Dual antiplatelet therapy: Difference between revisions

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==Superiority of Dual Antiplatelet Therapy (Thienopyridine Plus Aspirin) Over Coumadin Plus Aspirin in PCI Patients==
==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 <ref>Hall P, Nakamura S, Maiello L, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996;93:215-222.</ref><ref>Urban P, Macayo C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary stenting (MATIS). Circulation 1998;98:2126-2132.</ref><ref>Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-1089.</ref><ref>Leon MG, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-1667.</ref><ref>Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:1597-1603.</ref>. While progress was made over [[Warfarin|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]]<ref>Steinhubl SR, Tan WA, Foody JM, et al., for the EPISTENT Investigators. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA 1999;281:806-810.</ref>. Given the improved side effect profile and the results of the CLASSICS study, [[clopidogrel]] has replaced [[ticlopidine]] as the [[thienopyridine]] of choice <ref>Bertrand ME, Hans-Jürgen R, et al., for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting. Circulation 2000;102:624-629.</ref><ref>Mueller C, Buttner JH, Petrerson J, et al. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101:590-593.</ref><ref>Taniuchi M, Kurz HI, Smith SC, et al. Ticlid or Plavix Post-Stents (TOPPS) (Abstr). Circulation 1999;100(Suppl I):I-379</ref>.
Several studies during the early stent era demonstrated the superiority of the combination of [[ticlopidine]] plus [[aspirin]] over [[coumadin]] plus aspirin. has deployment<ref>Hall P, Nakamura S, Maiello L, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996;93:215-222.</ref><ref>Urban P, Macayo C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary stenting (MATIS). Circulation 1998;98:2126-2132.</ref><ref>Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-1089.</ref><ref>Leon MG, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-1667.</ref><ref>Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:1597-1603.</ref>. While progress was made over [[Warfarin|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]].<ref>Steinhubl SR, Tan WA, Foody JM, et al., for the EPISTENT Investigators. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA 1999;281:806-810.</ref> Given the improved side effect profile and the results of the CLASSICS study, [[clopidogrel]] has replaced [[ticlopidine]] as the [[thienopyridine]] of choice.<ref>Bertrand ME, Hans-Jürgen R, et al., for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting. Circulation 2000;102:624-629.</ref><ref>Mueller C, Buttner JH, Petrerson J, et al. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101:590-593.</ref><ref>Taniuchi M, Kurz HI, Smith SC, et al. Ticlid or Plavix Post-Stents (TOPPS) (Abstr). Circulation 1999;100(Suppl I):I-379</ref>


==Data Indicating that the Addition of Aspirin to a Thienopyridine Improves Clinical Outcomes in Patients with Acute Coronary Syndromes==
==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]].<ref>Makkar RR, Eigler NL, Kaul S, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998;10:1538-1546.</ref><ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref><ref>Cadroy Y, Bossavy J, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000;101:2823-2828.</ref> 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).<ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref>  Further, aspirin added to clopidogrel was more effective than either aspirin or clopidogrel alone after activation with low dose thrombin (p < 0.05).<ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref>  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 shunts|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 shunts|arteriovenous shunt]].<ref name="pmid9759636">{{cite journal |author=Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P |title=The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit |journal=[[Thrombosis and Haemostasis]] |volume=80 |issue=3 |pages=512–8 |year=1998 |month=September |pmid=9759636 |doi= |url=http://www.schattauer.de/index.php?id=1268&L=1&pii=th98090512&no_cache=1 |issn= |accessdate=2010-07-02}}</ref> 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]].<ref name="pmid20435201">{{cite journal |author=Eshtehardi P, Windecker S, Cook S, Billinger M, Togni M, Garachemani A, Meier B, Hess OM, Wenaweser P |title=Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation |journal=[[American Heart Journal]] |volume=159 |issue=5 |pages=891–898.e1 |year=2010 |month=May |pmid=20435201 |doi=10.1016/j.ahj.2010.02.025 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-8703(10)00169-9 |issn= |accessdate=2010-07-02}}</ref><ref name="pmid16237868">{{cite journal |author=Wenaweser P, Hess O |title=Stent thrombosis is associated with an impaired response to antiplatelet therapy |journal=[[Journal of the American College of Cardiology]] |volume=46 |issue=5 |pages=CS5–6 |year=2005 |month=September |pmid=16237868 |doi= |url= |issn= |accessdate=2010-07-02}}</ref>
There is surrogate marker data indicating that the level of [[platelet]] inhibition is greater among patients in whom [[aspirin]] is added to a [[thienopyridine]].<ref>Makkar RR, Eigler NL, Kaul S, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998;10:1538-1546.</ref><ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref><ref>Cadroy Y, Bossavy J, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000;101:2823-2828.</ref> 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).<ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref>  Further, aspirin added to clopidogrel was more effective than either aspirin or clopidogrel alone after activation with low dose thrombin (p < 0.05).<ref>Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.</ref>  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 shunts|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 shunts|arteriovenous shunt]].<ref name="pmid9759636">{{cite journal |author=Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P |title=The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit |journal=[[Thrombosis and Haemostasis]] |volume=80 |issue=3 |pages=512–8 |year=1998 |month=September |pmid=9759636 |doi= |url=http://www.schattauer.de/index.php?id=1268&L=1&pii=th98090512&no_cache=1 |issn= |accessdate=2010-07-02}}</ref> 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]].<ref name="pmid20435201">{{cite journal |author=Eshtehardi P, Windecker S, Cook S, Billinger M, Togni M, Garachemani A, Meier B, Hess OM, Wenaweser P |title=Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation |journal=[[American Heart Journal]] |volume=159 |issue=5 |pages=891–898.e1 |year=2010 |month=May |pmid=20435201 |doi=10.1016/j.ahj.2010.02.025 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-8703(10)00169-9 |issn= |accessdate=2010-07-02}}</ref><ref name="pmid16237868">{{cite journal |author=Wenaweser P, Hess O |title=Stent thrombosis is associated with an impaired response to antiplatelet therapy |journal=[[Journal of the American College of Cardiology]] |volume=46 |issue=5 |pages=CS5–6 |year=2005 |month=September |pmid=16237868 |doi= |url= |issn= |accessdate=2010-07-02}}</ref>


==DAPT in Aspirin Intolerant Patients==
==DAPT in Aspirin Intolerant Patients==
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===STEMI===
===STEMI===
In patients with [[STEMI]] undergoing [[PCI]], the following are the guidlelines for the use of DAPT<ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD,''et al.'' |title=2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines|journal=Circulation |volume= |issue= |pages= |year=2012|month=December|pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84 |url=}}</ref>:
In patients with [[STEMI]] undergoing [[PCI]], the following are the guidelines for the use of DAPT<ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD,''et al.'' |title=2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines|journal=Circulation |volume= |issue= |pages= |year=2012|month=December|pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84 |url=}}</ref>:


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===Short-Term Use 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]]<ref name="pmid17664375">{{cite journal |vauthors=Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E |title=Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment |journal=Circulation |volume=116 |issue=7 |pages=745–54 |year=2007 |pmid=17664375 |doi=10.1161/CIRCULATIONAHA.106.686048 |url=}}</ref>. 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<ref name="pmid25790881">{{cite journal |vauthors=Mehran R, Giustino G, Baber U |title=DAPT duration after DES: what is the "mandatory" duration? |journal=J. Am. Coll. Cardiol. |volume=65 |issue=11 |pages=1103–6 |year=2015 |pmid=25790881 |doi=10.1016/j.jacc.2015.01.024 |url=}}</ref>. 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<ref name="pmid17664375">{{cite journal |vauthors=Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E |title=Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment |journal=Circulation |volume=116 |issue=7 |pages=745–54 |year=2007 |pmid=17664375 |doi=10.1161/CIRCULATIONAHA.106.686048 |url=}}</ref>.
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]]<ref name="pmid17664375">{{cite journal |vauthors=Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E |title=Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment |journal=Circulation |volume=116 |issue=7 |pages=745–54 |year=2007 |pmid=17664375 |doi=10.1161/CIRCULATIONAHA.106.686048 |url=}}</ref>. 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<ref name="pmid25790881">{{cite journal |vauthors=Mehran R, Giustino G, Baber U |title=DAPT duration after DES: what is the "mandatory" duration? |journal=J. Am. Coll. Cardiol. |volume=65 |issue=11 |pages=1103–6 |year=2015 |pmid=25790881 |doi=10.1016/j.jacc.2015.01.024 |url=}}</ref>. 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.<ref name="pmid17664375">{{cite journal |vauthors=Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E |title=Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment |journal=Circulation |volume=116 |issue=7 |pages=745–54 |year=2007 |pmid=17664375 |doi=10.1161/CIRCULATIONAHA.106.686048 |url=}}</ref>


=== ''The Leaders Free Trial'' ===
=== 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 [[Percutaneous coronary intervention|PCI]] and [[Antithrombotic therapy|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 stent|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<ref name="pmid27806919">{{cite journal |vauthors=Garot P, Morice MC, Tresukosol D, Pocock SJ, Meredith IT, Abizaid A, Carrié D, Naber C, Iñiguez A, Talwar S, Menown IB, Christiansen EH, Gregson J, Copt S, Hovasse T, Lurz P, Maillard L, Krackhardt F, Ong P, Byrne J, Redwood S, Windhövel U, Greene S, Stoll HP, Urban P |title=Two-Year Outcomes of High Bleeding Risk Patients after Polymer-Free Drug-Coated Stents |journal=J. Am. Coll. Cardiol. |volume= |issue= |pages= |year=2016 |pmid=27806919 |doi=10.1016/j.jacc.2016.10.009 |url=}}</ref>.
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 [[Percutaneous coronary intervention|PCI]] and [[Antithrombotic therapy|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 stent|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<ref name="pmid27806919">{{cite journal |vauthors=Garot P, Morice MC, Tresukosol D, Pocock SJ, Meredith IT, Abizaid A, Carrié D, Naber C, Iñiguez A, Talwar S, Menown IB, Christiansen EH, Gregson J, Copt S, Hovasse T, Lurz P, Maillard L, Krackhardt F, Ong P, Byrne J, Redwood S, Windhövel U, Greene S, Stoll HP, Urban P |title=Two-Year Outcomes of High Bleeding Risk Patients after Polymer-Free Drug-Coated Stents |journal=J. Am. Coll. Cardiol. |volume= |issue= |pages= |year=2016 |pmid=27806919 |doi=10.1016/j.jacc.2016.10.009 |url=}}</ref>.
===Long-Term Use of DAPT===
===Long-Term Use of DAPT===
====The DAPT score====
====The DAPT trial====
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]]). A low DAPT score is associated with a higher risk of bleeding and a smaller reduction in ischemia. On the other hand, a high DAPT score translates into a greater reduction in ischemia, with a smaller risk of bleeding. The cut-off point has been set at the value of 2, such that a score of ≥2 is associated with a favorable benefit-to-risk ratio for prolonged DAPT, while a score of less than 2 is associated with an unfavorable benefit-to-risk ratio<ref name="pmid25399658">{{cite journal |vauthors=Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM |title=Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents |journal=N. Engl. J. Med. |volume=371 |issue=23 |pages=2155–66 |year=2014 |pmid=25399658 |pmc=4481318 |doi=10.1056/NEJMoa1409312 |url=}}</ref>.
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.<ref name="pmid25399658">{{cite journal |vauthors=Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM |title=Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents |journal=N. Engl. J. Med. |volume=371 |issue=23 |pages=2155–66 |year=2014 |pmid=25399658 |pmc=4481318 |doi=10.1056/NEJMoa1409312 |url=}}</ref> 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:<ref name="pmid27595509">{{cite journal |vauthors=Giustino G, Chieffo A, Palmerini T, Valgimigli M, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Gilard M, Morice MC, Sawaya F, Sardella G, Genereux P, Redfors B, Leon MB, Bhatt DL, Stone GW, Colombo A |title=Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI |journal=J. Am. Coll. Cardiol. |volume=68 |issue=17 |pages=1851–1864 |year=2016 |pmid=27595509 |doi=10.1016/j.jacc.2016.07.760 |url=}}</ref>
*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.<ref name="pmid26398078">{{cite journal |vauthors=Bonaca MP, Braunwald E, Sabatine MS |title=Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction |journal=N. Engl. J. Med. |volume=373 |issue=13 |pages=1274–5 |year=2015 |pmid=26398078 |doi=10.1056/NEJMc1508692 |url=}}</ref>
==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]]).<ref name="pmid25399658" />
===DAPT Score Calculator===
Shown below is the calculator for the DAPT score (check all the boxes that apply):
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===Interpretation===
====''The DAPT trial''====
* Score <2: Higher risk of bleeding and a smaller reduction in ischemia, associated with an unfavorable benefit-to-risk ratio for prolonged DAPT
''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.<ref name="pmid25399658">{{cite journal |vauthors=Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM |title=Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents |journal=N. Engl. J. Med. |volume=371 |issue=23 |pages=2155–66 |year=2014 |pmid=25399658 |pmc=4481318 |doi=10.1056/NEJMoa1409312 |url=}}</ref> 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<ref name="pmid27595509">{{cite journal |vauthors=Giustino G, Chieffo A, Palmerini T, Valgimigli M, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Gilard M, Morice MC, Sawaya F, Sardella G, Genereux P, Redfors B, Leon MB, Bhatt DL, Stone GW, Colombo A |title=Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI |journal=J. Am. Coll. Cardiol. |volume=68 |issue=17 |pages=1851–1864 |year=2016 |pmid=27595509 |doi=10.1016/j.jacc.2016.07.760 |url=}}</ref>:
* Score ≥2: Smaller risk of bleeding and a greater reduction in ischemia, associated with a favorable benefit-to-risk ratio for prolonged DAPT
*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 end point, 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.<ref name="pmid26398078">{{cite journal |vauthors=Bonaca MP, Braunwald E, Sabatine MS |title=Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction |journal=N. Engl. J. Med. |volume=373 |issue=13 |pages=1274–5 |year=2015 |pmid=26398078 |doi=10.1056/NEJMc1508692 |url=}}</ref>


==References==
==References==

Revision as of 00:49, 1 February 2019


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. T​he 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 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]

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]

DAPT Score Calculator

Shown below is the calculator for the DAPT score (check all the boxes that apply):

Variable Points
Age ≥75 years -2
Age 65 to less than 75 years -1
Age less than 65 years 0
Current cigarette smoker 1
Diabetes Mellitus 1
MI at presentation 1
Prior PCI or prior MI 1
Prior PCI or prior MI 1
Stent diameter less than 3mm 1
Paclitaxel-eluting stent 1
CHF or LVEF less than 30% 2
Saphenous vein graft PCI 2

Interpretation

  • Score <2: Higher risk of bleeding and a smaller reduction in ischemia, associated with an unfavorable benefit-to-risk ratio for prolonged DAPT
  • Score ≥2: Smaller risk of bleeding and a greater reduction in ischemia, associated with a favorable benefit-to-risk ratio for prolonged DAPT

References

  1. ↑ Hall P, Nakamura S, Maiello L, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996;93:215-222.
  2. ↑ Urban P, Macayo C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary stenting (MATIS). Circulation 1998;98:2126-2132.
  3. ↑ Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-1089.
  4. ↑ Leon MG, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-1667.
  5. ↑ Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:1597-1603.
  6. ↑ Steinhubl SR, Tan WA, Foody JM, et al., for the EPISTENT Investigators. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA 1999;281:806-810.
  7. ↑ Bertrand ME, Hans-Jürgen R, et al., for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting. Circulation 2000;102:624-629.
  8. ↑ Mueller C, Buttner JH, Petrerson J, et al. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101:590-593.
  9. ↑ Taniuchi M, Kurz HI, Smith SC, et al. Ticlid or Plavix Post-Stents (TOPPS) (Abstr). Circulation 1999;100(Suppl I):I-379
  10. ↑ Makkar RR, Eigler NL, Kaul S, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998;10:1538-1546.
  11. ↑ Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.
  12. ↑ Cadroy Y, Bossavy J, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000;101:2823-2828.
  13. ↑ Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.
  14. ↑ Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: Enhanced inhibitory effects of combination therapy. J Am Coll Cardiol 2000;36:699-705.
  15. ↑ Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P (1998). "The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit". Thrombosis and Haemostasis. 80 (3): 512–8. PMID 9759636. Retrieved 2010-07-02. Unknown parameter |month= ignored (help)
  16. ↑ Eshtehardi P, Windecker S, Cook S, Billinger M, Togni M, Garachemani A, Meier B, Hess OM, Wenaweser P (2010). "Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation". American Heart Journal. 159 (5): 891–898.e1. doi:10.1016/j.ahj.2010.02.025. PMID 20435201. Retrieved 2010-07-02. Unknown parameter |month= ignored (help)
  17. ↑ Wenaweser P, Hess O (2005). "Stent thrombosis is associated with an impaired response to antiplatelet therapy". Journal of the American College of Cardiology. 46 (5): CS5–6. PMID 16237868. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  18. ↑ Machraoui A, Germing A, Lindstaedt M, et al. Efficacy and safety of ticlopidine monotherapy versus ticlopidine and aspirin after coronary artery stenting. Follow-up results of a randomized study. J Invas Cardiol 2001;13:431-436.
  19. ↑ Awtry EH, Loscalzo J. Aspirin. Cardiovascular Drugs. Circulation 2000;101:1206-1218.
  20. ↑ Wilson S, Rihal CS, Bell MR, et al. Timing of coronary stent thrombosis in patients treated with ticlopidine and aspirin. Am J Cardiol 1999;83:1006-1011.
  21. ↑ Schiano P, Steg PG, Barbou F, Monségu J (2012). "A strategy for addressing aspirin hypersensitivity in patients requiring urgent PCI". Eur Heart J Acute Cardiovasc Care. 1 (1): 75–8. doi:10.1177/2048872612441580. PMC 3760547. PMID 24062892.
  22. ↑ Lambrakis P, Rushworth GF, Adamson J, Leslie SJ (2011). "Aspirin hypersensitivity and desensitization protocols: implications for cardiac patients". Ther Adv Drug Saf. 2 (6): 263–70. doi:10.1177/2042098611422558. PMC 4110834. PMID 25083218.
  23. ↑ McMullan KL, Wedner HJ (2013). "Safety of aspirin desensitization in patients with reported aspirin allergy and cardiovascular disease". Clin Cardiol. 36 (1): 25–30. doi:10.1002/clc.22054. PMID 22990948.
  24. ↑ 24.0 24.1 24.2 Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O'Gara PT, Sabatine MS, Smith PK, Smith SC, Halperin JL, Levine GN, Al-Khatib SM, Birtcher KK, Bozkurt B, Brindis RG, Cigarroa JE, Curtis LH, Fleisher LA, Gentile F, Gidding S, Hlatky MA, Ikonomidis JS, Joglar JA, Pressler SJ, Wijeysundera DN (2016). "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". J. Thorac. Cardiovasc. Surg. 152 (5): 1243–1275. doi:10.1016/j.jtcvs.2016.07.044. PMID 27751237.
  25. ↑ Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA (2014). "Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". Stroke. 45 (7): 2160–236. doi:10.1161/STR.0000000000000024. PMID 24788967.
  26. ↑ Kushner FG, Hand M, Smith SC, King SB, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO (2009). "2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 54 (23): 2205–41. doi:10.1016/j.jacc.2009.10.015. PMID 19942100. Retrieved 2011-12-06. Unknown parameter |month= ignored (help)
  27. ↑ O'Gara PT, Kushner FG, Ascheim DD; et al. (2012). "2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. doi:10.1161/CIR.0b013e3182742c84. PMID 23247303. Unknown parameter |month= ignored (help)
  28. ↑ Mehta SR, Bassand JP, Chrolavicius S; et al. (2010). "Dose comparisons of clopidogrel and aspirin in acute coronary syndromes". N. Engl. J. Med. 363 (10): 930–42. doi:10.1056/NEJMoa0909475. PMID 20818903. Unknown parameter |month= ignored (help)
  29. ↑ "Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients". BMJ. 324 (7329): 71–86. 2002. PMC 64503. PMID 11786451. Unknown parameter |month= ignored (help)
  30. ↑ Smith SC, Benjamin EJ, Bonow RO; et al. (2011). "AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation". Circulation. 124 (22): 2458–73. doi:10.1161/CIR.0b013e318235eb4d. PMID 22052934. Unknown parameter |month= ignored (help)
  31. ↑ Mehta SR, Tanguay JF, Eikelboom JW; et al. (2010). "Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial". Lancet. 376 (9748): 1233–43. doi:10.1016/S0140-6736(10)61088-4. PMID 20817281. Unknown parameter |month= ignored (help)
  32. ↑ 32.0 32.1 Chen ZM, Jiang LX, Chen YP; et al. (2005). "Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial". Lancet. 366 (9497): 1607–21. doi:10.1016/S0140-6736(05)67660-X. PMID 16271642. Unknown parameter |month= ignored (help)
  33. ↑ 33.0 33.1 Sabatine MS, Cannon CP, Gibson CM; et al. (2005). "Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation". N. Engl. J. Med. 352 (12): 1179–89. doi:10.1056/NEJMoa050522. PMID 15758000. Unknown parameter |month= ignored (help)
  34. ↑ Wiviott SD, Braunwald E, McCabe CH; et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes". N. Engl. J. Med. 357 (20): 2001–15. doi:10.1056/NEJMoa0706482. PMID 17982182. Unknown parameter |month= ignored (help)
  35. ↑ Montalescot G, Wiviott SD, Braunwald E; et al. (2009). "Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial". Lancet. 373 (9665): 723–31. doi:10.1016/S0140-6736(09)60441-4. PMID 19249633. Unknown parameter |month= ignored (help)
  36. ↑ 36.0 36.1 Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E (2007). "Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment". Circulation. 116 (7): 745–54. doi:10.1161/CIRCULATIONAHA.106.686048. PMID 17664375.
  37. ↑ Mehran R, Giustino G, Baber U (2015). "DAPT duration after DES: what is the "mandatory" duration?". J. Am. Coll. Cardiol. 65 (11): 1103–6. doi:10.1016/j.jacc.2015.01.024. PMID 25790881.
  38. ↑ Garot P, Morice MC, Tresukosol D, Pocock SJ, Meredith IT, Abizaid A, Carrié D, Naber C, Iñiguez A, Talwar S, Menown IB, Christiansen EH, Gregson J, Copt S, Hovasse T, Lurz P, Maillard L, Krackhardt F, Ong P, Byrne J, Redwood S, Windhövel U, Greene S, Stoll HP, Urban P (2016). "Two-Year Outcomes of High Bleeding Risk Patients after Polymer-Free Drug-Coated Stents". J. Am. Coll. Cardiol. doi:10.1016/j.jacc.2016.10.009. PMID 27806919.
  39. ↑ 39.0 39.1 Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM (2014). "Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents". N. Engl. J. Med. 371 (23): 2155–66. doi:10.1056/NEJMoa1409312. PMC 4481318. PMID 25399658.
  40. ↑ Giustino G, Chieffo A, Palmerini T, Valgimigli M, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Gilard M, Morice MC, Sawaya F, Sardella G, Genereux P, Redfors B, Leon MB, Bhatt DL, Stone GW, Colombo A (2016). "Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI". J. Am. Coll. Cardiol. 68 (17): 1851–1864. doi:10.1016/j.jacc.2016.07.760. PMID 27595509.
  41. ↑ Bonaca MP, Braunwald E, Sabatine MS (2015). "Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction". N. Engl. J. Med. 373 (13): 1274–5. doi:10.1056/NEJMc1508692. PMID 26398078.

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