European Heart Journal Advance Access published December 2, 2013
European Heart Journal REVIEW
doi:10.1093/eurheartj/eht461
Novel therapeutic concepts
Triple antithrombotic therapy in cardiac patients:
more questions than answers
Martin Moser*, Christoph B. Olivier, and Christoph Bode
Heart Center, Cardiology and Angiology I, Freiburg University, Hugstetter Strasse 55, Freiburg 79106, Germany
Received 5 March 2013; revised 10 October 2013; accepted 17 October 2013
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Many cardiac patients require combined antithrombotic therapy consisting of an anticoagulant and inhibition of platelet function. The most fre-
quent indications are atrial fibrillation (AF) in combination with drug-eluting stent implantation and/or the presence of an acute coronary syn-
drome (ACS). Currently, the optimal combination of anticoagulants and anti-platelet therapy is unknown, but it is well established that the
combination of regular doses and regimens as prescribed in AF or after ACS results in increased bleeding rates. In this review, we discuss the
current literature and describe approaches to reduce the risk of bleeding hoping not to increase the rate of ischaemic events.
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Keywords Atrial fibrillation † Antithrombotic therapy † Triple therapy † Platelets † Acute coronary syndrome
thrombosis it is still associated with an up to 70% rate of myocardial
Cardiac conditions requiring infarction (MI) and 20% mortality depending on the location of the
antithrombotic therapy respective stent within the coronary vascular tree and other circum-
Many cardiac patients require combined antithrombotic therapy stances.4
consisting of an anticoagulant and inhibition of platelet function. In addition to this risk, an ACS carries intrinsic risks for recurrent
Typical indications for the inhibition of the coagulation cascade in ischaemic events and cardiovascular mortality. Even with up-to-date
cardiovascular diseases are: atrial fibrillation (AF), deep venous anti-platelet therapy the residual risk of recurrent MI, stroke, or
thromboembolism, pulmonary embolism, or mechanical valve cardiovascular death remains at ≏10% per year.5,6
surgery. On the other side, an acute coronary syndrome (ACS) or
coronary stent implantation require ‘dual-anti-platelet therapy’
What are the antithrombotic strategies to
(DAPT), usually consisting of aspirin and a P2Y12 antagonist. ‘Triple
therapy’ (TT) is usually referred to as a combination of an anticoagu-
avoid stent thrombosis?
lant with two anti-platelet agents. Up to 30% of patients on vitamin K It is well established and recommended in the guidelines that DAPT
antagonism (VKA) for AF have the concomitant diagnosis of coronary comprising aspirin and a P2Y12 antagonist (usually clopidogrel) is cur-
artery disease (CAD) and are thus potential candidates for coronary rently the most effective strategy to prevent thrombosis after elective
stent implantation.1 Similarly, between 5 and 10% of patients under- stent implantation. Using this approach stent-thrombosis rates are
going coronary stent implantation (PCI) have been on VKA treat- reduced to ≏1% in the first month and to ≏1 –2% in the first
ment. For these patients, triple therapy (TT) needs to be considered.2 year.7 The time window of susceptibility for stent thrombosis
appears to be longer for drug-eluting stents (DESs) than for bare-
metal stents (BMS). Thus current guidelines recommend DAPT for
What are the thrombotic risks? 1 month after elective BMS implantation and for 6 months to
1 year after DES implantation.8 Recent data suggest that, with
Coronary stent thrombosis newer stent technologies, extended duration of DAPT may not be
Stent thrombosis after elective stent implantation is a rare but serious as beneficial as with earlier stents.9 – 11 Although these data have
event. Recent developments in stent technology resulted in further not been accounted for in the guidelines they still provide some
reduction of the stent-thrombosis rate.3 In the event of stent support for situations in which shorter DAPT is desired. After an
* Corresponding author. Tel: +49 761 270 34411, Fax: +49 761 270 34412, Email: martin.moser@universitaets-herzzentrum.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
, Page 2 of 10 M. Moser et al.
ACS DAPT has been proven beneficial in several trials and as a con- demonstrated that the incidence of ‘nuisance’ bleeding is associated
sequence this strategy is recommended for the duration of 1 year with clopidogrel therapy cessation in more than 10% of patients,
after ACS in current guidelines independent of the coronary revascu- which may then in turn result in an increased rate of stent throm-
larization strategy.12 – 14 bosis.28 Thus, bleeding events of any intensity should be avoided
Although early trials have shown that VKA may also be effective to but efficacy of anticoagulation should be maintained. To achieve
prevent recurrent events after a MI this approach is currently not this critical goal the individual bleeding risk of the patient may serve
recommended by the guideline committees. In the absence of platelet as a basis for adapted antithrombotic therapy. Assessing the individ-
inhibitors the number of stent thrombosis is substantially increased ual bleeding risk is a challenging task in clinical practice. Scores can be
and the bleeding rate with VKA is increased.15 In the STARS trial of limited help in this context. The HAS-BLED score has been recom-
VKA, even when combined with aspirin, was not as effective as mended by the European Society of Cardiology (ESC) to assess
DAPT to prevent stent thrombosis at the time and with the stent bleeding risk in patients with AF. Three or more of the following cri-
technology when the study was performed.16 Thus VKA alone is teria define a high bleeding risk: Hypertension, abnormal liver or renal
not an alternative to DAPT therapy in patients with ACS and stent function, stroke, bleeding history, labile INRs, elderly (.65 years)
implantation. Nonetheless and in contrast to the STARS data more (anti-platelet), drug or alcohol use. If a patient is considered to have
recent registries and one randomized trial suggest that the combin- a high bleeding risk careful attention should be given to the choice
ation of one anti-platelet and VKA may be effective to prevent of antithrombotic therapy. In clinical practice there is a large overlap
excessive stent thrombosis when used with modern DES types.17 – 19 between the HAS-BLED and the CHA2DS2-VASc score resulting in
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a dilemma. Patients who require effective anticoagulation frequently
Stroke and systemic embolism also have an increased bleeding risk. Thus individualized strategies
In patients with AF the thrombo-embolic risk depends on the pres- balancing bleeding and thrombotic risks are needed. In some patients
ence of additional risk factors being evaluated by scores such as the occlusion of the left atrial appendage should be considered.
CHADS2- and the CHA2DS2-VASc score. High scores are related
to a stroke and systemic embolism risk of up to 15% per year.20 Is there a benefit from triple
antithrombotic therapy in patients with
What are the antithrombotic atrial fibrillation and coronary stent
implantation or acute coronary syndrome?
strategies to avoid stroke and VKA given alone is not effective to prevent stent thrombosis,
systemic embolism in atrial whereas DAPT is inferior to VKA in the prevention of thrombo-
fibrillation patients? embolism in AF patients. As a consequence, combinations of antith-
rombotic drugs need to be considered in patients with a coronary
To reduce this risk oral anticoagulation (OAC) is recommended stent and AF.
when a CHA2DS2-VASc score of 2 or higher is reached. Traditionally It is not surprising that a combination of anticoagulants with anti-
VKA is used for anticoagulation and has proven effective in AF platelet drugs increases bleeding risk. The key challenge is to identify
patients providing a risk reduction of about 60% compared with the best combination and dose to keep bleeding risk low while opti-
placebo.21 In contrast aspirin alone appears not to have a specific mizing the antithrombotic effect for both thromboembolism in AF
antithromboembolic activity in AF as it results in a relative risk reduc- and prevention of stent thrombosis. A number of studies have
tion of about 20% only—a number that is comparable to the stroke been conducted using different strategic approaches (see Table 1).
risk reduction achieved by aspirin in atherosclerotic patients without Triple therapy has been compared with DAPT and/or with a combin-
AF.22 Even when aspirin is combined with clopidogrel it is not as ef- ation of VKA and a single-anti-platelet drug. Unfortunately there are
fective as VKA treatment.23 Recently, novel direct oral antagonists almost no randomized, prospective trials to elucidate this important
(NOAC) of coagulation factors Xa (rivaroxaban and apixaban) or clinical problem.
IIa (dabigatran) have demonstrated non-inferiority compared with
VKA and have been approved for clinical use in stroke preven- Triple therapy vs. dual-anti-platelet
tion.24 – 26 In the future these novel anticoagulants will most likely therapy
be used in the large majority of AF patients.
In one study involving 426 patients with AF undergoing PCI, DAPT
was reported in 41% and TT in 50% of all patients.29 In patients
What is the risk of antithrombotic without VKA mortality rates were higher [28 vs. 18%; hazard ratio
(HR) 3.43, 95% CI 1.61–7.54]. In another study 604 patients with
therapy? AF undergoing PCI were registered and matched using propensity
It is well established, e.g. from the OASIS-5 dataset, that severe bleed- scores.30 It was reported that OAC at discharge reduced major car-
ing may have deleterious effects on mortality.27 Mechanistically, not diovascular adverse events (HR 0.40, 95% CI 0.22– 0.74) and all-
only anaemia and hypovolemic shock contribute to mortality in cause mortality (0.34, 95% CI 0.17–0.68). Moreover, in a retrospect-
bleeding patients but also ischaemic events which can be triggered ive study 478 patients with an indication for OAC mostly due to AF
by inflammatory responses to bleeding or by discontinuation of who underwent PCI were analysed. Patients treated with DAPT
antithrombotic drug therapy. Notably, even the occurrence of compared with patients treated with TT had a significantly higher
minimal bleeding events may have fatal consequences: it has been rate of stroke (8.8 vs. 2.8%) or stent thrombosis (5.9 vs. 1.9%) at
