Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
FOCUS REVIEWS ON ISCHEMIC HEART DISEASE
Dual Antiplatelet Therapy for Coronary Artery Disease Cheol Whan Lee, MD
Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent placement, dual antiplatelet therapy (DAPT) with aspirin and ticlopidine dramatically reduces the risk of stent thrombosis, compared with anticoagulation therapy, and has become the standard of care for prevention of stent thrombosis. Clopidogrel is a second-generation thienopyridine that eliminates the serious side effects of ticlopidine, and new P2Y12 receptor blockers have emerged to overcome the limitations of clopidogrel. Current guidelines recommend DAPT with aspirin and clopidogrel for 1 month after implantation of bare-metal stents, and for 6–12 months after implantation of drug-eluting stents (DES). In patients with acute coronary syndrome (ACS), DAPT administration for 12 months was shown to be superior to aspirin alone for the prevention of recurrent events. Treatment with aspirin and new P2Y12 receptor blockers has further reduced the rate of cardiovascular death, myocardial infarction or stroke after ACS compared with aspirin and clopidogrel. Nonetheless, long-term DAPT increases the risk of major bleeding, requiring a delicate balance between anti-ischemic benefit and bleeding risk. In summary, DAPT should be maintained for at least 6–12 months after implantation of DES, and for at least 12 months after ACS, unless contraindicated. (Circ J 2015; 79: 255 – 262) Key Words: Acute coronary syndrome; Antiplatelet therapy; Drug-eluting stents
A
spirin prevents serious vascular events in patients at high risk of atherosclerosis.1,2 The mechanism of aspirin’s antiplatelet action was first described in 1971,3 but it took a long time before aspirin’s value was accepted in cardiovascular medicine. Early aspirin trials were mostly of questionable statistical significance. Moreover, the first large randomized trial, the Aspirin Myocardial Infarction Study (AMIS), showed that aspirin (1,000 mg/day) did not prevent cardiac death in patients who had already had a myocardial infarction (MI).4 Adverse side effects, including peptic ulcer and gastrointestinal bleeding, were higher in the aspirin group than in the placebo group. Based on the AMIS results, aspirin was not routinely recommended for patients who had survived a MI. In the large, randomized International Study of Infarct Survival (ISIS)-2, however, aspirin (160 mg/day) demonstrated a dramatic 23% reduction in vascular mortality compared with placebo in patients with acute MI.5 Thereafter, the use of aspirin in real-world clinical practice rapidly increased in advance of controlled studies, reflecting the ISIS-2 trial’s strong positive results.6 Furthermore, in most clinical studies, aspirin has become the default therapy for arterial thrombosis. Current guidelines recommend the use of low-dose aspirin (75– 325 mg/day) indefinitely for patients with established atherosclerotic cardiovascular disease.7
P2Y12 Receptor Blockers Evolution of P2Y12 Receptor Blockers Platelets are critical during the initial development of arterial
thrombi, and are activated when the vascular endothelium is damaged. Platelet activation can be triggered by many different agonists, including adenosine diphosphate, thromboxane A2, thrombin, etc. Adenosine diphosphate, as a P2Y12 receptor agonist, induces platelet degranulation and shape change, leading to amplification and stabilization of platelet aggregation.8 The central role of the P2Y12 receptor in platelet activation has made it a key target of antiplatelet agents. Ticlopidine, a firstgeneration thienopyridine, was discovered in 1972 and introduced as an antiplatelet agent in 1978. Despite its excellent antiplatelet effect, ticlopidine has rare but potentially fatal side effects, including aplastic anemia, neutropenia and thrombotic thrombocytopenic purpura, requiring routine hematological monitoring.9 Clopidogrel is a second-generation thienopyridine lacking the serious hematological side effects of ticlopidine and was approved for use in 1997. Clopidogrel has quickly replaced ticlopidine because of its equivalent efficacy and superior safety profile. P2Y12 receptor blocker development led to prasugrel and ticagrelor, which overcome the limitations of clopidogrel, such as delayed onset of action and high interindividual variability of antiplatelet response.10 Prasugrel is a third-generation thienopyridine with faster onset of action and less interindividual variability. It is more efficiently converted to an active metabolite than first- and second-generation thienopyridines. Thienopyridine derivatives exert their antiplatelet activity by irreversibly inhibiting the P2Y12 receptor. By contrast, ticagrelor is a new chemical class with faster onset of action and consistent platelet inhibition that does not require hepatic metabolism for its activity and causes reversible inhi-
Received December 9, 2014; accepted December 10, 2014; released online January 7, 2015 Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan, Seoul, Korea Mailing address: Cheol Whan Lee, MD, Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan, 88, Olympicro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1348 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, February 2015
256
LEE CW
Table 1. Randomized Clinical Trials Comparing P2Y12 Receptor Blockers to Aspirin Trial TASS AAASPS STAMI CAPRIE SOCRATES
Follow-up (months)
Primary endpoints
Ticlopidine vs. aspirin
36
Death/stroke
Ticlopidine vs. aspirin
24
Patients
n
Comparison
TIA, stroke
3,069
Stroke
1,470
Results
P value
RRR, 12%
0.048
95% CI (−2, 26) Vascular death/MI/ stroke
STEMI
1,809
Ticlopidine vs. aspirin
6
Death/MI/ stroke/angina
Post-MI, stroke, PAD
19,185
Clopidogrel vs. aspirin
23
Vascular death/MI/ stroke
TIA, stroke
9,600
Ticagrelor vs. aspirin
3
Death/MI/stroke
HR, 1.22
0.12
95% CI (0.94, 1.57) 8.0% vs. 8.0%
0.966
RRR, 8.7%
0.043
95% CI (0.3, 16.5) NCT01994720, ongoing
AAASPS, African American Antiplatelet Stroke Prevention Study; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; NA, not available; PAD, peripheral artery disease; RRR, relative risk reduction; STEMI, ST-elevation myocardial infarction; TASS, Ticlopidine Aspirin Stroke Study; TIA, transient ischemic attack.
bition of the P2Y12 receptor. P2Y12 Receptor Blockers vs. Aspirin Several randomized trials have investigated whether P2Y12 receptor blockers are safe and more effective than aspirin in patients with atherosclerotic cardiovascular disease (Table 1).11–14 In the Ticlopidine Aspirin Stroke Study (TASS), 3,069 patients with transient ischemic attack or mild stroke were randomized to take either ticlopidine (500 mg/day) or aspirin (1,300 mg/day).11 The 3-year event rate for death from any causes or nonfatal stroke was significantly lower in the ticlopidine group compared with the aspirin group (17% vs. 19%, respectively, P=0.048). The rates of fatal and nonfatal stroke at year 3 were 10% for ticlopidine and 13% for aspirin (P=0.024); however, skin rash and gastrointestinal side effects with severe reversible neutropenia were more common in the ticlopidine group than in the aspirin group. These findings suggest that ticlopidine may be more effective than aspirin at preventing strokes in patients with recent ischemic stroke; however, in the African American Antiplatelet Stroke Prevention Study (AAASPS), in which 1,809 African American patients with noncardioembolic ischemic stroke were randomized to receive either ticlopidine (500 mg/day) or aspirin (650 mg/day),13 the 2 drugs were similar in terms of preventing recurrent strokes. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial14 assessed the relative efficacy of clopidogrel (75 mg/day) and aspirin (325 mg/day) in reducing the risk of vascular death, MI or ischemic stroke (primary endpoints) in 19,185 patients with recent MI, recent ischemic stroke or symptomatic peripheral arterial disease. During a mean follow-up of 1.91 years, patients treated with clopidogrel had an annual 5.32% risk of primary endpoint compared with 5.83% with aspirin (relativerisk reduction 8.7%; 95% confidence interval [CI]; 0.3–16.5; P=0.043). The overall safety profile of clopidogrel was similar to that of aspirin. These findings show that clopidogrel is more effective than aspirin at preventing recurrent vascular events in patients with atherosclerotic vascular disease. Taken together, the thienopyridine derivatives seem to be slightly but significantly better than aspirin at preventing serious vascular events in patients with atherosclerotic cardiovascular disease. A large-scale randomized trial comparing the efficacy and safety of ticagrelor and aspirin in patients with acute stroke or transient ischemic attack is ongoing (Table 1) to assess the relative benefits of ticagrelor over aspirin in this population.
Antithrombotic Therapy for Stent Implantation Stent thrombosis has been a serious concern since the introduction of coronary artery stents in 1986. In early clinical experience, the rates of stent thrombosis were unacceptably high, approaching 20%.15 Optimal stent deployment with adjunctive dual antiplatelet therapy (DAPT) resulted in a marked reduction in stent thrombosis and bleeding complications.16–18 In the Stent Anticoagulation Restenosis Study (STARS),17 1,653 patients with successful stent placement were randomly assigned to 1 of 3 regimens: aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. Compared with aspirin alone (3.6%) and the combination of aspirin and warfarin (2.7%), the combination of aspirin and ticlopidine (0.5%) resulted in a lower rate of stent thrombosis within 30 days (P=0.001), demonstrating the superiority of aspirin and ticlopidine over aspirin and warfarin. DAPT with aspirin and clopidogrel for 1 month following bare-metal stent implantation was subsequently shown to be comparably effective and safer than aspirin and ticlopidine for the prevention of stent thrombosis,18 becoming the standard of care after coronary stent implantation.
DAPT After Drug-Eluting Stents (DES) Implantation DES have dramatically reduced the rate of restenosis and become the mainstream device for percutaneous coronary intervention (PCI); however, late stent thrombosis remains an important limitation of these devices,19 leading to the recommendation of DAPT with aspirin and clopidogrel for at least 6–12 months after placement.20,21 These recommendations were largely based on retrospective analyses with conflicting results,22–24 requiring adequately powered randomized controlled trials. Fortunately, several randomized controlled trials have been performed to determine the optimal duration of DAPT after DES implantation (Table 2).25–38 DAPT for 12 Months The benefit of DAPT beyond a 12-month period after PCI with DES was first tested in 2,701 patients who were free of major adverse cardiovascular events and major bleeding for at least 12 months after implantation.25 The cumulative risk of death from cardiac causes or MI at 24 months was 1.8% with DAPT, compared with 1.2% with aspirin monotherapy (hazard ratio [HR], 1.65; 95% CI: 0.80–3.36; P=0.17). No difference in the risk of bleeding complications was observed be-
Circulation Journal Vol.79, February 2015
DAPT for CAD
257
Table 2. Randomized Clinical Trials Comparing Short- and Long-Term DAPT After DES Implantation Trial
No. of patients
Stent type
Duration
ZEST/REAL-LATE
2,701
PES, SES, E-ZES
DES LATE
5,045
Any DES
ARTIC-interruption
1,259
DAPT
9,961
Primary endpoints
HR (95% CI)
P value
12 vs. >12 months
Cardiac death/MI
0.61 (0.30, 1.25)
0.17
12 vs. >12 months
Cardiac death/MI/stroke
0.94 (0.66, 1.35)
0.75
Any DES
12 vs. >12 months
Death/MI/stroke/ST/ urgent revascularization
1.17 (0.68, 2.03)
0.58
Any DES
12 vs. 30 months
ST or
3.45 (2.08–5.88)
FOCUS REVIEWS ON ISCHEMIC HEART DISEASE
Dual Antiplatelet Therapy for Coronary Artery Disease Cheol Whan Lee, MD
Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent placement, dual antiplatelet therapy (DAPT) with aspirin and ticlopidine dramatically reduces the risk of stent thrombosis, compared with anticoagulation therapy, and has become the standard of care for prevention of stent thrombosis. Clopidogrel is a second-generation thienopyridine that eliminates the serious side effects of ticlopidine, and new P2Y12 receptor blockers have emerged to overcome the limitations of clopidogrel. Current guidelines recommend DAPT with aspirin and clopidogrel for 1 month after implantation of bare-metal stents, and for 6–12 months after implantation of drug-eluting stents (DES). In patients with acute coronary syndrome (ACS), DAPT administration for 12 months was shown to be superior to aspirin alone for the prevention of recurrent events. Treatment with aspirin and new P2Y12 receptor blockers has further reduced the rate of cardiovascular death, myocardial infarction or stroke after ACS compared with aspirin and clopidogrel. Nonetheless, long-term DAPT increases the risk of major bleeding, requiring a delicate balance between anti-ischemic benefit and bleeding risk. In summary, DAPT should be maintained for at least 6–12 months after implantation of DES, and for at least 12 months after ACS, unless contraindicated. (Circ J 2015; 79: 255 – 262) Key Words: Acute coronary syndrome; Antiplatelet therapy; Drug-eluting stents
A
spirin prevents serious vascular events in patients at high risk of atherosclerosis.1,2 The mechanism of aspirin’s antiplatelet action was first described in 1971,3 but it took a long time before aspirin’s value was accepted in cardiovascular medicine. Early aspirin trials were mostly of questionable statistical significance. Moreover, the first large randomized trial, the Aspirin Myocardial Infarction Study (AMIS), showed that aspirin (1,000 mg/day) did not prevent cardiac death in patients who had already had a myocardial infarction (MI).4 Adverse side effects, including peptic ulcer and gastrointestinal bleeding, were higher in the aspirin group than in the placebo group. Based on the AMIS results, aspirin was not routinely recommended for patients who had survived a MI. In the large, randomized International Study of Infarct Survival (ISIS)-2, however, aspirin (160 mg/day) demonstrated a dramatic 23% reduction in vascular mortality compared with placebo in patients with acute MI.5 Thereafter, the use of aspirin in real-world clinical practice rapidly increased in advance of controlled studies, reflecting the ISIS-2 trial’s strong positive results.6 Furthermore, in most clinical studies, aspirin has become the default therapy for arterial thrombosis. Current guidelines recommend the use of low-dose aspirin (75– 325 mg/day) indefinitely for patients with established atherosclerotic cardiovascular disease.7
P2Y12 Receptor Blockers Evolution of P2Y12 Receptor Blockers Platelets are critical during the initial development of arterial
thrombi, and are activated when the vascular endothelium is damaged. Platelet activation can be triggered by many different agonists, including adenosine diphosphate, thromboxane A2, thrombin, etc. Adenosine diphosphate, as a P2Y12 receptor agonist, induces platelet degranulation and shape change, leading to amplification and stabilization of platelet aggregation.8 The central role of the P2Y12 receptor in platelet activation has made it a key target of antiplatelet agents. Ticlopidine, a firstgeneration thienopyridine, was discovered in 1972 and introduced as an antiplatelet agent in 1978. Despite its excellent antiplatelet effect, ticlopidine has rare but potentially fatal side effects, including aplastic anemia, neutropenia and thrombotic thrombocytopenic purpura, requiring routine hematological monitoring.9 Clopidogrel is a second-generation thienopyridine lacking the serious hematological side effects of ticlopidine and was approved for use in 1997. Clopidogrel has quickly replaced ticlopidine because of its equivalent efficacy and superior safety profile. P2Y12 receptor blocker development led to prasugrel and ticagrelor, which overcome the limitations of clopidogrel, such as delayed onset of action and high interindividual variability of antiplatelet response.10 Prasugrel is a third-generation thienopyridine with faster onset of action and less interindividual variability. It is more efficiently converted to an active metabolite than first- and second-generation thienopyridines. Thienopyridine derivatives exert their antiplatelet activity by irreversibly inhibiting the P2Y12 receptor. By contrast, ticagrelor is a new chemical class with faster onset of action and consistent platelet inhibition that does not require hepatic metabolism for its activity and causes reversible inhi-
Received December 9, 2014; accepted December 10, 2014; released online January 7, 2015 Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan, Seoul, Korea Mailing address: Cheol Whan Lee, MD, Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan, 88, Olympicro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1348 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, February 2015
256
LEE CW
Table 1. Randomized Clinical Trials Comparing P2Y12 Receptor Blockers to Aspirin Trial TASS AAASPS STAMI CAPRIE SOCRATES
Follow-up (months)
Primary endpoints
Ticlopidine vs. aspirin
36
Death/stroke
Ticlopidine vs. aspirin
24
Patients
n
Comparison
TIA, stroke
3,069
Stroke
1,470
Results
P value
RRR, 12%
0.048
95% CI (−2, 26) Vascular death/MI/ stroke
STEMI
1,809
Ticlopidine vs. aspirin
6
Death/MI/ stroke/angina
Post-MI, stroke, PAD
19,185
Clopidogrel vs. aspirin
23
Vascular death/MI/ stroke
TIA, stroke
9,600
Ticagrelor vs. aspirin
3
Death/MI/stroke
HR, 1.22
0.12
95% CI (0.94, 1.57) 8.0% vs. 8.0%
0.966
RRR, 8.7%
0.043
95% CI (0.3, 16.5) NCT01994720, ongoing
AAASPS, African American Antiplatelet Stroke Prevention Study; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; NA, not available; PAD, peripheral artery disease; RRR, relative risk reduction; STEMI, ST-elevation myocardial infarction; TASS, Ticlopidine Aspirin Stroke Study; TIA, transient ischemic attack.
bition of the P2Y12 receptor. P2Y12 Receptor Blockers vs. Aspirin Several randomized trials have investigated whether P2Y12 receptor blockers are safe and more effective than aspirin in patients with atherosclerotic cardiovascular disease (Table 1).11–14 In the Ticlopidine Aspirin Stroke Study (TASS), 3,069 patients with transient ischemic attack or mild stroke were randomized to take either ticlopidine (500 mg/day) or aspirin (1,300 mg/day).11 The 3-year event rate for death from any causes or nonfatal stroke was significantly lower in the ticlopidine group compared with the aspirin group (17% vs. 19%, respectively, P=0.048). The rates of fatal and nonfatal stroke at year 3 were 10% for ticlopidine and 13% for aspirin (P=0.024); however, skin rash and gastrointestinal side effects with severe reversible neutropenia were more common in the ticlopidine group than in the aspirin group. These findings suggest that ticlopidine may be more effective than aspirin at preventing strokes in patients with recent ischemic stroke; however, in the African American Antiplatelet Stroke Prevention Study (AAASPS), in which 1,809 African American patients with noncardioembolic ischemic stroke were randomized to receive either ticlopidine (500 mg/day) or aspirin (650 mg/day),13 the 2 drugs were similar in terms of preventing recurrent strokes. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial14 assessed the relative efficacy of clopidogrel (75 mg/day) and aspirin (325 mg/day) in reducing the risk of vascular death, MI or ischemic stroke (primary endpoints) in 19,185 patients with recent MI, recent ischemic stroke or symptomatic peripheral arterial disease. During a mean follow-up of 1.91 years, patients treated with clopidogrel had an annual 5.32% risk of primary endpoint compared with 5.83% with aspirin (relativerisk reduction 8.7%; 95% confidence interval [CI]; 0.3–16.5; P=0.043). The overall safety profile of clopidogrel was similar to that of aspirin. These findings show that clopidogrel is more effective than aspirin at preventing recurrent vascular events in patients with atherosclerotic vascular disease. Taken together, the thienopyridine derivatives seem to be slightly but significantly better than aspirin at preventing serious vascular events in patients with atherosclerotic cardiovascular disease. A large-scale randomized trial comparing the efficacy and safety of ticagrelor and aspirin in patients with acute stroke or transient ischemic attack is ongoing (Table 1) to assess the relative benefits of ticagrelor over aspirin in this population.
Antithrombotic Therapy for Stent Implantation Stent thrombosis has been a serious concern since the introduction of coronary artery stents in 1986. In early clinical experience, the rates of stent thrombosis were unacceptably high, approaching 20%.15 Optimal stent deployment with adjunctive dual antiplatelet therapy (DAPT) resulted in a marked reduction in stent thrombosis and bleeding complications.16–18 In the Stent Anticoagulation Restenosis Study (STARS),17 1,653 patients with successful stent placement were randomly assigned to 1 of 3 regimens: aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. Compared with aspirin alone (3.6%) and the combination of aspirin and warfarin (2.7%), the combination of aspirin and ticlopidine (0.5%) resulted in a lower rate of stent thrombosis within 30 days (P=0.001), demonstrating the superiority of aspirin and ticlopidine over aspirin and warfarin. DAPT with aspirin and clopidogrel for 1 month following bare-metal stent implantation was subsequently shown to be comparably effective and safer than aspirin and ticlopidine for the prevention of stent thrombosis,18 becoming the standard of care after coronary stent implantation.
DAPT After Drug-Eluting Stents (DES) Implantation DES have dramatically reduced the rate of restenosis and become the mainstream device for percutaneous coronary intervention (PCI); however, late stent thrombosis remains an important limitation of these devices,19 leading to the recommendation of DAPT with aspirin and clopidogrel for at least 6–12 months after placement.20,21 These recommendations were largely based on retrospective analyses with conflicting results,22–24 requiring adequately powered randomized controlled trials. Fortunately, several randomized controlled trials have been performed to determine the optimal duration of DAPT after DES implantation (Table 2).25–38 DAPT for 12 Months The benefit of DAPT beyond a 12-month period after PCI with DES was first tested in 2,701 patients who were free of major adverse cardiovascular events and major bleeding for at least 12 months after implantation.25 The cumulative risk of death from cardiac causes or MI at 24 months was 1.8% with DAPT, compared with 1.2% with aspirin monotherapy (hazard ratio [HR], 1.65; 95% CI: 0.80–3.36; P=0.17). No difference in the risk of bleeding complications was observed be-
Circulation Journal Vol.79, February 2015
DAPT for CAD
257
Table 2. Randomized Clinical Trials Comparing Short- and Long-Term DAPT After DES Implantation Trial
No. of patients
Stent type
Duration
ZEST/REAL-LATE
2,701
PES, SES, E-ZES
DES LATE
5,045
Any DES
ARTIC-interruption
1,259
DAPT
9,961
Primary endpoints
HR (95% CI)
P value
12 vs. >12 months
Cardiac death/MI
0.61 (0.30, 1.25)
0.17
12 vs. >12 months
Cardiac death/MI/stroke
0.94 (0.66, 1.35)
0.75
Any DES
12 vs. >12 months
Death/MI/stroke/ST/ urgent revascularization
1.17 (0.68, 2.03)
0.58
Any DES
12 vs. 30 months
ST or
3.45 (2.08–5.88)
