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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Antiplatelet treatment in non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention (ISAR-REACT 2 insight)

Dariusz Dudek1,2,*, Artur Dziewierz2, Bernadeta Chyrchel2, Lech Polonski3, Jacek Legutko2 and Jacek S. Dubiel2

1 Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Kopernika 17, 31-501 Krakow, Poland
2 2nd Department of Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Kopernika 17, 31-501 Krakow, Poland
3 Department of Cardiology, Silesian Center for Heart Diseases, Szpitalna 2, 41-800 Zabrze, Poland

* Corresponding author. Tel: +48 12 424 71 81; fax: +48 12 424 71 84. E-mail address: mcdudek{at}cyf-kr.edu.pl


   Abstract
Top
 Abstract
Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
 References
 
Non-ST-segment elevation acute coronary syndrome (NSTEACS) is the leading cause of hospital admission for ischaemic heart disease. Despite major progress in diagnosis and treatment, NSTEACS remains to be associated with poor short- and long-term prognoses. For this reason, it appears reasonable to follow the guidelines of the European Society of Cardiology and recommend optimal and intensive pharmacotherapy including antiplatelet agents and invasive cardiac procedures, especially in NSTEACS patients at high risk of death and/or myocardial infarction. Aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors are the most frequent antiplatelet agents used for the treatment of NSTEACS. This article summarizes current recommendations for use those agents in NSTEACS treatment.

Key Words: Non-ST-elevation • Acute coronary syndromes • Pharmacotherapy • Clopidogrel • GPIIb/IIIa inhibitors • Antithrombotic therapy


   Aspirin
Top
 Abstract
 Aspirin
Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
 References
 
Currently, the European Society of Cardiology recommends aspirin (a 300 mg loading dose and a 75–100 mg maintenance dose) in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients receiving both conservative and interventional treatment (Table 1).1,2 Randomized studies demonstrated the usefulness of aspirin in the acute phase of unstable angina.3,4 Collaborative meta-analysis showed reduced risk of cardiovascular death, myocardial infarction, and stroke by 46% in NSTEACS patients (from 13.3 to 8.0%).5 Nevertheless, treatment with aspirin alone does not appear to protect sufficiently from ischaemic events in most cases, especially in high-risk subjects. Moreover, patients admitted with NSTEACS already receiving aspirin chronically have a higher short-term risk for cardiovascular events and require more aggressive antiplatelet therapy or other therapeutic approach.6,7


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  		Table 1 Recommendations for antiplatelet and antithrombotic therapy in NSTEACS patients treated with PCI.2

 

   Clopidogrel
Top
 Abstract
 Aspirin
 Clopidogrel
GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
 References
 
Clopidogrel is a thienopyridine derivative that irreversibly inhibits platelet aggregation induced by adenosine diphosphate. It is used routinely in combination with aspirin to reduce the risk of acute or subacute in-stent thrombosis after percutaneous coronary interventions (PCI).2,8–10 The Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) study involving 12 562 patients evaluated the efficacy of clopidogrel combined with aspirin in NSTEACS patients. The loading dose of clopidogrel 300 mg, followed by maintenance doses for a mean of 9 months, reduced significantly the combined endpoint (cardiovascular death, non-fatal myocardial infarction, and stroke) from 11.4 to 9.3%, RR = 0.8, P < 0.001 as compared with placebo. There was also a significant reduction of recurrent ischaemia during hospitalization among patients receiving clopidogrel with the benefit showing within the first hours of enrolment.11 Moreover, patients undergoing PCI (PCI-CURE) also benefited from clopidogrel.12 However, the use of clopidogrel was associated with increased major (3.7 vs. 2.7%, P = 0.02) and minor (5.1 vs. 2.4%, P < 0.001) bleeding rates as compared with placebo. Overall, the benefits of reduced ischaemic complications after clopidogrel overweighed the bleeding risk. Both in patients receiving placebo and clopidogrel, the bleeding risk increased in relation to the aspirin dose: for aspirin ≤100, 100–300, and >300 mg, the major bleeding rates were 2.0, 2.2, and 4.0% among those receiving placebo and 2.5, 3.5, and 3.9% among those treated with clopidogrel.11 For this reason, the current guidelines recommend the reduction of aspirin dose to 75–100 mg/day when combined with clopidogrel for chronic use.

Recent studies have shown that clopidogrel in the standard loading dose (300 mg) may be insufficient to achieve early and more profound antiplatelet effect. In the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-2) study, the use of a 600 mg loading dose of clopidogrel 4–8 h prior to planned PCI was associated with a reduction of the composite endpoint (death/myocardial infarction/target vessel revascularization) within 30 days as compared with the standard loading dose (high vs. standard loading dose; 4 vs. 12%, P = 0.041). This favourable effect was associated mainly with reduction in risk of periprocedural myocardial infarction.13 The benefits of high-dose clopidogrel are related mainly to a short time interval (4–8 h) between clopidogrel administration and PCI (the higher dose provides quicker onset of action). The objective of the Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation, and Ongoing Necrosis (ALBION) study was to identify additional benefits of higher loading doses of clopidogrel (600 and 900 mg) in NSTEACS patients.14 In this study, the higher loading doses induced faster onset of action and higher levels of inhibition of platelet aggregation than the standard loading dose (300 mg). There was also a trend towards reduced markers of myocardial necrosis (troponin I) within the first 24 h after initiating treatment with the increasing loading dose (300 vs. 600 vs. 900 mg; 34.6 vs. 42.9 vs. 50.0%, P = NS). There was no difference in the rate of ischaemic complications between the study groups. The use of high loading doses did not increase the bleeding risk.14 High loading dose reduces also the incidence of non-responsiveness and high post-treatment platelet aggregation as compared with a 300 mg dose.15 More importantly, evidence supports a relationship between an inadequate pharmacologic response to aspirin and clopidogrel with increased risk of cardiovascular events in long-term follow-up.16 In this context, high doses of clopidogrel (600 and 900 mg) may be of major clinical benefit to patients with NSTEACS, especially when fast platelet inhibition is desired before interventional treatment. However, a 900 mg loading dose is not recommended for routine clinical use.

Clopidogrel should be initiated as quickly as possible in patients with NSTEACS and the current guidelines recommend high loading doses of clopidogrel.2 Initiation of antiplatelet treatment in high-risk patients with a greater probability of multiple vessel disease and/or left main stenosis requiring coronary artery bypass grafting is still a matter of debate. The CURE study showed a trend towards increased bleeding rates in patients undergoing bypass grafting in whom clopidogrel was not discontinued 5 days prior to the procedure (9.6 vs. 6.3%, P = 0.06).11 On the other hand, high-risk patients may potentially receive the most benefit from early antiplatelet treatment.17 Recent studies have shown that coronary artery bypass grafting in patients receiving clopidogrel may be associated with the reduction of ischaemic complications (death, myocardial infarction, and stroke) in the periprocedural period.18 Progress in surgical revascularization techniques and wide use of aminocaproic acid, aprotinin (?) and other antifibrinolytic agents also lead to the reduction of bleeding risk related to cardiac surgery.19 In some individuals, it is also possible to discontinue clopidogrel 5 days before coronary artery bypass grafting to reduce bleeding risk. In those patients, it seems justified to initiate treatment with rapidly reversible small molecule GPIIb/IIIa inhibitors to maintain the antiplatelet effect while waiting for the operation.1

Thienopyridine derivatives appear to show some promise. Prasugrel, a novel platelet inhibitor provides a faster and more profound antiplatelet effect than clopidogrel. When used in patients undergoing PCI, it reduced the risk of PCI-related thrombosis and showed a trend towards reduction of other ischaemic complications as compared with patients receiving clopidogrel. The rate of bleeding events was similar in both groups.20 The efficacy and safety of prasugrel vs. clopidogrel in patients with ACS undergoing PCI is currently being evaluated in the Trial to assess Improvement of Therapeutic outcomes by Optimizing platelet inhibitioN with prasugrel-TIMI 38 study (TRITON-TIMI 38). AZD6140 is a reversible inhibitor of the P2Y12 receptor. Its efficacy and safety was evaluated in the DISPERSE 2-TIMI 33 study (safety, tolerability, and preliminary efficacy of AZD6140, the first oral reversible adp receptor antagonist, compared with clopidogrel in patients with NSTEACS). The rates of bleeding and ischaemic events were similar in patients receiving AZD6140 and clopidogrel. Also, potent, short-acting intravenous P2Y12 receptor inhibitor (cangrelor) is in phase III clinical trials. Among platelet inhibitors, the rapidity of onset and reversibility are unique to this agent with potential therapeutic and safety implications during NSTEACS treatment, such as those targeted for an early invasive strategy, in need of urgent percutaneous or emergent surgical revascularization.21


   GPIIb/IIIa inhibitors
Top
 Abstract
 Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
 References
 
The clinical benefits of GPIIb/IIIa inhibitors have been documented in NSTEACS patients both treated conservatively and undergoing PCI.2,22,23 The current European Society of Cardiology guidelines recommend GPIIb/IIIa inhibitors, especially in NSTEACS patients at high risk of thrombotic complications.2 It is not clear yet which GPIIb/IIIa inhibitor and when should be optimally administered (before or after coronary angiography).

Boersma et al.23 in a meta-analysis of six randomized clinical trials (GUSTO IV-ACS, PARAGON A, PARAGON B, PRISM, PRISM-PLUS, and PURSUIT) involving 31 402 patients with NSTEACS not undergoing routine PCI showed that GPIIb/IIIa inhibitors significantly reduced the risk of death or myocardial infarction as compared with placebo at 30-day follow-up (10.8 vs. 11.8%, OR 0.91, P = 0.015). The therapeutic outcome was most pronounced in high-risk patients including those with positive troponin levels and patients undergoing PCI. Roffi et al.24 in a similar group of patients showed a significant reduction of 30-day mortality after the use of GPIIb/IIIa inhibitors in patients with NSTEACS and diabetes mellitus (30-day mortality: GPIIb/IIIa inhibitor vs. placebo, 6.2 vs. 4.6%, OR 0.74, P = 0.007; including patients undergoing PCI 4.0 vs. 1.2%, OR 0.3, P = 0.002). The National Registry of Myocardial Infarction confirms these findings.25

The current European Society of Cardiology guidelines strongly recommend coronary angiography followed by PCI in high-risk patients with NSTEACS.1,2 Multiple randomized studies confirm the advantages of invasive treatment over pharmacotherapy.26 The FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) study on PCI was performed in 71% of patients treated invasively and only in 9% of conservatively treated individuals.26 In that study, PCI was associated with increased risk of early ischaemic complications (myocardial infarction) within 30 days, but ultimately significantly reduced the combined endpoint of death and myocardial infarction at 6 and 12 months. The increased periprocedural risk of PCI was mainly associated with a low rate of using intravenous GPIIb/IIIa inhibitors during the procedure (10% of patients).26 Aggressive antiplatelet treatment with a GPIIb/IIIa inhibitor in a large number of patients (94% of patients received trofiban) in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI 18) eliminated early risk of periprocedural ischaemic complications and significantly reduced complication rates in patients treated invasively (invasive vs. non-invasive treatment; death, myocardial infarction, and rehospitalization within 30 days, 7.4 vs. 10.5%, P = 0.009; death and myocardial infarction within 30 days, 4.7 vs. 7.0%, P = 0.02). The beneficial effect continued until 6 months of follow-up.27 Also, data from the Polish Registry of Acute Coronary Syndromes (PL-ACS) definitely confirm the benefit of invasive strategy implementation during hospital stay in NSTEACS patients. In a group of 108 880 patients admitted with ACS in between October 2003 and September 2006, 75 069 (68.9%) patients were diagnosed with NSTEACS. In 29.5% of them, coronary angiography was performed, whereas 19.1% were treated with PCI. Coronary artery bypass grafting was undertaken in 1.1% of all cases. In-hospital mortality was significantly higher in the group with conservative treatment (conservative vs. invasive, 3.7 vs. 1.4%, P < 0.001). Similarly, a reduction of myocardial infarction occurrence was observed (2.9 vs. 1.6%, P < 0.001), and in combined endpoint (death + non-fatal myocardial infarction + stroke, 6.4 vs. 3.0%, P < 0.001) (Lech Polonski, PL-ACS registry principal investigator, personal communication).

It is difficult to determine the optimal time for intervention in patients with NSTEACS. Delay of intervention may potentially favour plaque stabilization and reduce the risk of thrombus formation at PCI site, and in this way reduce the risk of distal microembolization and periprocedural myocardial infarction. On the other hand, Kereiakes et al.28 showed that early PCI with stent implantation in 81% of patients and intravenous GPIIb/IIIa inhibitor (abciximab) in 75% of patients is associated with a very low risk of ischaemic complications of PCI. The Intracoronary Stenting with Antithrombotic Regimen Cooling-Off Trial (ISAR-COOL) study compared the strategy of immediate PCI in high-risk patients with NSTEACS with the pharmacological cooling-off using aspirin, clopidogrel, and tirofiban and performing PCI 3–5 days after pretreatment. Very early PCI (mean 2.4 h after the onset of symptoms) resulted in a 50% reduction of the composite endpoint (death and myocardial infarction at 30 days, 5.9 vs. 11.6%, P = 0.04).29 In this context, the delay of PCI to achieve pharmacological stabilization is not warranted. If very early invasive strategy is not possible for organizational reasons, a solution is to administer early intravenous GPIIb/IIIa inhibitors followed by PCI within 48 h after the onset of symptoms.2 The potential benefits of such a strategy were confirmed by the TACTICS-TIMI 18 study in which the composite rate of death and myocardial infarction (4.7%) was the lowest among all studies performed in NSTEACS patients.30 Combined analysis of the results of Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial (CAPTURE) study with abciximab, PURSUIT with eptifibatide and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM PLUS) with tirofiban showed that early intravenous administration of GPIIb/IIIa inhibitors not only reduced ischaemic complications before PCI but also provided additional protection during the procedure.22,23 In the PURSUIT study (eptifibatide), the most favourable clinical outcome was seen in patients who received a GPIIb/IIIa inhibitor followed by PCI within 24 h after the onset of symptoms.31 In the study of Bolognese et al. early administration of tirofiban before PCI in high-risk patients with NSTEACS was associated with improved myocardial perfusion on coronary angiography before and after PCI and reduced myocardial damage.32


   GPIIb/IIIa inhibitors after high doses of clopidogrel (ISAR-REACT 2 study)
Top
 Abstract
 Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
Direct thrombin inhibitors as...
 Conclusion
 References
 
The high efficacy of clopidogrel, especially when using high loading doses to prevent ischaemic complications after PCI raises questions about the necessity and benefits of GPIIb/IIIa inhibitors during PCI in patients pretreated with clopidogrel. Doubts were even stronger when the results of the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) study became available showing that low- and moderate-risk patients undergoing planned PCI pretreated with a 600 mg loading dose of clopidogrel at least 2 h prior to the procedure may not benefit from administration of a GPIIb/IIIa inhibitor (death, myocardial infarction, urgent target vessel revascularization; placebo vs. abciximab 4.0 vs. 4.2%, P = NS).33 On the other hand, clopidogrel may not sufficiently reduce platelet activation in clinical conditions that are associated with intensive thrombin generation such as in ACS.34 In this context, it appears reasonable to use intravenous GPIIb/IIIa inhibitors in high-risk NSTEACS patients receiving clopidogrel because the addition of the inhibitor provides additional platelet inhibition compared with aspirin and clopidogrel alone.35,36 In the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study, (120 patients with stable angina undergoing planned PCI) platelet inhibition after administration of a GPIIb/IIIa inhibitor (eptifibatide) was twice as strong compared with a 600 mg loading dose of clopidogrel and the risk of periprocedural myocardial necrosis was significantly reduced.37 The Eptifibatide in planned coronary stent implantation (ESPRIT) study confirmed that administration of a GPIIb/IIIa inhibitor (eptifibatide) during planned PCI in patients pretreated with aspirin plus thienopyridine (97% of patients, a loading dose of ticlopidine or clopidogrel on the day of the procedure) was associated with a significant reduction of an overall risk for the composite of death, myocardial infarction, and urgent target vessel revascularization by 30 days.38 The ADVANCE trial also demonstrated that administration of a GPIIb/IIIa inhibitor in patients pretreated with aspirin plus clopidogrel provided additional reduction of risk for ischaemic complications within 30 days.39 In the Early or Late Intervention in unStable Angina (ELISA-II) study, triple antiplatelet therapy (aspirin, a 300 mg loading dose of clopidogrel, and tirofiban) in patients with non-ST-segment elevation myocardial infarction receiving invasive treatment within 24–48 h after the onset of symptoms was not associated with reduction of infarct size determined by the analysis of lactic dehydrogenase and creatine kinase levels compared with aspirin and clopidogrel (a 600 mg loading dose). However, aggressive antiplatelet therapy resulted in a higher proportion of patients with preserved blood flow in the infarct-related artery in baseline coronary angiography and a trend towards reduction in risk of myocardial infarction.40

The ISAR-REACT 2 study provided more definitive answers.41 The study had a similar design to ISAR-REACT but involved patients with ACS. Overall, 2022 patients with NSTEACS were randomized to receive a GPIIb/IIIa inhibitor (abciximab, n = 1012) or placebo (n = 1010). All patients were given a 600 mg loading dose of clopidogrel at least 2 h prior to PCI and 500 mg aspirin. The primary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularization within 30 days after randomization. Addition of abciximab to aspirin and clopidogrel was associated with a significant reduction in the primary endpoint (abciximab vs. placebo, 8.9 vs. 11.9%, RR = 0.75, P = 0.03), with the most pronounced difference in patients with a positive troponin test at baseline [for troponin (+), abciximab vs. placebo, 13.1 vs. 18.3%, RR = 0.71, P = 0.02; for troponin (–), 4.6 vs. 4.6%, RR = 0.99, P = 0.98]. The reduction in the risk of ischaemic complications was independent of accompanying diabetes mellitus or duration of pretreatment with clopidogrel. There were no differences in the rate of major and minor bleeding events or urgent blood transfusion.41 In this context, administration of GPIIb/IIIa inhibitors appears particularly useful in patients with a positive troponin test, i.e. those being at high short- and long-term risks of ischaemic complications.42


   Direct thrombin inhibitors as an alternative to GPIIb/IIIa inhibitors
Top
 Abstract
 Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
Conclusion
 References
 
Direct thrombin inhibitors offer an attractive alternative to routine combination therapy with unfractionated heparin (UFH) and GPIIb/IIIa inhibitors. Bivalirudin is the most commonly used anticoagulant among direct thrombin inhibitors. Bittl et al.,43 who replaced UFH with bivalirudin in patients with NSTEACS, demonstrated reduction in bleeding and ischaemic complications. The Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET) study also showed that bivalirudin (with emergency administration of a GPIIb/IIIa inhibitor) was superior to UFH with planned abciximab administration (composite of death, myocardial infarction, urgent target vessel revascularization, major bleeding events; bivalirudin vs. UFH + abciximab, 3.1 vs. 14.1%, P < 0.013).44 These results were confirmed by the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) study. Bivalirudin reduced cardiac ischaemic events equally effectively as UFH + abciximab/eptifibatide (composite of death, myocardial infarction, urgent target vessel revascularization; bivalirudin vs. UFH + abciximab/eptifibatide, 7.6 vs. 7.1%, P = NS), and significantly reduced bleeding events (2.4 vs. 4.1%, P < 0.05) in favour of bivalirudin.45 In patients receiving bivalirudin, there was a trend (an absolute difference of 0.8%) towards a higher rate of myocardial infarction within 30 days. However, it was mainly non-Q-wave infarction with a moderate increase in myocardial necrosis markers (CK-MB levels increased 5–10 times the upper limit of normal). Evidence shows that bivalirudin as an alternative to UFH in combination with GPIIb/IIIa inhibitors may be used in patients undergoing planned PCI or having low-risk NSTEACS (the population of REPLACE-2). The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) study provided data on the efficacy and safety of bivalirudin in patients with NSTEACS.46 The study involved 13 819 patients with moderate- and high-risk NSTEACS who were randomized to receive UFH or enoxaparin in combination with a GPIIb/IIIa inhibitor (control group) compared with bivalirudin plus a GPIIb/IIIa inhibitor and bivalirudin plus a GPIIb/IIIa inhibitor given only during PCI complications. All patients received also aspirin and clopidogrel and underwent coronary angiography within 72 h after randomization. The primary endpoint of ACUITY was a composite of bleeding and ischaemic events (death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days). The study was the first to analyse this composite of complications. The composite endpoint was similar in all study groups. Bivalirudin showed a trend towards increased ischaemic events but bleeding complications were less frequent. However, the ACUITY study cannot be compared to ISAR-REACT 2 because different types of GPIIb/IIIa inhibitors (abciximab or eptifibatide) were used in the ACUITY. Moreover, in the ACUITY trial the studied groups were categorized to low-to-moderate risk in comparison to high-risk group in ISAR-REACT 2. It is still not clear whether the results of ACUITY can be applicable for high-risk NSTEACS patients with the thrombus containing lesions and/or positive troponin test (NSTEMI). Moreover, in many experienced centers bleeding complications after GPIIb/IIIa inhibitors could be decreased by broad usage of transradial approach.


   Conclusion
Top
 Abstract
 Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
References
 
Aspirin and clopidogrel should be used in all patients with NSTEACS. Evidence shows that optimal strategy in high-risk patients with NSTEACS is to perform PCI as early as possible (within 48 h). GPIIb/IIIa inhibitors should be used more commonly in patients with NSTEMI (patients with positive cardiac markers) planned for invasive treatment. In low-risk patients with NSTEACS, direct thrombin inhibitors offer an alternative combination of UFH and GPIIb/IIIa inhibitors. The value of combined therapy with aspirin, clopidogrel and bivalirudin as an alternative to aspirin, clopidogrel, UFH, and GPIIb/IIIa inhibitor in high-risk patients (NSTEMI) requires further randomized studies.

Conflict of interest: research sponsored by Lilly Company.


   References
Top
 Abstract
 Aspirin
 Clopidogrel
 GPIIb/IIIa inhibitors
 GPIIb/IIIa inhibitors after high...
 Direct thrombin inhibitors as...
 Conclusion
 References
 

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