Answers to difficult questions in antiplatelet therapy

1 - How long should my patient be on dual antiplatelet therapy?

When considering length of dual antiplatelet therapy - aspirin + an anti-clotting agent such as a thienopyridine, a P2Y12 inhibitor - consider these two questions: 1) Is there a reason to suspect an excessive risk of bleeding and to stop dual antipatelet therapy ? 2) Are there contra-indications, such as mandatory urgent surgery with a high bleeding risk? If the answer to each these questions is no, then general agreement is that dual antiplatelet therapy should be maintained for at least 12 months (1). 
On whether more prolonged dual antiplatelet therapy would be more effective in preventing adverse cardiovascular events, study results vary. They have shown, regarding likelihood of:

1. Late stent thrombosis (sirolimus, everolimus and other drug-eluting stents ): the risk of stent throbosis is a continuous hazard lasting up to at least up to 5 years after implantation as demonstrated in the J-Cypher registry (2, 3), however little or no known difference is available for therapy maintained beyond 6 or 12 months, as resulting from the Veterans Administration Study and a recent meta-analysis (4, 5). Nevertheless PROTECT, presented at ESC Munich 2012, showed a protective effect on late state thrombosis attributed in part to dual antiplatelet therapy at three years in both the zotarolimus-eluting and sirolimus-eluting stents (with better results in the sirolimus arm).  
2. Death or myocardial infarction: a lower risk with clopidogrel in drug-eluting stent patients beyond 12 months (6).
3. Death of any cause, myocardial infarction or cerebrovascular accidents: with clopidogrel + aspirin for 6 months vs. 24 months (7); no significant difference, extending previous data obtained in the LATE trials (REAL-LATE and ZEST-LATE) that showed no significant benefit in patients assigned to clopidogrel regimens over 12 months, while presenting an additional risk of bleeding (both groups had a balanced proportion of drug-eluting stents and bare-metal stents). 

With data expected to be collected by December 2013, the Dual Antiplatelet Therapy Study will have assigned over twenty thousand patients to either 12 or 30 months of dual antiplatelet therapy. It aims to determine the appropriate duration for dual antiplatelet therapy as well as safety and effectiveness. It could definitely help answer the question of which is the optimal duration of antiplatelet therapy. For the time being, individual risk stratification considering, among other parameters, 1) the type of stent (a bare-metal stent will require only 4 weeks of dual antiplatelet therapy, and complexity of lesions and implantation procedure, balanced with 2) bleeding risk and 3) careful assessment of the need for discontinuation of dual antiplatelet therapy seems the most prudent attitude, keeping the 12 month dual antiplatelet therapy recommendation as default strategy.

2 - When to add anticoagulation and which to use?

The most common indications for anticoagulation in coronary artery disease patients with dual antiplatelet therapy (triple therapy) are 1) atrial fibrillation and 2) mechanical heart valves. Specific and clear recommendations in atrial fibrillation are in the latest ESC Guidelines and offer a clear roadmap for management of vitamin K-antagonists together with antiplatelet drugs (10).  
The focused update refers to the 2010 guidelines and states that a period of triple therapy is needed (oral anticoagulant plus aspirin plus clopidogrel), followed by the combination of an oral anticoagulant plus a single antiplatelet drug and, after one year, management can be with an oral anticoagulant alone in stable patients, where an oral anticoagulant can be adjusted-dose K-antagonists therapy or probably a novel anticoagulant. The novel anticoagulants, the update goes on to state, offer better efficacy, safety, and convenience the update goes on to state, compared with oral anticoagulants with adjusted-dose K-antagonists. Thus, where an oral anticoagulant is recommended, one of the novel anticoagulants — either a direct thrombin inhibitor (dabigatran) or an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)—should be considered instead of adjusted-dose K-antagonists (INR 2–3) for most patients with atrial fibrillation. (11)
Thus, dabigatran and rivaroxaban for example have come as added options to previously developed anticoagulants, combined to antiplatelet drugs which are often needed in atrial fibrillation (approximately one third of patients included in the RELY, ARISTOTLE and ROCKET-AFstudies were on anticoagulants and antiplatelet drugs). These trials have shown regarding:

1. Stroke or major bleeding: In an ARISTOTLE subgroup analysis, there was no significant difference between patients who had received aspirin and those who hadn’t (12-13). In a RELY post-hoc analysis, groups receiving dabigatran at 110mg and 150 mg dose presented non-inferiority and superiority respectively to warfarin in stroke prevention regardless of concomitant antiplatelet therapy. Both sub-groups receiving antiplatelet agents as well as dabigatran showed no overall significant increase in bleeding complications compared to the sub-group of subjects on concomitantly on antiplatelets and warfarin, although the rate of major bleeding was significantly increased when adjusted by several factors (14). No subgroup analysis of the ROCKET-AF study with this regard is available.
2. Myocardial infarction: It should also be noted that patients receiving apixaban and rivaroxaban in the respective studies, showed a slightly lower rate of MI, while those receiving dabigatran in the RELY study showed a non-significant increase in the incidence of MI (12, 15).

In the future, results from two trials comparing dual antiplatelet therapy with triple therapy will become available comparing:

• Six weeks versus 6 months after stent implantation, in patients with an indication for oral anticoagulation and a drug-eluting stent implantation, the ISAR Triple trial. 
• Twelve months after stent implantation in patients with atrial fibrillation and a low-moderate risk of stroke (CHADS ≤ 2) MUSICA-2 trial.

In patients with mechanical heart valves, there is a general consensus to 1) restrict the implantation of DES and 2) shorten the use of triple therapy as much as possible (16) as well as to 3) weekly monitor INR to avoid over-anticoagulation. A recent review of best evidence available on this topic concludes that triple therapy is associated with the best clinical outcome, and that it should be maintained for 3 months after sirolimus and 6 months after paclitaxel DES implantation, followed by long-term oral anticoagulation plus single antiplatelet therapy (17).
Nevertheless WOEST study results show that a strategy of adding clopidogrel only to anticoagulants (and not using aspirin) causes less bleeding and helps to prevent thrombotic and thromboembolic complications such as stent thrombosis. (18).

3 - How do I switch among antiplatelet agents?

Evidence on this topic is scarce, and is mostly drawn from pharmacodynamic studies a recent of which has suggested 30 mg as the optimal re-loading dose of prasugrel when switching patients pre-treated with an initial 300 mg clopidogrel loading dose (19). Definite optimal strategy, however, remains to be determined through large clinical studies. Thus, in spite of extensive reviews on this issue (20), the decision as to whether to switch among antiplatelet agents, appropriate timing for doing so and whether to administer a loading dose of the antiplatelet agent, is at the discretion of each treating physician. 
A cost-effective regimen for the 12 month post-intervention course suggested by S. Sharma, of alternate day clopidogrel would provide protection from thrombosis (19). More recently, measurements of platelet aggregation in clopidogrel-treated patients indicated in the MADONNA study that one out of four patients is a non-responder to the drug. Personalised antiplatelet treatment according to the platelet function testing with MEA (multiple electrode aggregometry), with patients either receiving clopidogrel only, or repeated doses of clopidogrel and prasugrel in non-responders, resulted in an improved efficacy (non-guided group were at a 7.9-fold higher risk to develop stent thrombosis) and equal safety compared to standard treatment (22).

Conclusion

In coronary artery disease patients undergoing percutaneous coronary intervention:

• A general recommendation is that individualised risk stratification considering namely, 1) the type of stent and complexity of lesions and implantation procedure, balanced with 2) bleeding risk and 3) a careful assessment of the need for discontinuation of dual antiplatelet therapy seems the most prudent attitude, keeping the 12 month dual antiplatelet therapy recommendation as default strategy.
• Regarding patients with atrial fibrillation, a period of triple therapy by combination of an oral anticoagulant plus a single antiplatelet drug and, after one year, an oral anticoagulant alone in stable patients, where an oral anticoagulant can be adjusted-dose K-antagonists therapy or probably a novel anticoagulant -  dabigatran or rivaroxaban, or apixabanshould be considered instead of adjusted-dose K-antagonists (INR 2–3) for most (11).
• In patients with mechanical heart valves, there is a general consensus to 1) restrict the implantation of DES and 2) shorten the use of triple therapy as much as possible, (14)  3) weekly monitor INR to avoid over-anticoagulation. 
• In all triple therapy however, consider not using aspirin (18) 
• Using multiple electrode aggregometry to measure patients responsiveness to antiplatelet therapy might be a tool to individualising treatment (22).