Dual antiplatelet therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Dual antiplatelet therapy (or DAPT) refers to the combination of aspirin and a P2Y12 receptor antagonist. DAPT is approved for SIHD and interventions for ACS, such as stent placement following PCI or CABG. The duration of treatment with DAPT for each of these categories differs and guidelines for treatment have been updated in the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease. Much of the studies done on DAPT compared the use of different types of P2Y12 receptor antagonists, the dosage of drugs, as well as the duration of treatment. While the use of DAPT is associated with decreased risk of stent thrombosis, the benefits of treatment should be weighed against the increased risk of major bleeding.

Superiority of Dual Antiplatelet Therapy (Thienopyridine Plus Aspirin) Over Coumadin Plus Aspirin in PCI Patients

Several studies during the early stent era demonstrated the superiority of the combination of ticlopidine plus aspirin over coumadin plus aspirin. has deployment[1][2][3][4][5]. While progress was made over coumadin, Ticlopidine itself was associated with side effects and complications which included neutropenia in > 1%, thrombotic thrombocytopenia purpura in 0.2%, rash, nausea and diarrhea.[6] Given the improved side effect profile and the results of the CLASSICS study, clopidogrel has replaced ticlopidine as the thienopyridine of choice.[7][8][9]

Data Indicating that the Addition of Aspirin to a Thienopyridine Improves Clinical Outcomes in Patients with Acute Coronary Syndromes

There is surrogate marker data indicating that the level of platelet inhibition is greater among patients in whom aspirin is added to a thienopyridine.[10][11][12] In one study, aspirin added to clopidogrel was associated with a greater degree of inhibition of collagen-induced aggregation. The level of platelet aggregation for the combination was only 16.4 +/- 2.4%, which is less than that for aspirin alone (36.5 +/- 4.2%) or clopidogrel alone (59.3 +/- 5.1%, 3 way p < 0.001).[13] Further, aspirin added to clopidogrel was more effective than either aspirin or clopidogrel alone after activation with low dose thrombin (p < 0.05).[14] In rabbit models of stent thrombosis, aspirin potentiated the antithrombotic activity of clopidogrel in the following models: 1)thrombosis induced by a silk thread; 2) thrombosis in stents placed in an arteriovenous shunt; 3) thrombus formation following electrical stimulation of the rabbit carotid artery; and 4) 111 In-labeled platelet deposition on a stent implanted in an arteriovenous shunt.[15] The clinical benefit of adding aspirin to clopidogrel is also demonstrated indirectly by the following observation: among patients on clopidogrel, patients with stent thrombosis were more often resistant to aspirin.[16][17]

DAPT in Aspirin Intolerant Patients

One question that arises among patients who have aspirin hypersensitivity is the safety and efficacy of thienopyridine monotherapy in the mangement of the PCI patient including those who have been stented. There is one single center, small randomized trial purporting to compare the safety and efficacy of thienopyridine monotherapy to that of thienopyridine plus aspirin[18]. 378 stents were placed in 243 patients who were randomly assigned to treatment with either 2 x 250 mg of ticlopidine (n=121) or the combination of 2 x 250 mg ticlopidine + 100 mg aspirin (122 patients) daily. All patients received 500 mg of intravenous aspirin at the time of the procedure. Two hundred and thirty-seven patients (97.5%) were free from the primary endpoint of death, cardiac events and vascular access-site complications through three months with no differences between treatment groups. Although 2 stent thromboses were observed in the combined treatment group, none were observed in the ticlopidine monotherapy group. There are several important limitations to this study. One is the fact that all patients received a high (500 mg) intravenous aspirin during the PCI which would have led to significant levels of platelet inhibition over the next week due to irreversible acetylation and inhibition of prostaglandin H-synthase/cyclooxygenase[19]. This is a period of high vulnerability to stent thrombosis and ischemic complications[20]. Thus, this was not truly a study of thienopyridine monotherapy as all patients received intravenous aspirin. The study by Machraoui is also limited by its small sample size. Finally, the study administered ticlopidine, which is not a pro-drug and may be associated with a lower rate of hyporesponsiveness than clopidogrel. In patients with aspirin hypersensitivity or intolerance, aspirin desensitization may be done[21][22]. There are currently no guidelines or recommendations for the use of dual P2Y12 inhibitors as an alternative for DAPT in patients with aspirin hypersensitivity or intolerance[23].

Types and Dosage of Drugs

Aspirin

Aspirin 81 mg once daily (range 75-100 mg) is used in all patients with Stable Ischemic Heart Disease (SIHD), stent placement following PCI or CABG. The use of aspirin should be continued indefinitely.

P2Y12 Inhibitors

There are several P2Y12 inhibitors currently on the market and they are given in the following doses:

The drug of choice and duration of treatment depends on the medical condition and current recommendations[24].

Recommendations

The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease includes recommendations for ACS treated with medical therapy and/or PCI, ACS treated with CABG, as well as stable ischemic heart disease[24]:

The use of DAPT in Stroke

The 2014 AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack included the following updated recommendations for the use of DAPT in stroke patients[25]:

Class IIb
"1. The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Level of Evidence: B)"
"2. For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Level of Evidence: C). Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy."
Class III (Harm)
"1. The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA(Level of Evidence: A)"
"2. Prasugrel should not be administered to patients with a prior history of stroke or TIA (Level of Evidence: B)"[24]

Pre-Procedural Use of DAPT

Unstable Angina/ NSTEMI

In patients with unstable angina/ NSTEMI undergoing PCI, the following are the guidlelines for the use of DAPT[26]:

Class I
"1. Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive dual antiplatelet therapy (Level of Evidence: A). Aspirin should be initiated on presentation (Level of Evidence: A), clopidogrel (before or at the time of PCI) (Level of Evidence: A) or prasugrel (at the time of PCI) (Level of Evidence: B) is recommended as a second antiplatelet agent."

STEMI

In patients with STEMI undergoing PCI, the following are the guidelines for the use of DAPT[27]:

Class I
"1. After PCI, aspirin should be continued indefinitely.[28][29][30][31][32][33](Level of Evidence: A) "
"2. Clopidogrel should be provided as follows:
"a. A 300-mg loading dose should be given before or at the time of PCI to patients who did not receive a previous loading dose and who are undergoing PCI within 24 hours of receiving fibrinolytic therapy (Level of Evidence: C) ";
"b. A 600-mg loading dose should be given before or at the time of PCI to patients who did not receive a previous loading dose and who are undergoing PCI more than 24 hours after receiving fibrinolytic therapy (Level of Evidence: C) "; and
"c. A dose of 75 mg daily should be given after PCI.[34][35][32][33](Level of Evidence: C) "

Post-Procedural Duration of DAPT

Short-Term Use of DAPT

The risk of thrombotic events is highest during the first few weeks to months after PCI. In addition, premature cessation of DAPT is an independent risk factor for stent thrombosis, with the risk being highest in the first 6 months following PCI[36]. While the optimal duration after PCI and DES implantation remains unclear, the decision to continue therapy beyond standard recommendations should be tailored according to patient's risk factors for bleeding, as well as type of stent used. A shorter duration of DAPT treatment means less bleeding. However, no significant difference in major adverse cardiac events (MACE) exists between short (3-6 months) and long (≥12 months) term duration of DAPT[37]. An ST segment elevation MI following DES implantation beyond 6 months may be a complex and multifactorial phenomenon, which may not be solely related to the discontinuation of thienopyridine therapy.[36]

The Leaders Free Trial

The Leaders Free Trial looks at the use of a very short duration of DAPT in patients with high bleeding risk following PCI and the insertion of a stent. Patients with a high bleeding risk are often times excluded from clinical trials on PCI and anti-thrombotic therapy. In this trial, high bleeding risk patients were given 1 month of DAPT following PCI and the insertion of either a bare metal stent (BMS) or a drug-coated stent (DCS) and were followed up for a period of two years. While it was initially thought that bare metal stents are superior to other types of stents in patients with high bleeding risk, the results of the Leaders Free Trial suggest that the incidence of coronary thrombotic events in patients who received a drug-coated stent were lower than those who received a bare metal stent, with no significant difference in the incidence of major bleeding between the two groups[38].

Long-Term Use of DAPT

The DAPT score

The DAPT score is a risk score derived from the DAPT Trial. It has been designed as a helpful tool for the continuation of dual antiplatelet therapy following PCI and the insertion of a drug-eluting stent (DES).[39]

To calculate the DAPT score, click here.

The DAPT trial

The DAPT trial published in 2014 compared the duration of DAPT following DES implantation. The study compared the standard 12 month therapy versus 30 months of DAPT. Results showed decreased risk of stent thrombosis, MI and stroke with prolonged DAPT. However, those benefits were counterbalanced by an increased risk of major bleeding. Patients with a DAPT score of ≥2 can be considered for prolonged therapy.[39] In addition, it has been suggested that patients with a complex PCI might benefit from extended duration of DAPT therapy, as those patients are more likely to undergo revascularization or suffer from stent thrombosis. A complex PCI is a procedure with one or more of the following angiographic findings:[40]

  • 3 vessels treated
  • ≥3 stents implanted
  • Bifurcation with 2 stents implanted
  • Total stent length of more than 60mm
  • Chronic total occlusion as target lesion

The PEGASUS-TIMI 54 Trial

The PEGASUS-TIMI 54 Trial published in 2015 looked at the long-term use of ticagrelor in addition to aspirin for 1-3 years following an acute coronary syndrome. The study compared the use of placebo versus ticagrelor at 60 and 90mg doses. While the use of ticagrelor at either dose was superior to placebo in the primary efficacy end-point, which was a composite of MI, stroke and cardiovascular death, it was associated a higher primary safety endpoint, which was major bleeding. Comparing 60mg to 90mg of ticagrelor, the 60mg dosage offered a better safety profile and fewer side effects of bleeding, dyspnea and attacks of gout. However, the results were not statistically significant.[41]


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