What Is the Optimal Regimen for Triple Antithrombotic Therapy?

Dual antiplatelet (DAT) therapy with aspirin and an ADP-receptor antagonist is the standard therapy after coronary stenting. It is assumed that approximately 5-10% of patients undergoing coronary stenting have an additional indication for oral anticoagulation (OAC)(1) and will thus require a so called “triple therapy” consisting of aspirin, an ADP-receptor antagonist and OAC. The most common combination currently consists of aspirin, clopidogrel and a vitamin K antagonist.

Table 1: ESC recommendations for antithrombotic therapy in patients with atrial fibrillation undergoing coronary stent implantation 10

For elective procedures in patients at low or intermediate bleeding risk who receive DES: triple therapy for three months with -olimus and six months with paclitaxel DES. After this initial period, up to 12 months of OAC with either aspirin or clopidogrel.

For procedures in ACS patients at low to intermediate bleeding risk (only BMS are recommended): triple therapy for six months. After this initial period, up to 12 months of OAC with either aspirin or clopidogrel.

For elective procedures in patients at high bleeding risk (only BMS): triple therapy for two to four weeks.

For urgent procedures in ACS patients at high bleeding risk (only BMS): triple therapy for four weeks. After this initial period, up to 12 months with OAC with either aspirin or clopidogrel.

ACS: acute coronary syndrome; BMS: bare-metal stent; DES: drug-eluting stent ; OAC: oral anticoagulation.
The optimal regimen regarding combination, duration and dosage of these antithrombotic agents for this high risk population is not easy to define however, as data upon efficacy and safety of triple therapy comes exclusively from retrospective studies. As expected, these studies revealed that there is a 3-5 fold increase in bleeding rates associated with triple therapy as compared to various combinations of DAT.(1-8) But as a meta-analysis could demonstrate, it was also shown that triple therapy is more efficacious than dual antiplatelet therapy in the prevention of major adverse cardiovascular events and that there is a significant reduction in all-cause mortality.(9)

Currently there is one consensus document by the European Society of Cardiology (ESC) working group of thrombosis(10) which has been implemented in the recent ESC atrial fibrillation guidelines,(11) and another consensus document giving the “North-American perspective”(12) on indication and duration of triple therapy.

In general these recommendations all advocate triple therapy in patients on OAC undergoing coronary stent implantation. In patients with a low bleeding risk bare-metal stents (BMS) as well as drug-eluting stents (DES) are feasible options whereas in patients with a high bleeding risk DES implantation is not recommended by either document because of the need of prolonged clopidogrel therapy. After BMS implantation triple therapy shall be prescribed for 2-4 weeks followed by OAC plus one antiplatelet alone (aspirin or clopidogrel) whereas there is currently no overall consensus upon duration of triple therapy in patients who have received DES. The ESC recommends 3 months triple therapy in patients with –olimus-eluting stents, and 6 months with paclitaxel-eluting stents (Table 1),(11) while the North American perspective favours 6-12 months (Table 2)(12) of triple therapy according to the patients’ stent thrombosis risk.

To further evaluate the optimal duration of triple therapy in patients receiving DES, we are currently undertaking the randomized ISAR-TRIPLE trial (NCT00776633) which compares 6 weeks vs. 6 months of triple therapy followed by aspirin and OAC. Other ongoing randomized trials in this field are evaluating efficacy and safety of a combination of clopidogrel plus OAC as compared to triple therapy (WOEST, NCT00769938), or DAT with aspirin and clopidogrel as compared to triple therapy in patients with a CHADS2 Score ≤2 (MUSICA-2, NCT01141153).

All guidelines agree that due to the increased bleeding risk the INR should be monitored closely(11,13,14) and the recommended INR range shall be lowered to 2.0 to 2.5 in patients with atrial fibrillation requiring triple therapy after PCI.(13) In this high-risk population, gastric acid suppressing agents, preferably a PPI other than omeprazole, should be given,(12) and DES implantation should be restricted to patients with an expected high risk of restenosis such as diabetes or complex lesions.(1)

Is a NEW-TRIPLE Therapy with Either Prasugrel/Ticagrelor or Dabigatran/Rivaroxaban/Apixaban an Option?

The newer P2Y12 inhibitors prasugrel and ticagrelor have both shown to reduce cardiovascular events as compared to clopidogrel in patients with acute coronary syndromes.(15,16) The downside of this therapy however is a significant increase in bleeding events in patients undergoing PCI, so we do not recommend the routine use of these agents in patients requiring additional OAC. Although the relevance of platelet function testing in the guidance of antiplatelet therapy is still not established, clopidogrel resistant patients might be considered for the use of newer P2Y12 inhibitors.

In the setting of atrial fibrillation the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban have all been studied as compared to warfarin(17-19) because these agents may overcome the limitations of vitamin K antagonists such as the narrow therapeutic window of adequate anticoagulation and the highly variable dose-response relation among individuals that requires monitoring by laboratory testing.

Table 2: A North-American perspective of antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting12

Low stroke risk (CHADS2=0) and any stent thrombosis or bleeding risk

  • BMS : DAT with aspirin and clopidogrel or prasugrel for one month and preferably for 12 months
  • DES: DAT with aspirin and clopidogrel or prasugrel for 12 months or longer
  • Moderate/high stroke risk (CHADS2>1), low stent thrombosis risk and low bleeding risk

  • BMS: Triple therapy for at least one month then OAC + single AP (aspirin or clopidogrel) for 12 months
  • DES: Triple therapy for at least six months then OAC + single AP for 12 months
  • Moderate/high stroke risk and high stent thrombosis risk and low bleeding risk.

  • BMS: Triple therapy for at least six months then OAC + single AP for 12 months
  • DES: Triple therapy for 12 months
  • Moderate/high stroke risk and any stent thrombosis risk and high bleeding risk

  • BMS: Triple therapy for at least one month then OAC + single AP for 12 months
  • DES: not recommended
  • AP: antiplatelet agent; BMS: bare-metal stent; DAT: dual antiplatelet therapy; DES: drug-eluting stent; OAC: oral anticoagulation.

    These studies have shown that (i) dabigatran 110 mg BID as well as apixaban 5mg BID are associated with lower rates of major haemorrhages;(17,19) (ii) dabigatran 150 mg BID as well as apixaban 5mg BID are associated with lower rates of stroke and systemic embolism;(17,19) and (iii) rivaroxaban 20mg QD is noninferior for the prevention of stroke or systemic embolism without a significant between group difference in the rates of major bleeding.(18) All three agents significantly reduce the rates of intracranial bleeding,(17-19) and apixaban significantly reduces the rate of death.(19)

    All of these agents have also been assessed against placebo in patients with acute coronary syndromes (>78 % on DAT with aspirin and clopidogrel). It has to be noted however that the patients included in these trials did not have an indication for OAC. The results may be summarized as follows: (i) dabigatran, rivaroxaban and apixaban significantly increase the rates of major bleeding in a dose dependent manner;(20-22) (ii) apixaban and dabigatran are not associated with a significant reduction in ischemic outcomes;(20,21) and as recently shown, (iii) rivaroxaban at a dose of 2.5mg to 5mg BID reduces ischemic outcomes.(22) However, the doses used in this trial are ¼ to ½ lower as compared to the tested dose of 20mg rivaroxaban QD in patients with atrial fibrillation.(18)

    Data concerning outcomes with the newer anticoagulants as compared to warfarin in patients on concomitant dual antiplatelet therapy are very limited. An abstract presented at the recent ESC congress 2011 has revealed that concomitant use of antiplatelets did not affect the efficacy and safety of dabigatran in the RE-LY trial.(23) In patients on either one or two antiplatelet agents, dabigatran 110mg was non-inferior and dabigatran 150mg was superior to warfarin in the reduction of stroke and systemic embolism. There was an 1.6 times increase in the risk of major bleeding with concomitant antiplatelet use in all treatment groups, but the absolute risks were lowest with dabigatran 110mg. Major bleeding events were comparable to warfarin in patients receiving a dose of 150mg/d. The authors state that the results were unaffected by duration of use or number of antiplatelets used. Similar findings have been observed with apixaban. In the subgroup analysis of the ARISTOTLE trial it was shown that the better antiischemic and bleeding profile of apixaban was not changed whether patients received aspirin at baseline or not.(19) However, no information is available upon the use of antiplatelet therapy during the whole trial or upon the use of clopidogrel.

    Triple therapy with warfarin has been used for several years now and data upon its efficacy and safety is available while there is currently no published data upon the use of triple therapy with the newer oral anticoagulants. Although it seems promising that some of the newer anticoagulants may lower the risk of bleeding as compared to conventional OAC in patients receiving triple therapy, further studies are needed to evaluate this therapy before recommendation may be given whether these agents may be used in addition to DAT. We believe however that for patients needing DAT and anticoagulation, dabigatran 110mg or apixaban 5mg may be an alternative to conventional OAC in a subset of patients such as those who are unable to take warfarin because of difficulties in INR monitoring or patients with an excessive bleeding risk.


    References

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