Antithrombotic strategies in patients on oral anticoagulant therapy undergoing percutaneous coronary intervention: A proposed algorithm based on individual risk stratification

Clinical Decision Making

Antithrombotic Strategies in Patients on OralAnticoagulant Therapy Undergoing Percutaneous

Coronary Intervention: A Proposed AlgorithmBased on Individual Risk Stratification

Giuseppe Patti, MD, FACC and Germano Di Sciascio,* MD, FACC, FSCAI

An increasing number of patients on chronic oral anticoagulant therapy undergo per-cutaneous coronary intervention. There is a lack of evidence-based data and no prac-tice guidelines are available about the optimal antithrombotic treatment of suchpatients after the procedure; thus, the adopted strategies are highly variable and areoften left to the discretion of the attending physician. In this article, we review currentevidence and propose an algorithm of antithrombotic strategies tailored to the individ-ual patient, which takes into account the relative risks of bleeding, ischemic complica-tions, and thromboembolism. VC 2009 Wiley-Liss, Inc.

Key words: percutaneous coronary intervention; stent; VKAs; antiplatelet therapy;outcome

INTRODUCTION

Dual antiplatelet therapy with aspirin and thienopyri-dines after percutaneous coronary intervention (PCI) isthe treatment of choice for the prevention of postproce-dural myocardial ischemic events and stent thrombosisafter implantation of bare metal stents (BMS) [1–4];use of drug-eluting stents (DES) requires a more pro-longed dual antiplatelet therapy, because of enhancedrisk of late stent thrombosis [5,6]. A number ofpatients undergoing coronary stenting have indicationfor both dual antiplatelet therapy and long-term oralanticoagulation, owing to, among others, concomitantatrial fibrillation, prosthetic heart valve, left ventricularthrombus, or previous thromboembolic episodes. In ourInstitution, this subgroup of patients constitutes �5%of those receiving coronary stents; such percentage islikely to increase, because of advancing age of patientsundergoing PCI and attendant comorbidities. In thissetting the major concern is bleeding, if vitamin Kantagonists (VKAs) are utilized in association withdual antiplatelet therapy (triple therapy), especiallylong-term; on the other hand, concerns about adequacyof antiaggregation or anticoagulation (with potentialincrease of stent thrombosis or stroke risk) arise ifeither one of the antiplatelet agents or VKAs were dis-

continued after PCI. Guidelines of the InternationalCardiovascular Societies [5,7] give Class of Recom-mendation IIb and Level of Evidence C for triple ther-apy; however, such strategy is still the object of anongoing debate; we have reviewed the current evidenceand we propose an algorithm based on specific individ-ualized risk stratification.

CURRENT EVIDENCE

After careful review of available published studies[8–19], the following considerations are in order: (1)

Department of Cardiovascular Sciences, Campus Bio-MedicoUniversity of Rome, Via Alvaro del Portillo, Rome, Italy

Conflict of interest: Nothing to report.

*Correspondence to: Germano Di Sciascio, MD, FACC, FSCAI,

Department of Cardiovascular Sciences, Campus Bio-Medico Univer-

sity, Via Alvaro del Portillo 200, 00128 Rome, Italy.

E-mail: [email protected]

Received 14 April 2009; Revision accepted 18 June 2009

DOI 10.1002/ccd.22200

Published online 7 August 2009 in Wiley InterScience (www.

interscience.wiley.com)

VC 2009 Wiley-Liss, Inc.

Catheterization and Cardiovascular Interventions 75:128–134 (2010)

The most common indication for oral anticoagulationof patients undergoing PCI is atrial fibrillation (about64%); �45% of patients have an acute coronary syn-drome as clinical presentation and DES penetration isless than 40%; (2) As expected, patients on tripletherapy have a three- to five-fold overall increase inbleeding risk, which translates into higher mortality[9,13,15,17]; however, wide variability of major bleed-ing rates is reported, because of differences in bleedingdefinitions, intensity of anticoagulant regimens, andconcomitant aspirin doses [11,13,14] (Tables I and II).Hemorrhagic complications are more frequent inpatients with higher bleeding risk, higher maintenanceINR values and typically involve the gastrointestinaltract [9,10,11,15,17]. Moreover, prolonged duration oftriple therapy (>6 month) is associated with a twofoldincreased occurrence of major bleeding, compared witha limited duration (1 month); (3) Patients receivingeither triple therapy or VKAs plus a single antiplatelet

agent have a threefold lower incidence of stroke orthromboembolic events compared with those treatedwith aspirin plus a thienopyridine alone [11,13]; (4) Alarge variability is also reported with regard to follow-up incidence of MI [11–14], probably due to variableclinical risk profiles and endpoint definitions. Therapywith clopidogrel in addition to VKAs seems to be bet-ter than treatment with aspirin plus oral anticoagulationfor prevention of cardiac events in patients at high is-chemic risk [11,12]. However, high MI rates are paral-leled by high stent thrombosis rates, mainly in studieswith higher DES use and in the subgroup of patientsreceiving VKAs plus aspirin alone after intervention[11]. In the latter, incidence of stent thrombosis at1-year is higher (15%) than that reported (�1%) inpatients receiving dual antiplatelet therapy after eitherBMS or DES implantation in randomized trials [20];(5) Longer follow-up data are needed to evaluate long-term incidence of stent thrombosis in patients with

TABLE I. Main Characteristics of Published Studies

Study Type of study

No. of

patients

Patients with

AF (%)

Patients with

DES (%)

Follow-up

duration

Rubboli et al. [8] Retrospective 27 51 – 1 month

Porter et al. [19] Retrospective 180 37 NA 1 month

Khurram et al. [9] Retrospective 214 80 75 Mean 8 months

Orford et al. [10] Retrospective 66 NA – Up to 2.7 years

DeEugenio et al. [15] Retrospective 194 59 28 Median 182 days

Karjalainen et al. [11] Retrospective 478 70 42 1 year

Nguyen et al. [12] Retrospective 800 37 27 6 months

Ruiz-Nodar et al. [13] Retrospective 426 100 40 Median 595 days

Rogacka et al. [14] Prospective 127 59 56 21 � 20 months

Sarafoff et al. [16] Prospective 515 78 100 2 years

Rossini et al. [17] Prospective 204 33 48 18 months

Manzano-Fernandez

et al. [18]

Retrospective 104 100 66 12 months

AF, atrial fibrillation; DES, drug-eluting stents.

TABLE II. Main Outcomes of Published Studies

Triple therapy VKAs þ single antiplatelet Dual antiplatelet

Major

bleeding MI ST Stroke

Major


Major


Rubboli et al. [8] 7 – – – – – 3.5 – – – – –

Porter et al. [19] 1 NA NA NA – – – – – – – –

Khurram et al. [9] 6.6 NA NA NA – – – – 0 NA NA NA

Orford et al. [10] 3 – – – NA NA NA NA NA NA NA NA

DeEugenio et al. [15] 14a NA NA NA – – – – 3a NA NA NA

Karjalainen et al. [11] 6.6 8.5 1.9 2.8 9 14.1 6.4 1.3 11.8 5.9 5.9 8.8

Nguyen et al. [12] NA 3.3 NA 0.7a NA 4.5 NA 3.4a NA NA NA NA

Ruiz-Nodar et al. [13] 14.9 6.5 1.2 1.7a,b NA NA NA NA 9 10.4 1.3 6.9a,b

Rogacka et al. [14] 4.7 1.6 0.8 3 NA NA NA NA NA NA NA NA

Sarafoff et al. [16] 1.4 3.7 0.3 1.1 – – – – 3.1 2.5 1.5 3.9

Rossini et al. [17] 2.9 2 1 1 – – – – 2 2 2 2

Manzano-Fernandez et al. [18] 21.6% – 2 7.8b NA NA NA NA NA NA NA NA

Data are given as percentage of patients; aP < 0.05; bStroke þ any thromboembolism.

MI, myocardial infarction; ST, stent thrombosis; VKAs, vitamin K antagonists.

VKAs Therapy in PCI Patients 129

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

indication for oral anticoagulation and receiving differ-ent antithrombotic regimens after DES implantation[21,22]. Patients requiring oral anticoagulation areoften excluded from controlled, randomized PCI trials;available studies derive from single-center registries orsmall case-controlled series [8,10] and concern patientspopulations with different risk profiles and characteris-tics (i.e., different indications for anticoagulant therapy,variable DES penetration), with variable strategicapproaches and follow-up durations; ‘‘ad hoc’’ prospec-tive large studies with direct comparisons of differentantithrombotic strategies have not been performed.

As we await for prospective clinical trials adequatelypowered for such evaluation, we believe that the thera-peutic strategy should be tailored to the individualpatient, balancing the risk of bleeding, ischemic com-plications, and thromboembolism.

DESCRIPTORS OF PATIENTS RISK LEVEL

Bleeding Risk

Bleeding is a major contemporary concern in inter-ventional cardiology, and it is recognized as a strongpredictor of unfavorable prognosis and mortality afterPCI [23,24].

In the evaluation of the bleeding risk, patients maybe classified as being at high or low risk according tothe presence or absence of the conditions listed inTable III [25–32]: of relevance are the newly emergingrisk factors such as older age (>75 years: each 1-yearincrease in age has been associated with a 3% increasein bleeding rate during oral anticoagulant therapy, witha further 15% increased risk with VKAs coupled withantiplatelet therapy) [25], renal failure [28,29,31], andlow body weight [32].

Even entry-site bleeding may be a potentially unfav-orable event [23,24]: recent data suggest that perform-ing PCI by radial vs. femoral approach may reducesuch complications [33], thereby improving the overallpatients prognosis.

Ischemic Risk

Patients can be considered at high ischemic risk inthe presence of variables increasing restenosis rate(possibly requiring DES implantation) or stent throm-bosis (acute, subacute, late, very late) (Table IV): (a)diabetes mellitus (1.27 increased relative risk of repeatcoronary revascularization) [34]; (b) acute coronary syn-dromes [35]; (c) stent diameter (a vessel size <2.8 mmpresents about 60% increased risk of adverse cardiacevents at 1 year compared with a size >3.2 mm) [36];(d) implantation of long or multiple stents (>25%increase in the risk of restenosis) [37,38]; (e) interven-tion for in-stent restenosis, in which repeat PCI is asso-ciated with an incidence of second recurrence rangingfrom 26 to 39% in patients not receiving DES [39,40].Moreover, patients at high ischemic risk are those inwhom the events of restenosis or thrombosis could belife-threatening, i.e., patients with large areas of jeopar-dized myocardium (also including left main diseaseand multivessel disease), severe left ventricular dys-function [41], or severe diffuse coronary disease [42].

Thromboembolic Risk

A careful stratification of thromboembolic risk ismandatory in patients undergoing PCI and requiringchronic oral anticoagulant therapy. Extrapolating fromthe indications of the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy [43] on theannualized risk of thromboembolic complications (inthe absence of anticoagulant therapy), the averagethromboembolic risk due to temporary interruption ofVKAs for 1 month (i.e., the minimum duration of dualantiplatelet therapy after coronary stenting) can bedefined as: low, with <1% hypothesized incidence ofthromboembolic events at 30 days, intermediate, with1–2% risk/month, and high, with >2% risk/month(Table V).

DESCRIPTION OF THE PROPOSED ALGORITHM

Based on the above discussions, we thus recommendthe initial stratification be based on the patients’ bleed-ing risk (Fig. 1).

TABLE III. Indicators of High Bleeding Risk

Age > 75 years [25]

Previous hemorrhagic stroke [26]

Bleeding requiring hospitalization/transfusions in the previous

6 months [27]

Uncontrolled systemic hypertension [27]

Bleeding-prone genitourinary or gastrointestinal lesions [26–30]

Severe hematological disorders [26,28]

Malignancies at risk of bleeding [26,28]

Severe renal failure [28,29,31]

Severe liver diseases [28]

Low body weight [32]

TABLE IV. Indicators of High Ischemic Risk

Diabetes mellitus [34]

Acute coronary syndromes [35]

Small stent diameter [36]

Implantation of long or multiple stents [37,38]

Intervention for in-stent restenosis [39,40]

Patients with large areas of jeopardized myocardium [41,42]

Patients with severe left ventricular dysfunction [41]

Patients with severe diffuse coronary disease [42]

130 Patti and Di Sciascio


Patients With Low Bleeding Risk

Once patients are classified into a low bleeding riskcategory (i.e., absence of factors indicated in TableIII), they will then be evaluated for low or high ische-mic risk, according to the descriptors illustrated inTable IV.

Patients with low bleeding risk and low ischemicrisk can be candidate for BMS (i.e., patients with low

risk of restenosis); thus, because of the low bleedingrisk, triple therapy can be given for 1 month andVKAs in association with aspirin alone can then becontinued indefinitely [44].

On the contrary, patients with low bleeding risk buthigh ischemic risk, as described in Table IV, mayrequire DES to decrease restenosis rate and, because ofthe low risk of bleeding, may receive triple therapy for1 year after intervention, which can then be switchedto VKAs plus clopidogrel afterwards [11,12].

All patients with low bleeding risk will safelycontinue VKAs throughout for thromboembolicprevention.

Patients With High Bleeding Risk

Patients with high bleeding risk will also be evaluatedfor low or high ischemic risk and will be further strati-fied for thromboembolic risk (according to Table V).

Patients with high bleeding risk and low ischemicrisk. Patients assessed to be at high bleeding risk, lowischemic risk, and low thromboembolic risk can betreated with BMS because of the low ischemic risk,and also to avoid prolonged dual antiplatelet therapy.This can be given just for the first 30 days; during thisperiod, the low thromboembolic risk may allow tempo-rary discontinuation of oral anticoagulation, while after1 month treatment with VKAs can be resumed

TABLE V. Thromboembolic Risk at 30 Days in the Absence ofAnticoagulant Therapy [43]

Low risk (<1%)

Lone atrial fibrillation

Atrial fibrillation without risk factorsa

Intermediate risk (1–2%)

Atrial fibrillation with risk factorsa

Bi-leaflet aortic prostheses without risk factors for thromboembolismb

Previous venous thromboembolism > 3 months before

(without evidence of malignancies or antiphospholipid antibodies)

High risk (>2%)

Tilting-disk or caged-ball aortic prostheses

Mitral prostheses

Bi-leaflet aortic prostheses with risk factorsb

Venous thromboembolism in the previous 3 months

Arterial embolism in the previous month

Hypercoagulable states

aAge > 75 years, left ventricular dysfunction, previous transient ische-

mic attack/ischemic stroke, mitral valve disease.bAtrial fibrillation, heart failure, previous thromboembolism.

Fig. 1. Proposed antithrombotic algorithm in patients with indication for oral anticoagulanttherapy undergoing percutaneous coronary intervention, according to their bleeding, ische-mic, and thromboembolic risks. *VKAs given to all patients because of low bleeding riskregardless of thromboembolic risk. ASA, aspirin; BMS, bare metal stents; DES, drug-elutingstents; PLT, platelet; VKAs, vitamin K antagonists.



associated with aspirin alone. In fact, the temporaryexchange of oral anticoagulation for dual antiplatelettherapy may be acceptable in patients with low throm-boembolic risk; this is in agreement with results of therandomized CLAAF pilot study on patients with non-high risk permanent or persistent atrial fibrillation,which demonstrates comparable incidence of throm-boembolic and hemorrhagic events after dual antiplate-let therapy or oral anticoagulation [45].

However, when such patients have intermediate orhigh thromboembolic risk, oral anticoagulation is man-datory [26] despite the high bleeding risk, but a pro-longed triple therapy would not be recommended, anda less aggressive antiplatelet treatment may be utilized,because of the low ischemic risk. Thus, BMS would bethe best option followed by therapy with VKAs andaspirin alone indefinitely.

Patients with high bleeding and high ischemicrisk. In patients at high risk of both bleeding andischemia, but with low thromboembolic risk, BMSshould be preferred and oral anticoagulation can betemporarily discontinued during the first month afterPCI; in this time period, dual antiplatelet therapy canbe given, followed by VKAs and clopidogrel alone,because VKAs and aspirin were associated with higherrisk of MI and stent thrombosis [11].

In patients carrying the worst scenario of high bleed-ing, high ischemic, and intermediate/high thrombo-embolic risks, a prolonged, aggressive antithrombotictherapy cannot be recommended owing to the highbleeding risk; yet, dual antiplatelet treatment cannot beavoided (because of the high ischemic risk), as well asoral anticoagulation (due to the high thromboembolicrisk). Thus, BMS should be used, followed by dualantiplatelet therapy and reduced intensity of anticoagu-lation (INR about 2) for 1 month after PCI; VKAswith INR within therapeutic range plus clopidogrelalone could then be continued thereafter [11,12].

We believe that in all patients receiving triple ther-apy, the dose of aspirin should be as low as possible(�100 mg) and a standard daily dose of 75 mg clopi-dogrel is given; prophylactic proton pump inhibitorsshould be used, although a caveat regarding adecreased antiplatelet effect of clopidogrel with the useof proton pump inhibitors may exist [46].

This algorithm is derived from literature evidenceand from our clinical judgment and experience, takinginto account all possible factors influencing the choiceof different antithrombotic strategies in patients under-going PCI who require oral anticoagulant therapy. It isan attempt to provide a reasonable individualized ther-apeutic scheme in this complex clinical setting; largeprospective studies are needed to validate thisapproach.

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