Dual antiplatelet therapy (DAPT) includes the addition of a second antiplatelet agent to aspirin monotherapy. Inherently, this requires a tradeoff between decreasing ischemic risk and stent thrombosis with an increased bleeding risk. Decisions regarding the treatment and duration of DAPT require an individualized assessment of the risk-benefit equation for each patient.

Aspirin Therapy

For most patients with stable ischemic heart disease (SIHD), aspirin therapy should be continued indefinitely. A high dose of aspirin does not provide greater efficacy than low-dose aspirin and is associated with increased adverse events. Clinical data support that low-dose aspirin (75-150 mg daily) is adequate for long-term use.¹ The use of higher dosages of aspirin, particularly with DAPT, is associated with an increased risk of bleeding, specifically gastrointestinal bleeding.² The recommended daily dose of aspirin in patients treated with DAPT is 81 mg.

Antiplatelet Therapy Beyond Aspirin

The thienopyridine and cyclopentyl-triazolo-pyrimidine (CPTP) classes of drugs all block the P2Y12 receptor. Their mechanisms of action, however, differ between drugs. Thienopyridines are irreversible, pro-drugs that inhibit platelet aggregation through P2Y12 adenosine diphosphate (ADP) receptor blockade.² Clopidogrel is a pro-drug that must undergo a two-step oxidation to form an active metabolite, whereas prasugrel is a pro-drug that must undergo a one-step oxidation to become an active metabolite.³ Ticagrelor is an active agent that acts via reversible inhibition of ADP receptors and is part of the CPTP class of drugs. Prasugrel and ticagrelor have approximately double the potency compared with clopidogrel based on inhibition of ADP-mediated platelet aggregation. Due to a high prevalence of high on-treatment platelet reactivity with clopidogrel, selection of antiplatelet agent should be individualized, especially in patients with an increased risk for stent thrombosis.⁴

Clinical Evidence

The CREDO (Clopidogrel for Reduction of Events During Observation) trial evaluated patients undergoing elective percutaneous coronary intervention (PCI), mostly with stable coronary artery disease (CAD), who were treated with aspirin and randomized to clopidogrel 75 mg for 30 days, followed by continued clopidogrel versus placebo from 30 days to 1 year. Patients randomized to clopidogrel had significant reduction in the composite endpoint of death, myocardial infarction (MI), or stroke (relative risk reduction 0.73 (0.56,0.06); p = 0.02).⁵ However, there was no significant difference in mortality and an increased incidence of bleeding. Following CREDO, numerous studies have sought to identify the optimal treatment combination to balance a reduction in ischemic events while minimizing the risk of bleeding. Clinical data from key trials are summarized in Table 1.

Table 1: Key Randomized Clinical Trials

Study NameREF (Year)	Size [n=]	Population	Intervention	Outcomes
Clopidogrel for Reduction of Events During Observation (CREDO)5 (2003)	2,116	Elective PCI	Clopidogrel plus aspirin versus aspirin monotherapy	12 months of DAPT after elective PCI reduced the incidence of death, MI, and stroke compared with DAPT administered for 30 days followed by aspirin alone.
Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance (CHARISMA)6,7 (2006)	15,603	Known cardiovascular disease or at high risk for atherothrombotic events	Clopidogrel plus aspirin versus aspirin monotherapy	DAPT therapy in a post-hoc analysis of SIHD patients with a history of MI was more effective than aspirin in reducing ischemic events but with an increase in bleeding.
Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE)8 (2013)	3,119	Stable CAD or history of low-risk acute coronary syndrome undergoing PCI with zotarolimus-eluting stents	Clopidogrel and aspirin for 3 versus 12 months	3 months of DAPT was noninferior to 12 months for adverse events without significantly increasing the risk of stent thrombosis.
The Dual Antiplatelet Therapy Study (DAPT)9 (2014)	9,961	Patients treated with a drug-eluting stent who completed 1 year of DAPT	DAPT (clopidogrel or prasugrel) versus aspirin monotherapy	Patients who continued DAPT beyond 1 year benefited from a reduction in thrombotic events but with an increase in bleeding.
Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54)10 (2015)	21,162	History of MI in the prior 1-3 years	DAPT with ticagrelor and aspirin versus aspirin monotherapy	Reduction in thrombotic endpoints with ticagrelor with increased bleeding.

DAPT Duration

First-generation drug-eluting stents (DES) have been associated with incomplete stent strut coverage and delayed vascular healing, risk factors for late stent thrombosis.¹¹ Second-generation DES have lower thrombogenicity and are associated with lower rates of stent thrombosis compared with first generation DES and, as a result, may not require as prolonged DAPT.¹²

PCI and disease complexity are important factors to consider when assessing ischemic risk to determine the duration of therapy with DAPT.¹³ A meta-analysis of 10 randomized clinical trials involving 31,666 patients assessing DAPT duration demonstrated that longer DAPT reduced ischemic complications, with a 25% reduction in MI with prolonged DAPT (p = 0.01) and 41% reduction in stent thrombosis (p = 0.06), but a 72% increase in major bleeding (p < 0.0001) and a 22% increase in mortality (p = 0.02) occurred.¹⁴ Consequently, in stable CAD, DAPT is not typically recommended beyond 6 months duration.

Patients at increased ischemic risk post-PCI who may benefit from prolonged DAPT include those who continue to smoke, have diabetes, or had a prior ischemic event on DAPT and those who had technical procedural factors related to the PCI that increase their risk of stent thrombosis. Important procedural factors to consider that increase ischemic risk include multiple stents, overlapping stents, long stents, small-sized stents, first-generation DES, and double stents in bifurcations.⁸ In these patients, prolonged DAPT extending beyond 1 year is favored.

Patients at increased bleeding risk can benefit from shorter duration of DAPT. Increased emphasis should be placed on incorporating clinical judgement and tailoring care to individualize optimal therapy.

Guidelines for SIHD

According to the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease, in patients with SIHD treated with DAPT after DES implantation, P2Y12 inhibitor therapy with clopidogrel should be given for at least 6 months (Class I). The guidelines offer flexibility in treatment duration beyond 6 months.¹⁵ American College of Cardiology and American Heart Association guidelines recommend that elective noncardiac surgery should be delayed 30 days after bare-metal stent (BMS) implantation and optimally 6 months after DES implantation. In patients treated with DAPT after PCI who must undergo surgical procedures that mandate the discontinuation of DAPT, it is recommended that aspirin be continued if possible and the additional agent be restarted as soon as possible after surgery (Class I). DAPT should generally be discontinued 3-7 days prior to elective surgery. The most recent society guidelines are summarized in Table 2.

Table 2: Indications and Guidelines for DAPT After PCI in Patients With SIHD

Recommendations
2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease15	All patients with SIHD treated with DAPT should receive 75-100 mg aspirin daily (Class I)
DES Placement	P2Y12 inhibitor therapy should be given for at least 6 months (Class I) Not at high bleeding risk or bleeding complication, DAPT >6 months may be reasonable (Class IIb) High bleeding risk, may discharge/discontinue P2Y12 inhibitor after 3 months (Class IIb)
BMS Placement	Clopidogrel, minimum 1 month duration, no ideal maximum duration (Class I) Not at high bleeding risk, DAPT with clopidogrel >1 month may be reasonable (Class IIb)

Future Directions

Given the inherent bleeding risk with DAPT, there is a push for shorter duration of DAPT with contemporary stents. Newer stent designs including a polymer-free drug-coated stent (Biolimus A9 [Biosensors International Group, Ltd; Singapore]) and cobalt-chromium stent with a layer of Polyzene-F (COBRA [CeloNova BioSciences, Inc.; San Antonio, TX]) have shown favorable outcomes with short-term DAPT.^16,17

Incorporating intravascular imaging into the decision-making process may guide assessment for which patients at an increased bleeding risk can safely discontinue DAPT.¹⁸ Findings post stent implantation including uncovered stent struts and stent underexpansion and malapposition are associated with an increased risk for stent thrombosis. As such, patients with these features on intravascular imaging may benefit from prolonged DAPT.

Summary

In selecting therapies and determining duration of treatment, physicians must always weigh the risks and benefits for their patient to individualize care. Duration of DAPT should be modified based on the patient's ischemic risk and balanced with their bleeding risk. Standard duration of DAPT in patients with SIHD treated with a contemporary DES should be 6 months. Shorter duration (3-6 months) may be reasonable in patients at higher bleeding risk or with a low risk of ischemic events. Prolonged DAPT (>12 months) should be reserved for patients at an increased risk of ischemic events. We recommend an individualized approach to determine the optimal antiplatelet treatment combination for your patients with SIHD who have had PCI.

References

1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
2. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
3. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
4. Lee MS, Shlofmitz E, Haag E, et al. Optimal Same-Day Platelet Inhibition in Patients Receiving Drug-Eluting Stents With or Without Previous Maintenance Thienopyridine Therapy: from the Evaluation of Platelet Inhibition in Patients Having A VerifyNow Assay (EPIPHANY) Trial. Am J Cardiol 2017;119:991-5.
5. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.
6. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
7. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982-8.
8. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510-22.
9. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.
10. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.
11. Claessen BE, Henriques JP, Jaffer FA, Mehran R, Piek JJ, Dangas GD. Stent thrombosis: a clinical perspective. JACC Cardiovasc Interv 2014;7:1081-92.
12. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015;65:1298-1310.
13. Palmerini T, Stone GW. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: conceptual evolution based on emerging evidence. Eur Heart J 2016;37:353-64.
14. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015;385:2371-82.
15. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016;134:e123-55.
16. Cutlip DE, Garratt KN, Novack V, et al. 9-Month Clinical and Angiographic Outcomes of the COBRA Polyzene-F NanoCoated Coronary Stent System. JACC Cardiovasc Interv 2017;10:160-7.
17. Urban P, Meredith IT, Abizaid A, et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med 2015;373:2038-47.
18. Iliescu CA, Cilingiroglu M, Giza DE, et al. "Bringing on the light" in a complex clinical scenario: Optical coherence tomography-guided discontinuation of antiplatelet therapy in cancer patients with coronary artery disease (PROTECT-OCT registry). Am Heart J 2017;194:83-91.

Keywords: Angina, Stable, Acute Coronary Syndrome, Adenosine, Adenosine Diphosphate, Aspirin, Biosensing Techniques, Blood Platelets, Chromium, Coronary Artery Disease, Diabetes Mellitus, Drug-Eluting Stents, Drug-Eluting Stents, Hemorrhage, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Aggregation, Platelet Aggregation Inhibitors, Polymers, Prevalence, Prodrugs, Pyridines, Pyrimidines, Receptors, Purinergic P2, Risk Assessment, Risk Factors, Sirolimus, Stents, Stroke, Thienopyridines, Thrombosis, Purinergic P2Y Receptor Antagonists, Ticlopidine

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