2.5, and bleeding stops.

The bleeding risk of patients on anticoagulants is 6.5-fold higher than in those off these drugs (14).

From a practical standpoint, and in the emergency set-ting, the right thing to do is to initially use a prothrom-bin complex concentrate, which is the fastest option to achieve reversal.

The approach modestly changes with the new oral anticoagulants (NOACs) as neither vitamin K nor fresh plasma have proven effective (15). Attitude will logically

Fig. 1. Algorithm for acute bleeding in patients on anticoagulation.

ACUTE GI BLEEDING IN AN ANTICOAGULATED PATIENT

No withdrawal

High Low

Mild bleeding

Moderate bleeding

Severe bleeding

Mild bleeding Severe bleeding

Sequential therapy

Vitamin K

Prothrombin complex

concentrate

Achieve reversal of INRto 1.5-2.5

No risk of relapse

Reinitiate anticoagulants (1-5 days) +/- use of IV heparin sodium if high thrombotic

risk

NOAC ACENOCOUMAROL/WARFARIN

Thrombotic risk WITHDRAWAL

Withdrawal Specific management (endoscopy)

Platelets if < 60,000 if dabigatran, keep adequate urine

output

Prothrombin complex

concentrate

+ +

Vol. 107, N.º 5, 2015 MANAGEMENT OF ANTITHROMBOTIC DRUGS IN ASSOCIATION WITH ENDOSCOPIC PROCEDURES 291


depend on bleeding severity, paying particular attention to renal function especially in patients on dabigatran, as it prolongs its anticoagulating action. This is also the case with apixaban and rivaroxaban in hepatocellular dysfunc-tion.

Antiplatelets and NSAID discontinuation will not al-ter the natural history as effects on hemostasis will linger for a few days; however, we should bear this in mind for lesions that predictably will not heal fast. The fact that as-pirin and NSAIDs may also be a cause of bleeding is not to be forgotten. Their effect may, nevertheless, be partly reversed with fresh platelet transfusions when advisable according to bleeding severity.

WHAT COAGULATION CHANGES SHOULD BE CONSIDERED BEFORE ENDOSCOPY AND HOW CAN THEY BE CORRECTED? (TABLE I)

In extreme situations (fewer than 10,000 platelets, INR higher than 6, etc.) with active bleeding, we must cor-rect such changes before the endoscopic technique, as this may stop the bleeding and render the technique –and its potential complications– unnecessary.

In patients with thrombocytopenia our attitude will de-pend on procedure type: for high-risk procedures platelet count must be higher than 50,000/µl; for low-risk proce-dures a platelet count > 20,000/µl is acceptable. Plate-let deficiency is corrected on a schedule using infusions during the technique and immediately before it. It suffices with increasing platelet numbers to 40,000-50,000/mm3. Each platelet unit increases the count by 5,000-10,000 per mm3, and the dose is 1 U/10 kg of body weight. In case of platelet refractoriness with severe bleeding evidence the use of recombinant activated factor VIl (rVlla) (Novosev-en®) is recommended, with hemostatic action in patients with severe thrombocytopenia and thrombocyte disease, at a dose of 90 to 150 µg/kg every two hours intravenous-ly until bleeding resolution.

Prothrombine activity lower than 50% (vs. INR > 1.4) is usually found in chronic liver disease, factor VII and X deficiencies, and oral anticoagulation. In such case the above schemes are used for anticoagulated patients. Gen-

erally speaking, only severe FVII and FX deficiencies need correction (< 10%).

Activated partial prothrombin time (APTT) is mea-sured as an extension of PT. It may be seen in the (de-creasing) use of heparin sodium i.v. and in some patients with LMWH. As regards heparin sodium APTT becomes normal after discontinuation within 4 to 6 hours. How-ever, should faster reversal be desirable in an emergency setting, protamine sulphate is to be used. As for LMWH, the effect usually clears within 12-24 h, and APTT nor-malization may take slightly longer. In the case of LMWH protamine is of limited help. APTT prolongation may also be seen in factor deficiencies (hemophilia A/B/C), and in the presence of lupus anticoagulants.

WHAT ENDOSCOPIC TECHNIQUES ARE CONSIDERED TO BE ASSOCIATED WITH A HIGHER BLEEDING RISK?

Bleeding risk has been stratified by expert consensus, as indicated in clinical guidelines (2) and manuals, into two risk levels (Table II). Basically agreeing with this classification, we may importantly increase risk strat-ification, as an endoscopic sphincterotomy in a patients with multiple conditions is clearly unlike the excision of a pedicled polyp. It is therefore important that the endos-copist’s view be taken into account particularly after the procedure when considering antiplatelets/anticoagulant reintroduction times.

– Colonoscopy: This is a technique that in itself does not increase bleeding risk in patients with coagula-tion issues.

– Biopsy: Bleeding risk during biopsy taking is ex-tremely rare, approximately 1‰ (16).

– Polypectomy: Polypectomy-related major bleeding risk in several extensive series oscillates between 0.05% and 1%, but it may be up to 4.3% for polyps greater than 1 cm, and 6.7% for those larger than 2 cm (17-19). This risk seemingly increases for pol-yp sizes above 2 cm, and pedunculated polyps have been seen to bleed more severely than sessile ones, hence associating a risk-reducing technique such as

Table I. Drug-related hemostatic changes

Agent Normal hemostasis Prot. time/INR PTTA

Antiplatelets 2-10 days Normal Normal

NSAIDs 1-3 days Normal Normal

IV heparin sodium 2-4 hours Longer * Longer +++

LMW heparin 12 hours Normal Normal

Oral anticoagulants 4-6 days Longer +++ Longer *

NOACs 12 h-4 daysNormalLonger + with rivaroxaban

NormalLonger + with rivaroxaban



the use of prophylactic adrenaline, endoloop, and endoclips is advisable for patients with coagulation issues (19).

Two types of bleeding exist: Immediate bleeding when nurturing vessels are improperly coagulated, and delayed bleeding, after 1 to 14 days, which is more se-rious; this should be considered before antiplatelets re-introduction.

In antiaggregated patients its role for GI bleeding has been poorly analyzed; in an animal study, 7-mm lesions in the colon showed an increase in bleeding time among those on aspirin vs. no therapy (155 seconds vs. 169 seconds – p < 0.05) (20); similarly bleeding has been found to be increased at biopsy sites in patients on aspi-rin versus controls or NSAIDs (21). However, these ex-perimental studies have found no clinical application in the literature regarding patients undergoing endoscopic procedures.

Aspirin and NSAIDs have not been shown to increase bleeding risk during polypectomies, albeit these are the retrospective or limited-analysis studies on which both the ASGE and Euroean guidelines were based; these guidelines do not recommend antiplatelet discontinu-ation before endoscopy (22). However, a prospective study amongst them, while not showing increased com-plications, does find trace amounts of blood in the stools of up to 6.3% of patients versus 2.1% of subjects on placebo (23). The most relevant complication, name-ly delayed bleeding, was specifically discussed in a case-control study, thus confirming no increased bleed-ing in the subgroup on aspirin versus placebo; however, the use of aspirin was not studied beyond 3 days fol-lowing the procedure, and bleeding episodes have been described up to 19 days afterwards (24). Hence, some authors recommend that antiplatelets be discontinued within 4 to 7 days of risky techniques, and reintroduced after 7 days when used as secondary prevention, or 14 days when used as primary prevention, following pol-ypectomy (25).

In anticoagulated patients bleeding risk after polypec-tomy is increased, even when anticoagulation is discontin-ued before the procedure (2.6% vs. 0.2%, p = 0.005) (26).

In an extensive registry of 120,886 procedures in 95,807 patients bleeding was only identified in 2% of patients having discontinued heparin (27). Another paper only describes 3 bleeding episodes among 225 polypectomies for 123 anticoagulated patients where anticoagulants had been discontinued previously (28). Recently, a paper was reported where polyps smaller than 10 mm were excised in 70 patients on acenocoumarol, which found higher bleeding rates in the group treated with a hot loop versus a cold loop, both regarding early (23% vs. 5.7%) and de-layed (14% vs. 0%) bleeding (29).

ERCP and sphincterotomy. The incidence of bleed-ing falls between 2.5% and 5% (30). Different studies define anticoagulation as a clear risk factor for bleed-ing. Regarding antiaggregation only two retrospective studies (31,32) have discussed this effect, with incon-clusive results as considered in the American Society’s clinical guidelines, but with a risk for acute bleeding in one of them (32) of 9.7% vs. 3.9% (ASA vs. controls, p < 0.001), and a risk for delayed bleeding of 6.5% vs. 2.7% (p = 0.04), which suggests that, except for emergency settings, discontinuation is desirable at least 7 days be-fore the technique. Balloon sphincteroplasty has been proposed as an alternative technique for patients in need of urgent bile duct opening and with coagulation disor-ders (33), as well as in the transient use of biliary pros-theses without sphincterotomy.

Enteroscopy. The simple technique seems to pose no risk whatsoever, but should be considered a risky tech-nique when used as a therapeutic, interventional approach, which is the case in up to 64% of cases (34).

Endoscopic submucosal dissection (ESD). In a recently reported retrospective paper in patients undergoing 1,166 ESDs delayed bleeding was analyzed, and the use of anti-thrombotic medications was shown to be an independent risk factor, higher still when two drugs were used (no sta-tistical significance) (36).

Percutaneous endoscopic gastrostomy (PEG). Sev-eral papers exist that retrospectively discuss the role of antithrombotics in this procedure, and fail to detect any increased bleeding risk when aspirin and clopidogrel are used, even concomitantly (36).

Table II. Bleeding risk during endoscopic procedures

Low (< 1%) High (1-6%)

Diagnostic endoscopy with or without biopsy Polypectomy

Diagnostic endoscopic retrogade cholangiopancreatography Laser coagulation and ablation

Biliary stent insertion without sphincterotomy Sphincterotomy

Echoendoscopy Benign or malignant stenosis dilation

Push enteroscopy Percutaneous endoscopic gastrostomy

EUS-FNAP

Balloon enteroscopy

Submucosal dissection and mucosectomy



WHICH ARE THE PRIMARY ANTIPLATELETS AVAILABLE IN SPAIN?

Antiplatelets are drugs that act by inhibiting platelet functioning at various levels, as seen in figure 2. Its classi-fication depends on their mechanism of action (Table III).

There is a wide spectrum of actions, and both antiplate-lets effects and duration seem to vary for each one of them (Table IV).

A factor for consideration is their association with non-steroidal anti-inflammatory drugs (NSAIDs), which may enhance antiaggregating effects.

The novel ADP receptor blockers are key to the prevention of acute coronary syndrome, mainly following the placement of stents. From a gastroenterologist’s standpoint, we should know their antiaggregation effect is immediate and stronger than that of aspirin, and therefore we should discontinue them within 5 to 7 days of a high-risk procedure (37) (Table V).

WHAT ARE THE PRIMARY INDICATIONS OF ANTIPLATELETS?

As gastroenterologists we must now these indications, as well as the impact that the discontinuation of a properly indicated drug may have for patients (8).

Indications include (38):– AMI with or without ST elevation: dual antiaggrega-

tion (DA), aspirin plus clopidogrel (or prasugrel or ticagrelor), for 12 months.

– Unstable angina or AMI without ST elevation not requiring coronariography: DA for 1 to 12 months.

– Metallic stent placement: DA up to 12 months.– Antiproliferative drug-sluting stents: DA for 12

months.– After fibrinolysis (up to 12 months).– Stable coronary disease: Only aspirin (clopidrogrel

in aspirin intolerants).– Heart disease primary prevention in patients at risk:

No DA necessary, only aspirin or clopidogrel, which may be discontinued without risk.

– AMI without reperfusion therapy (at least 1 month, ideally up to 12 months).

– Ischemic stroke associated with large-vessel and small-vessel arteriosclerosis (aspirin, cilostazol or clopidogrel) (39).

WHAT IS THE RISK OF DISCONTINUING A PROPERLY INDICATED ANTIPLATELET THERAPY?

Early dual (aspirin + clopidogrel) antiplatelet therapy discontinuation entails a stent thrombosis risk of 29% (8%-30%) (40). Discontinuing dual antiaggregation after stent implantation increases the risk for potentially-le-thal subacute stent thrombosis by 15% to 45% within a month. In the secondary prophylaxis of AMI risk is higher (3-fold) for discontinuation within 14 days. Risk also in-creases within 3 days of balloon angioplasty (41).

Fig. 2. The mechanism of action of antiplatelets.

PAR-1PAR-4

Thrombin

P2Y1

P2y12

ADP

TXA2RThromboxane A2

GPIIb-I IIa Fgno.

PLATELET

Dense granule

Prot. G Pepducins

cAMP

Phosphodiesterase DipyridamoleCilostazol

AMP

AspirinTrifusal

Cyclooxygenase

Arachidonic acid EptifatideTirofiban

Abciximab

ClopidogrelTiclopidine



ARE ALL ANTIPLATELETS ALIKE IN ANTIPLETELET POWER AND SECONDARY BLEEDING RISK? DO ALL ANTIPLATELETS DOSES BEHAVE THE SAME WAY?

Aspirin does not contraindicate any diagnostic or ther-apeutic procedure (7).

No differences have been found between aspirin 100 mg and 300 mg in antiplatelet power; only aspirin 300 mg in three daily 100 mg doses has a somewhat high-er antiplatelet strength, hence no differential management is warranted for patients according to their dosage (42).

Table III. Classification of antiplatelets

Types Drugs

Platelet adhesion inhibitors Von Willebrand factor inhibitors

Act on platelet activation mediators

TXA2 production inhibitors

Acetylsalicylic acid (AAS®, Adiro®, Bioplak®, Therasacard®, Tromalyt©, generic)IndobufenTriflusal (Anpeval®, Disgren®, generic)Sulfinpyrazone

Phosphodiesterase inhibitors

Dipyridamole (Persantin®) DitazolePentoxifyllineCilostazol (for intermittent claudication)Trapidil

ADP receptor antagonists (thienopyridines)

Ticlopidine (Ticlid®)Clopidogrel [Plavix®, Iscover®, Duoplavix®, (Clopidogrel 75 + aspirin 100)]Ticagrelor (Brilique®)Prasugrel (Effient®)

GP IIb/IIIa receptor antagonists

Intravenous useAbciximabEptifibatideTirofiban (Aggrastat®)

Oral use XemilofibanOrbofibanLotrafiban

Analogs of natural platelet aggregation inhibitors Epoprostenol (for pulmonary hypertension)Iloprost (for peripheral artery disease)

Table IV. Duration of antiaggregation and activity of antiplatelets and NSAIDs

Antiplatelets NSAIDs

10 d. Ticlopidine

Strong (7 d.):Piroxicam, tenoxicam, indomethacin, ketorolac, flurbiprofen7 d.

PrasugrelTriflusal

5 d.ClopidogrelAspirinTicagrelor Weak (12 h.):

Meloxicam, sulindac, nabumetone, diflunisal, paracetamol, dipyrone

1 d.DipyridamoleTirofiban

Table V. Pharmacodynamics of new antiplatelets

Clopidogrel Prasugrel Ticagrelor

Class Thienopyridine Thienopyridine Triazolopyrimidine

Reversibility Irreversible Irreversible Reversible

Activation Prodrug. Limited by metabolism Prodrug. Not limited by metabolism Active drug

Onset of effect 2-4 h 30 minutes 30 minutes

Duration of effect 3-10 days 5-10 days 3-4 days

Withdrawal before major surgery 5 days 7 days 5 days



No prospective, randomized studies in the non-cardiac surgery setting have been carried out to assess the risk for surgical bleeding in association with clopidogrel alone or plus aspirin in stent carriers, and increased bleeding has only been described for associated aspirin doses in excess of 200 mg.

Ticagrelor and prasugrel seemingly have a greater an-tiplatelet effect as compared even with clopidogrel, hence the bleeding risk related to these new antiplatelets would be higher.

In view of this information -with a low evidence level- clopidogrel and ticagrelor should be discontinued 5 days, and prasugrel 7 days, before any procedure with high bleeding risk (43).

IS ANTIAGGREGATION, WHETHER SINGLE OR DUAL, A CONTRAINDICATION FOR ANY ENDOSCOPIC TECHNIQUE?

No convincing data are available that turn single an-tiaggregation into an absolute contraindication for any endoscopic technique (7), but ASA –where this algorithm may be used somewhat safely– and novel antiplatelets –which may require a more careful assessment– should probably be considered on an individual basis.

As regards dual antiaggregation no papers discuss its actions, although in view of the current data intervention-al procedures should likely be avoided during its use. At any rate, the decision should be made based on endoscop-ic and thrombotic risk: In the presence of low endoscopic risk both drugs may be used; regarding high risk, this will hinge upon thrombotic risk –if low, clopidogrel will be discontinued and the procedure will be performed under aspirin; when high, attempts will be made to delay the endoscopic procedure or a bridge therapy may be consid-ered with glycoprotein IIb-IIIa inhibitors.

WHAT IS IN PRACTICE THE REGIMEN USED TO REVERSE ANTIAGGREGATION?

In all cases delaying therapy until thrombotic risk is minimal is most desirable; in cases on dual antiaggrega-tion, clopidogrel can be discontinued 7 days before while maintaining aspirin as per the prescribed regimen.

The different guidelines (6) have posited suggestions for managing antiaggregation that are mainly based on defin-ing whether indication is urgent, and assessing extant indi-cations: For primary and secondary indications, consider-ing their low thrombotic risk, aspirin may be withdrawn; aspirin is to be maintained for all other scenarios.

In a consensus paper between the American College of Cardiology and the American College of Gastroenterolo-gy time periods are established from the time of coronar-iography to stent implantation or angioplasty regarding

actions to be taken with antiplatelets. The cut-off is set in 14 days to avoid elective procedures or to undertake them with aspirin alone; waiting time should be 30 to 45 days for angioplasty with metallic stents, and 1 year for cov-ered stents (15).

The indication of a bridge therapy with LMWH in an-tiaggregated patients undergoing endoscopy with an add-on procedure is now much debated. No evidence exists for its benefits (40), and the fact that it will not effectively protect from thrombosis in patients with coronary stents seems clear, although its potential protective role in situ-ations at risk of thrombosis and bleeding with relatively undelayable endoscopies has been suggested because of its antiaggregating role.

Upon antiplatelet drug reintroduction we should re-assess both bleeding and thrombosis risks. Initially, they will be reintroduced at 24 hours after the endoscopic pro-cedure, except in situations with high bleeding risk, where a cardiologist or neurologist or hematologist should be in-cluded in the assessment.

Based on this we developed a working paper to aid cli-nicians in their decision-making before endoscopy pro-cedures, delineating a procedure’s bleeding risk and then defining its thrombotic risk (Fig. 3).

WHAT IS THE ROLE OF A GLYCOPROTEIN IIb-IIIa INHIBITOR IN THE REVERSAL OF ANTIAGGREGATION?

In a prospective, non-controlled study of 30 patients undergoing undelayable major surgery within 6 months following the placement of a coated stent a glycoprotein IIb-IIIa inhibitor, tirofiban i.v. (Fig. 4), was used as bridge therapy, with clopidogrel being discontinued 5 days be-fore, with no resulting coronary or bleeding condition: this represents an interesting possibility for this subgroup of patients (44). However, no other papers have been re-ported on this topic, hence we must follow on cautiously and consider it an option only in the setting of joint pro-tocols involving cardiology and hematology departments.

WHICH ARE THE PRIMARY ANTICOAGULANTS AVAILABLE IN SPAIN (OTHER THAN HEPARINS)? (TABLE VI)

Figure 5 shows where primary anticoagulants act. Most common options, warfarin and acenocoumarol, are well known and possess a longer half-life, which may lead to consider bridge therapies with low molecular weight hep-arin in settings with bleeding risk.

New oral anticoagulant (NOAC) drugs have been mar-keted of late, including direct thrombin inhibitors (dab-igatran) and factor Xa inhibitors (rivaroxaban and apix-aban). Edoxaban remains unavailable as of today. These



drugs have no specific antidote, therefore it is advisable that sites implement action protocols for the management of bleeding complications, surgery preparation, and inva-sive procedures in patients receiving NOACs. Their anti-coagulant effect lasts for approximately 24 hours, but may be longer in the presence of renal failure (up to 4 days), each one having a different clearance rate. Knowing this is therefore crucial to establish a NOAC discontinuation

Fig. 3. Antiplatelet discontinuation schedule.

ENDOSCOPY IN ANTIAGGREGATED PATIENTS

Perform endoscopy with aspirin

Clopidogrel or ticlopidine Dual antiaggregation

Perform endoscopy

+/- Tx suspension

Suspend Tx +/- replace with aspirin

Assess bridge therapy with

tirofiban

LOW:Primary preventionUncovered stents (> 3 m)Covered stents (> 15 m)

Perform endoscopy

Endoscopy with high bleeding risk Endoscopy with low bleeding risk

MID:uncovered stents (1-3 m)covered stents (12-15 m)

HIGH:uncovered stents (1 m)covered stents (12 m)acute coronary syndrome +/- stent (12 m)

Aspirin or trifusal

Clopidogrel

Suspend Tx +/- replace with aspirin

Delay endoscopy

Perform endoscopy

Delay endoscopy

Perform endoscopy

Thrombosis risk

CLOPIDOGREL

ASPIRIN

TIROFIBAN

Initiate with oral diet 300 mg/24 hrs, then 75 mg/day

Fig. 4. Tirofiban bridge therapy schedule.

If renal failure (CrCl < 30 mL/min), reduce dosage by 50% and double both discontinuation time (8 hrs) and reintroduction time (4 hrs) with respect to the procedure

End 6 hrs after onset of clopidogrel

TreatmentNo treatment

0.4 mcg/kg/min/30 min, then 0.1 mcg/kg/min. (*)

Procedure

(*)

-5 -4 -3 -2

+2h-4h

-1 -0 +1 +2 +3 +4 +5

Table VI. Classification of anticoagulants (except heparin)

Type Drugs

Vitamin K inhibitionAcenocumarol (Sintrom®)Warfarin (Aldocumar®)Tecarfarin

Direct thrombin inhibitors

Dabigatran (Pradaxa®)DesirudinLepirudinArgatrobanBivalirudin

Direct factor Xa inhibitors Rivaroxaban (Xarelto®)Apixaban (Eliquis®)Edoxaban (Savaysa®)

Selective factor Xa inhibitors Fondaparinux (Arixtra®)

oror



scheme before an interventional procedure. While they prolong bleeding time, coagulation tests are useless for level monitoring, albeit dabigatran will be considered to no longer have anticoagulant effect when APTT becomes normal (45). Using therapeutic doses the APTT value may be longer than the control by a factor of 2 or 3.

In patients undergoing procedures with low bleeding risk discontinuation could be restricted to just one dose (that is, 10 h for dabigatran and apixaban; 20 h for ri-varoxaban) or could even be skipped for gastroscopy or colonoscopy, with or without biopsy taking; in the pres-ence of high risk (Table VII) they should be discontinued for between 2 to 3 times the half-life (45). These drugs are reintroduced after 24 hrs as their fast action provides an-ticoagulation immediately. However, this may be delayed for 2 days for procedures with high bleeding risk.

Dabigatran and rivaroxaban increase the risk of GI bleeding by 1.5 as compared to warfarin, whereas apix-aban is similar to the latter (46).

WHAT INDICATIONS DO ANTICOAGULANTS HAVE? (TABLE VIII)

A gastroenterologist should know his trade, even more so when indications for these drugs, which have reduced vascular mortality in patients at risk, are increasingly nu-merous.

Regarding atrial fibrillation, their indication is estab-lished for patients with valve involvement and patients with thrombotic risk according to the CHA

2DS

2-VASc (47)

classification (C- congestive heart failure or left ventric-

Fig. 5. The mechanism of action of anticoagulants

TISSUE FACTOR

PLASMA CLEARANCE CASCADE

PROTHROMBIN (factor II)

EXTRINSIC PATHWAY (factor VII, tissue factor)

INTRINSIC PATHWAY (factors IX, XI, XII)

Coagulation factor activation in the liver

(mediated by vitamin K)

ACENOCOUMAROL WARFARIN

FONDAPARINUX

ENOXABANRIBAROXABAN

APIXABAN

LMWH

BIVALIRUDINA

THROMBIN (factor IIa)

DABIGATRAN

FACTOR Xa

FIBRINOGEN FIBRIN

THROMBUS

Table VII. NOAC management in high bleeding-risk procedures

Dabigatran Rivaroxaban Apibaxan

CrCl -5 -4 -3 -2 -1 0 +1 +2 +3 -5 -4 -3 -2 -1 0 +1 +2 +3 -5 -4 -3 -2 -1 0 +1 +2 +3

≥ 80 Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes

50-80 Yes Yes No No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes

30-50 Yes No No No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes

≤ 30 n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i. n.i.

APTT Yes No No



ular dysfunction, H- hypertension, A- age ≥ 75, D- dia-betes, S- prior stroke or thrombotic accident (CVA, TIA, PTE), V- vascular disease (prior myocardial infarction, peripheral arteriopathy or aortic plaques), A- age between 65 and 74, and S- female sex). Anticoagulation is deemed indicated when a criterion is met in the setting of atrial fibrillation (48) (Table IX). The higher the number of cri-teria met, the higher the risk for thrombosis should antico-agulation be discontinued (49).

On the other hand, when making decisions for patients with heart disease the HAS-BLED score is also used, which assesses bleeding risk:

– H- Hypertension: 1 point if not controlled, with SBP ≥ 160.

– A- Impaired renal (1 point) or hepatic (1 point) or renal and hepatic (2 points) function.

– S- History of stroke (1 point), especially of the la-cunar type.

– B- History of bleeding, anemia, or predisposition to bleeding (1 point).

– L- Labile, unstable or high INR, or INR with less than 60% of time within the therapeutic range (1 point).

– E- Age ≥ 65 years (1 point).– D- Drugs and/or alcohol: antiplatelet drugs (1 point),

drinking 8 or more alcohol-containing beverages per week (1 point), or both (2 points).

A score of 3 or above suggests a higher bleeding risk the year after anticoagulation, hence increased follow-up or dose reductions for anticoagulants such as dabigatran might be indicated.

IS ANTICOAGULATION A CONTRAINDICATION FOR ANY ENDOSCOPIC TECHNIQUE?

– Yes, for endoscopic techniques with high bleeding risk.

– No, not for diagnostic procedures, including biopsy taking (7).

– In the emergency setting any technique may be con-sidered after reversing anticoagulation.

There is doubt about the adequate INR value for en-doscopic procedures with high bleeding risk. Endoscop-ic guidelines mention levels above 1.4 on the day of the procedure (laboratory monitoring is mandatory), although some cardiology guidelines advocate for levels below 2.0. Bleeding risk, as already mentioned, continues to increase

Table VIII. Indications of oral anticoagulants

Indication Recommended INR Duration

Deep venous thrombosis 2-3 Postoperative or reversible risk factors > 3 months

Pulmonary embolism 2-3* Idiopathic: > 6 months* Relapsing or persistent cause: indefinite

Selective cardioversion 2-3From three weeks before cardioversion to at 4 weeks after cardioversion

Biological valve prostheses or mitral valve disease (includes mitral prolapse) with some of the following: LA > 55 mm, thrombi inside, A-Fib, prior PTE

2-3 Indefinite

Dilated cardiomyopathy with LVEF < 25% 2-3 Indefinite

Extensive prior AMI with some of the following: intraventricular thrombi, dilated LV, LVEF < 35%, CHF

2-3 3 months

Recurrent AMI 2.5-3.5 Indefinite

Mechanical valve prostheses (Medtronic May, anticoagulation, Carbomedics, St Jude)

2.5-3.5Indefinite: (if PTE during refer to Cardiology to consider adding antiplatelets)

Mechanical valve protheses (older, Starr-Edwards type) 3-4.5 Indefinite

Antiphospholipid syndrome 2.5-3.5 Indefinite

Atrial fibrillation, CHA2DS

2-VASc ≥ 1 2-3 Indefinite

Table IX. Thrombotic risk in A-Fib

CHA2DS

2-VASc score

Ref. Condition Points

C Congestive heart failure / LV dysfunction 1

H Hypertension 1

A Age ≥ 75 yrs 2

D Diabetes 1

S Prior stroke or TIA or PTE 2

V Vascular disease (AMI, atheromatosis) 1

A Age = 65-74 yrs 1

S Female sex 1



even when guidelines are properly followed, thus we may assume the 1.4 value as general recommendation, even if higher levels might be endorsed in situations with very high thrombotic risk, such as the use of metallic prostheses.

WHICH CONDITIONS ENTAIL A HIGHER THROMBOTIC RISK WHEN REVERSING ANTICOAGULATION?

The ASGE (2) defines thrombotic risk as comprising two levels (Table X).

This has been generally endorsed by other authors, in manuals (50), reviews (51), and clinical guidelines (7), even though the CHA

2DS

2-VASc classification is fa-

voured in cardiology environments, specifically when referring to atrial fibrillation. Distinguishing three levels of thrombotic risk might be practical when considering the various options available to act and to apply bridge therapies (52) (Table XI), and this is what we include in our proposed algorithm. We distinguish between high and very high risk mainly for practical purposes, since only in very high risk settings have the prophylactic benefits of enoxaparin in divided doses, as opposed to other LM-WHs, been demonstrated.

WHICH IS THE MOST PRACTICAL REGIMEN TO REVERSE ANTICOAGULATION?

In a decision analysis based on the implementation of the ASGE clinical guidelines (2,4) the following strate-gies were deemed most cost-effective (53):

– In patients with low thrombotic risk (for instance atrial fibrillation without valve disease) or if pol-ypectomy possibilities exceed 60%, stop warfarin 5 days before.

– In screening colonoscopies, where polyps are ex-pected in over 35% of patients, maintain warfarin at reduced dosage.

– For polypectomy possibilities equal to or lower than 1%, continue with warfarin.

There is a somewhat defined agreement on the right regimen, according to both endoscopy type and anticoag-ulation indication (9).

Attitude will be defined based on the endoscopic pro-cedure’s bleeding risk, and then action will be according to the type of anticoagulant the patient is on: If the pa-tient is taking acenocoumarol or warfarin (the latter must be discontinued for one extra day as compared to aceno-coumarol) we must initiate a bridge therapy with LMWH adjusted to thrombotic risk. If on a NOAC, decisions will be made depending on creatinine clearance (CrCl), as the discontinuation scheme varies depending upon the molecule in use (Fig. 6). Whether a bridge therapy with LMWH should be used for patients previously on a NOAC is subject to debate, but should discontinuation be adjusted according to CrCl the patient will not be unpro-tected or overmedicated.

The reintroduction of an anticoagulant after the proce-dure will usually take place after 6 hours, except in high-risk situations, where it may be delayed 24 hours should thrombotic risk allow it. Subjects on bridge therapy will be dosed at 24 hours, and LMWH may be extended and anticoagulant reintroduction delayed when bleeding risk is high, always with agreement by a cardiologist, neurol-ogist or hematologist.

WHAT IS THE ROLE OF LOW MOLECULAR WEIGHT HEPARIN IN THE REVERSAL OF ANTICOAGULATION?

In their guidelines, the ASGE (4) suggests a manage-ment scheme using low molecular weight heparin as bridge for high thrombotic risk patients; the problem is that neither doses nor the proper timing for heparin rein-troduction have been defined, although this is deemed to oscillate between 2 and 6 hours after the procedure, and consensus is to be sought with the remaining specialists

Table XI. Thrombosis risk during anticoagulation

Low High Very high

A-Fib with CHA2DS

2-VASc = 1-2 A-Fib with CHA

2DS

2-VASc > 3-5, PTE

Antiphospholipid syndromePrevious multiple thromboses

A-Fib with CHA2DS

2-VASc > 5

Mechanical mitral or tricuspid prosthesis

Table X. Thrombosis risk in patients on anticoagulants (ESGE)

Low risk (1-2% if anticoagulation is interrupted for 4-7 days) High risk

– Deep venous thrombosis– Paroxysmal or chronic A-Fib not complicated with valve disease – Biological valve prosthesis– Metallic aortic prosthesis

– A-Fib with valve disease– Metallic mitral prosthesis– Metallic valve with previous thrombotic event



involved. Other authors suggest a reduction of LMWH doses before interventional procedures, with early reintro-duction in high-risk patients, even if this is described for diagnostic catheterisms rather than techniques with high bleeding risk in an assay (Table XII).

LMWH has been used in high and double doses (54). However, there is no clear evidence regarding its supe-riority over low, single doses, but bleeding does seem to increase (7). Many coagulation clinics establish dose ti-tration regimens according to thrombotic risk, and every site should define theirs in agreement with hematologists and cardiologists.

The effectiveness and safety of various LMWH schemes as bridge therapy for the management of antico-agulation withdrawal has been demonstrated in non-ran-domized studies with enoxaparin sodium (55), dalteparin (56) or bemiparin (57), the latter providing the potential benefit of single doses. A Spanish paper assesses its pro-tective effect for gastroscopy and colonoscopy using a user-friendly protocol consisting of single doses of

3,500 units of bemiparin (57). However, this was about gastroscopy and colonoscopy with low bleeding risk, and a dose of 3,500 units might be inadequate in high throm-botic risk settings.

However, bridge therapy poses some concern regard-ing effect enhancement when giving two anticoagulants concomitantly, which may increase bleeding risk. Fur-thermore, renal LMWH clearance may be problematic because of overdosing in subjects with uncontrolled or unknown renal failure.

WHAT SHOULD BE DONE IN CASES WITH CONCOMITANT ANTIAGGREGATION AND ANTICOAGULATION?

Such regimen would only be indicated for a condition demanding oral anticoagulation (atrial fibrillation, deep venous thrombosis, pulmonary embolism, or valvular prosthesis) and coronary disease (acute coronary syn-

Fig. 6. Anticoagulation management schedule.

ENDOSCOPY FOR ANTICOAGULATED PATIENTS ON VITAMIN K ANTAGONISTS

Perform endoscopy

Perform endoscopy

Delay endoscopy

*In very high bleeding-risk procedures (sphincterotomy, etc.) with INR < 1.4. For polypectomy,

etc., 2.0 is enough

Very high thrombotic risk

CA-AFib with CHA

2DS

2-VASc >5,

mechanical mitral prosthesis

High thrombotic risk

CA-AFib with CHA

2DS

2-VASc 2-5,

PTE, mechanical valve with prior PTE, antiphospholipid sd.,

multiple prior thromboses

Low thrombotic risk

CA-AFib with CHA

2DS

2-VASc 1-2,

aortic valve disease, biologic mitral prosthesis

High bleeding-risk endoscopy Low bleeding-risk endoscopy

Undelayable condition

Perform endoscopy

INR reversal < 1.4– Vitamin K– Prothrombin

complex concentrate

Delayable condition

Acenocoumarol/Warfarin NOAC

Withdraw according to

CrCl data

Perform endoscopy

Discontinue anticoagulant

Bridge therapy with LMWH


Bridge therapy with LMWH (full dose)


Bridge therapy with LMWH (half dose)

INR < 1.4* INR ≥ 1.4*



drome and/or stent implantation) (58). At any rate, it is advisable that this scheme be maintained for the short-est time possible. No recommendations are available in the existing guidelines and papers in endoscopic pro-cedures. Recommendations do exist in some consensus European guidelines in the field of cardiology, where it is stated that in the presence of severe acute bleeding and triple therapy the monitoring of INR levels below 2 may be necessary while maintaining clopidogrel and low-dose aspirin. This is an increasingly common sit-uation, and cases should be managed on an individual basis.

WHAT SHOULD BE DONE FOR PATIENTS ON ASPIRIN, ANTIPLATELETS OR ANTICOAGULANTS OUTSIDE ACCEPTED INDICATIONS?

In such situations therapy discontinuation before the endoscopic procedure would be most appropriate, as in-creasing the risk of bleeding, however small, while main-taining the thrombotic risk would be senseless.

MAY WE RECOMMEND A PRACTICAL SCHEME FOR ANTIAGGREGATED AND/OR ANTICOAGULATED PATIENTS?

Mixed management together with cardiologists, hema-tologists, and neurologists is important, considering pa-tient conditions on an individual basis.

While a practical proposal is made at the end of the protocol (Annex 1), we must combine the risk estimates and feelings the endoscopist may have after the procedure with those of a cardiologist, hematologist or neurologist in order to agree on the timing for discontinuation (rather stable) and reintroduction (more flexible).

Guidelines are helpful in the decision-making under-lying medical acts, rather than tight schemes to be fol-lowed stringently, as evidence for the latter is presently weak.

IS SCREENING COLONOSCOPY A TECHNIQUE REQUIRING A DIFFERENT BEHAVIOUR AS COMPARED TO STANDARD DIAGNOSTIC COLONOSCOPY?

In the various series of screening colonoscopies in our setting, the possibility of significant polypectomy –for polyps larger than 10 mm– is encountered in 50% to 60% of patients.

As seen above, a reduction of anticoagulant doses is con-sidered to be cost-effective (50), albeit this is uncommon in our setting. In these patients a bridge therapy with LMWH is perhaps most appropriate from a practical standpoint.

As regards antiplatelets, aspirin will not be withdrawn, regardless of dosage. If on clopidogrel, we shall inform the patient that the bleeding risk is slightly increased, or we may change it for aspirin, and about the possibility of delaying the procedure until it may be withdrawn.

If on dual antiaggregation, consider clopidogrel dis-continuation if possible (as per established schemes) and maintain aspirin.

With a consensual attitude in our team, we chose to manage screening as a high-risk endoscopy given the high rate of polypectomies (> 50%), in order to prevent second procedures from happening, although patients should be involved in the decision-making.

HOW IMPORTANT IS PATIENT PERSPECTIVE WHEN THE DECISION IS MADE TO DISCONTINUE AN ANTICOAGULANT OR ANTIPLATELETS DRUG?

This point was discussed given the relevance of dis-continuation for patient health, and patients prefer the risk of side effects (including bleeding) to the risk of poten-tial cardiovascular events (59). This appreciation should prompt us to make decisions on an individual basis prior to the procedure, with time enough for the patient to make up his or her mind.

The finding of polyps during colonoscopy is increas-ingly common in patients on anticoagulants and/or anti-

Table XII. Bridge therapy regimen with anticoagulants

-5 -4 -3 -2 -1 0 1 2 3 4

Kovacs, 2004

Disc OACLMWH 200/kg

LMWH 200/kg

INR > 1.4 → Vit. K 1 mgINR < 1.4 → disc

LMWH 100/kg

HBPM 200/kgInit. OAC

LMWH 200/kg

LMWH 200/kg

Zuckerman, 2005

Disc OAC LMWH LMWH LMWH withhold LMWH LMWH LMWH

Constans, 2007

Disc warfarin

Nothing Bemip 3500Bemip 3500 Bemip 3500 Bemip 3500

Init. AOBemip 3500

Bemip 3500Bemip 3500

Bemip 3500

Disc acenocm

Nothing



platelet drugs. In such case decisions should be agreed upon before the procedure, particularly for sedated pa-tients. The informed consent should approach potential polypectomy, and describe its benefits and risks, as well as the need to repeat both the procedure and the prepara-tion should polypectomy be decided against.

ACKNOWLEDGEMENTS

We are grateful to the board members of SEED, SEPD, GTCV-SEC, and SETH for their contributions and correc-tions in order to improve and make sense of this document.

We particularly acknowledge Dra. Inmaculada Roldán (Servicio de Cardiología, Hospital La Paz, Madrid) and Dr. Enric Brullet (Servicio de Digestivo, Hospital Parc Taulí, Sabadell) for their specific contributions.

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ANNEX 1

PATIENT INFORMATION

You are to undergo a ____________________ procedure on _________, as requested by Dr. _________________, at the _________________ clinic, with diagnostic or therapeutic intent.

Since you are taking the following medications _________________________, your bleeding risk is increased, hence adjusting your doses may be desirable in order to reduce this risk.

Furthermore, you are taking these drugs to prevent thrombosis, hence any adjustments should be assessed by your doctor.This is why this management protocol was developed, based on the available medical literature.Any application of this protocol is to be attempted under medical surveillance and judgment, and schemes may be changed ac-

cording to clinical variability criteria.If pregnant or at risk of pregnancy, please inform your doctor.

It is advisable for patients previously with poorly controlled anticoagulation that adjustments be made at the Anticoagulation Room

In cardiology patients with difficult decision-making because of intermediate situations, refer to cardiologist to reach agree-ment on ensuing actions.

The requesting doctor is to mark every option appropriate for his/her patient

TREATMENT WITH ANTIPLATELETS

1. Techniques with LOW BLEEDING RISK are to be performed (gastroscopies/colonoscopies with/without biopsy, single polipectomies, echoendoscopy without puncturing, prosthesis placement without dilation):

□ Drug discontinuation and dose adjustments are unnecessary. Biopsies may be taken from moderately vascularized lesions. □ Should lesions amenable to treatment (such as polyps) be found during the procedure, they may be excised if the endosco-

pist judges bleeding risk is low.

2. Techniques with HIGH BLEEDING RISK are to be performed (complex polypectomy, sphincterotomy and ERCP, dila-tion, endoscopic gastrostomy, echoendoscopy with puncturing, varices management, balloon enteroscopy, liver biopsy; also screening colonoscopy should the patient consent).

2.1. Situations with very low thrombotic risk (primary prevention). □ Antiplatelet may be discontinued.

2.2. Situations with low thrombotic risk [uncovered stents (> 6 months) and covered stents (> 18 months)]: Patients are usually on aspirin alone (ASA®, Adiro®, Bioplak®, Therasacard®, Tromalyt®) or triflusal (Anpeval®, Disgren®):

□ No dose adjustment necessary, may be performed while on these drugs. □ Should a particularly high bleeding risk exist, these may be discontinued and the procedure may be scheduled in their

absence.

2.3. Situations with intermediate thrombotic risk [uncovered stents (1-6 months) and covered stents (12-18 months), acute coronary syndrome with stent (6-12 months)]: they are usually on monotherapy with ticlopidine (Tiklid®) or clopidogrel (Plavix®, Iscover®), or some times on dual antiplatelet therapy:

□ Replace antiplatelet_____________ with aspirin, 100 mg/day. □ In case of dual antiaggregation, discontinue clopidogrel 5 days before, and perform with aspirin. □ Attempt to delay endoscopy until stent-related thrombotic risk is lower (go to section 2.2).

2.4. Situations with high thrombotic risk [uncovered stents (1 month) and covered stents (12 months), acute coronary syn-drome without stent (12 months) and with stent (1-6 months)]: they are usually on dual therapy [ASA + clopidogrel (or prasugrel (Effient®) or ticagrelor (Brilique®)]:



□ Attempt delaying endoscopy until thrombotic risk is reduced (consult with cardiology) and perform the procedure 5 days following ticlopidine or clopidogrel discontinuation, or 7 days following ticagrelor or prasugrel discontinuation, keeping aspirin though.

□ If the procedure cannot be delayed, the use of tirofibran as bridge therapy may be considered, following consultation with cardiology, as it requires admission and IV medication.

Antiplatelets will be reintroduced the next day after the procedure, except when the endoscopist feels there is a high risk of bleeding - in such a case, discuss with cardiology/neurology/hematology.

FILL IN PATIENT INSTRUCTIONS (circle corresponding options)

TREATMENT WITH ANTICOAGULANTS

1. Endoscopies with LOW BLEEDING RISK are to be performed (gastroscopies/colonoscopies with/without biopsy, single polipectomies, echoendoscopy without puncturing, prosthesis placement without dilation):

□ Endoscopy, even biopsy taking, may be performed without risk. □ However, to be safe, the scheme 2 may be performed in the corresponding group, just in case a polyp or another manageable

lesion is found during the procedure, and a future repeat procedure is undesirable.

2. Endoscopies with HIGH BLEEDING RISK are to be performed:

2-1. Patients on acenocoumarol (Sintrom®) or warfarin (Aldocumar®)

Day -7 -6 -5 -4 -3 -2 -1 Test +1 +2 +3

Date

Antiplatelet 1 _____________ Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes Yes Yes

Antiplatelet 2 _____________ Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No No Yes Yes Yes

Day -4 -3 -2 -1 0 +1 +2 +3 +4

Date

Acenocumarol yesno no no PD PD PD PD PD

Warfarin no

THRO

MBO

SIS

RISK

Very high (CA x AFib with CHA

2DS

2-VASc > 5, mitral

or tricuspideal mechanical prosthesis)

ENOXAPARIN

Ac.

no

no

yes yes* no yes* yes yes

no

Wf. yes yes

High (CA x AFib with CHA

2DS

2-VASc 3-5, prior PTE,

antiphospholipid syndrome, prior multiple thrombosis)

BEMIPARINDALTEPARINENOXAPARINNADROPARINTINZAPARIN

Ac.

no

no

yes yes* no sí* sí yes

no

Wf. yes yes

Low (CA x AFib with CHA

2DS

2-VASc 1-2)

No bridge therapy

Testing previously (*): INR < 1,4 X



- The last dose of heparin will be 24 hours before the test (adjusted if cited in the afternoon).- To test it takes INR below 1.4- DP: Previous dose. On the day of the test will be as soon as 6 hours after it. If you consider that there is a high risk of bleeding can prolong and delay the restart LMWH anticoagulant.- The dose of LMWH will be considered therapeutic (see box).

b/ Patients with dabigatran (Pradaxa®), rivaroxaban (Xarelto®) or apixaban (Eliquis®):

CrCl: creatinin clearance.Not indicated (may be used without >15 according to some guidelines)* Except for very high risk of bleeding as judged by the endoscopist- No reliable data available for edoxaban (not marketed)- ATTP will be assessed for patients with renal failure and Cr Cl < 50: if APTT >2 times above control, delay procedure- In patients with CrCl ≥ 80 and manageable bleeding risk they could be withdrawn for only 24 hours

TREATMENT WITH ANTICOAGULANTS + ANTIPLATELETS

The most appropriate scheme remains unclear, hence procedures with high bleeding risk should be delayed as much as possible, and true thrombotic risk should be evaluated jointly with the Cardiology, Neurology or Hematology department.

IDENTIFICATION OF PROBLEMS AFTER THE PROCEDURE

Should any suspected bleeding episode arise (blood in vomit, foul-smelling tarry stools or sustained dizziness with hypotension), please visit the emergency room taking this sheet and your test results with you.

Date: ____________________ Signed: Dr. ____________________

For any questions or concerns, please contact the Digestive Endoscopy Unit (Tel.: 0)

CHA2DS

2-VASc

C-Heart failure/dysfunction VI 1

H-Hypertension 1

A-Age ≥75 yrs. 2

D-Diabetes 1

S-Prior thrombosis (CVA,TIA, PTE) 2

V-Vascular disease (AMI, atheromatosis) 1

A-Age 65-74 1

S-Female sex 1

LMWH Prophylactic dose Therapeutic dose

BEMIPARIN (Hibor©) 2500-3500 U/d 115 U/kg/d

DALTEPARIN (Fragmin©) 2500-5000 U/d200 U/kg/d

(o 100 U/kg/12 h)

ENOXAPARIN (Clexane©) 20-40 U/d 1-1,5 mg/kg/12 h

NADROPARIN (Fraxiparina©) 7500-15000 U/d 0,1 ml/10 kg/12 h

TINZAPARIN (Innohep©) 3500-4500 U/d 175 U/kg/d

DABIGATRAN RIVAROXABAN APIXABAN

CrCl -5 -4 -3 -2 -1 0 +1 +2 +3 -5 -4 -3 -2 -1 0 +1 +2 +3 -5 -4 -3 -2 -1 0 +1 +2 +3

≥ 80 Y Y Y N N N Y Y Y Y Y Y N N N Y Y Y Y Y Y N N N Y Y Y

50-80 Y Y N N N N Y Y Y Y Y Y N N N Y Y Y Y Y Y N N N Y Y Y

30-50 Y N N N N N Y Y Y Y Y Y N N N Y Y Y Y Y Y N N N Y Y Y

≤ 30 Not indicated Not indicated Not indicated

ATTP yes no no

management of antithrombotic drugs in association with

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