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Expanding Options: The New Era of Triple Antithrombotic Therapy after PCI
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Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor inhibitor is required to decrease the risk for acute and long-term thrombotic complications in patients undergoing PCI. Oral anticoagulation is recommended for patients with atrial fibrillation, mechanical heart valves, deep vein thrombosis, pulmonary embolism and left ventricular thrombi to decrease the risk for stroke or systemic thromboembolism.
Eric R. Bates
Therefore, there are some patients — and the number is increasing — who will require triple antithrombotic therapy for overlapping clinical indications, despite the increased risk for bleeding events with the combination treatment strategy of DAPT and oral anticoagulation (OAC).
Efficacy of Antithrombotic Therapy
DAPT has been shown to be superior to aspirin monotherapy or aspirin plus OAC in decreasing stent thrombosis, MI and CV death rates after PCI. The minimum duration of DAPT after bare-metal stent implantation is 4 weeks (2 weeks if the patient is at high risk for bleeding) because of rapid endothelialization of BMS struts, although 12 months is encouraged. In contrast, delayed endothelialization of drug-eluting stent struts has led to the recommendation that DAPT should be continued for at least 12 months after DES implantation. Some recent studies have suggested that 6 months may be sufficient with second-generation stents in which the risk for stent thrombosis may be lower due to thinner struts and improved polymer coatings. Randomized trials are currently comparing shorter- and longer-duration DAPT with 12 months of DAPT to clarify the debate on recommended treatment duration.
Nonvalvular AF is the most frequent indication for OAC. Previous studies have shown that OAC is superior to aspirin or DAPT in reducing the long-term risk for stroke. However, the net treatment benefit depends on the patient’s risk for both stroke and bleeding. The CHADS2 score is most commonly used to risk stratify patients. It is calculated by giving 1 point each for congestive HF, hypertension, age older than 74 years or diabetes mellitus; and 2 points for prior stroke or transient ischemic attack. The annual risk for stroke increases from 1.9% for a score of 0 to 12.5% for a score of 5. Patients with a CHADS2 score of 0 require no therapy, those with a CHADS2 score of 1 can be treated with DAPT or OAC, and those with increasing CHADS2 scores greater than 1 derive incremental benefit for stroke risk reduction with OAC compared with the annual bleeding risk of 1% to 2%.
A more recent risk score (CHA2DS2-VASc) additionally takes into account the extent of vascular disease, intermediate age and sex. It has better discrimination of stroke risk in low-risk patients, increasing the number of patients recommended for OAC. The recommended international normalized ratio (INR) target in AF is 2.0 to 3.0 because lower levels have been associated with increased stroke risk and higher levels have been associated with increased bleeding risk.
Triple Antithrombotic Therapy
Although cilostazol (Pletal, Otsuka Pharmaceutical) and vorapaxar (Merck) have been used with DAPT as triple antiplatelet therapy, triple antithrombotic therapy is usually defined as the combination of DAPT and OAC. Approximately 5% to 10% of patients undergoing PCI are candidates for triple therapy. Exposure time can be decreased by implanting a BMS in lesions with a lower risk for restenosis (eg, diameter >3 mm, length <15 mm or de novo lesions) and limiting DES to patients with smaller arteries, longer lesions or diabetes. After 4 weeks of triple therapy, treatment with OAC and one antiplatelet agent through 1 year is recommended and then OAC can be continued as monotherapy.
The risk for bleeding with 1 month of triple therapy is approximately 2%, which is small compared with the risk for stent thrombosis or stroke if DAPT and warfarin (Coumadin, Bristol-Myers Squibb) are not given in combination during that critical period; however, it increases to approximately 12% at 1 year, thus the concern about treatment duration. Managing bleeding that occurs on triple therapy is a complex problem. Severe or life-threatening bleeding requires reversal of warfarin therapy, and platelet transfusions may rarely be needed. If DAPT is discontinued, patients should be closely monitored for stent thrombosis. Therapy should be reinitiated as soon as possible.
Newer Antithrombotic Drugs
Prasugrel (Effient, Daiichi Sankyo/Eli Lilly) and ticagrelor (Brilinta, AstraZeneca) are more effective antiplatelet agents than clopidogrel (Plavix, Sanofi-Aventis) in patients with ACS. However, they also increase the risk for bleeding. Therefore, if these agents are ultimately shown to be superior to clopidogrel when included in triple antithrombotic therapy, the duration or dosing of these agents may need to be lowered to minimize bleeding risk.
Dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Janssen Pharmaceuticals) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) are more effective than warfarin in nonvalvular AF and cause less intracerebral hemorrhage. They should be attractive OAC options in patients requiring triple antithrombotic therapy, but this has yet to be proven in randomized trials or tested in clinical registries. Therefore, triple therapy should consist of aspirin, clopidogrel and warfarin until a superior strategy is proven to be safe and effective.
Recommendations
The American College of Cardiology, American Heart Association and European Society of Cardiology guideline committees have been cautious in recommending triple therapy due to the limited information about efficacy and safety. The ESC’s Working Group on Thrombosis (Table) and a North American consensus group have published treatment recommendations.
Conclusion
Triple antithrombotic therapy is required in patients with indications for both DAPT and OAC. The treatment goal is to minimize the exposure to triple therapy because of increased bleeding risk. The conundrum is that OAC withdrawal may increase the risk for stroke, whereas DAPT withdrawal may increase the risk for stent thrombosis, so the duration of triple therapy depends on the balance of risks.
Patients with deep venous thrombosis, pulmonary embolism or LV thrombi should have elective PCI deferred 3 to 6 months until OAC can be discontinued. For most patients on chronic OAC, postponing PCI is not an option. Patients with mechanical valves should have the INR target lowered to 2.5 to 3.0. Patients with AF at low risk for stroke (CHADS2 score 0 or 1) or high risk for bleeding (age ≥75 years, severe renal dysfunction, recent gastrointestinal bleed, prior stroke, uncontrolled hypertension) should be treated with DAPT alone after PCI. Patients who are at high risk for stroke (CHADS2 score ≥1) without high risk for bleeding should receive triple antithrombotic therapy with an INR target of 2.0 to 2.5. BMS should be implanted instead of DES, if possible, so that triple therapy exposure can be limited to 1 month. If DES are implanted, triple therapy should be limited to 3 to 6 months. Moreover, it is critically important to minimize bleeding risk by using low-dose aspirin (≤100 mg/day), avoiding concomitant nonsteroidal anti-inflammatory agent use and adding a proton pump inhibitor to the treatment regimen as prophylaxis against gastrointestinal bleeding.
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Eric R. Bates, MD, is professor of cardiovascular medicine at the University of Michigan, Ann Arbor, and is a Cardiology Today Intervention Editorial Board member.
Disclosure: Dr. Bates receives minor advisory board honoraria from all of the platelet drug companies mentioned in the article.