Unstable angina / non ST elevation myocardial infarction antiplatelet therapy: Difference between revisions
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==Glycoprotein IIb/IIIa Inhibitors== | ==Glycoprotein IIb/IIIa Inhibitors== | ||
GP IIb/IIIa inhibitors inhibit the fibrinogen-mediated cross linkage of platelets, which is the final common pathway of platelet aggregation. Three agents currently available are [[Abciximab]], [[Eptifibatide]] and [[Tirofiban]], all three of which are now | GP IIb/IIIa inhibitors inhibit the fibrinogen-mediated cross linkage of platelets, which is the final common pathway of platelet aggregation. Three agents currently available are [[Abciximab]], [[Eptifibatide]] and [[Tirofiban]], all three of which are now included by the ACC/AHA guidelines for use in [[PCI]]. All three agents are for intravenous usage and are given by bolus and continuous infusion. | ||
ISAR-REACT 2 trial<ref name="pmid16533938">{{cite journal |author=Kastrati A, Mehilli J, Neumann FJ, ''et al.'' |title=Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial |journal=JAMA |volume=295 |issue=13 |pages=1531–8 |year=2006 |month=April |pmid=16533938 |doi=10.1001/jama.295.13.joc60034 |url=}}</ref> studied Abciximab in [[NSTEMI]] patients. This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 2022 patients with non-ST-segment elevation ACS undergoing PCI. Results showed that Abciximab reduces the risk of adverse events in patients with non-ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level. | |||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview of Antiplatelet Therapy in UA / NSTEMI
Antiplatelet therapy plays a major role in the management of UA/NSTEMI. This class of medication is directed towards one of the three pathways listed below:
- Decreasing Thomboxane A2 formation(Aspirin)
- Inhibiting the P2Y12 component of the adenosine diphosphate (ADP) receptor pathway(thienopyridines)
- Direct inhibitors of platelet aggregation (GP IIb/IIIa inhibitors)
Aspirin
One of the medications which has consistently been shown to reduce mortality in ACS or CAD patients is ASA. Until recently, no trial had directly compared the efficacy of different doses of ASA in patients who present with UA/NSTEMI. But CURRENT OASIS 7 trial, which was a randomized, multicenter, multinational trial enrolling 25,087 patients with ACS showed no difference in cardiovascular outcomes of death from MI or stroke between low dose aspirin(75-100mg) compared to high dose aspirin(300-325mg) at the end of 30 days. The Second International Study of Infarct Survival (ISIS-2) trial[1] led to the recommendation that ASA be initiated immediately in the ED once the diagnosis of ACS is made or suspected. Aspirin therapy can also be initiated in prehospital setting when ACS is suspected. However, on the basis of previous randomized trials, the current recommendation for initial dose of aspirin is 162-325mg. Non enteric coated formulaitons are preferred due to rapid buccal absorption. For safety (e.g., gastrointestinal bleeding), a couple of large observational studies have found that the rate of bleeding appears to be lower with low-dose aspirin(75-100mg daily) as compared with high dose aspirin (325 mg daily) in patients receiving medical therapy, percutaneous coromary intervention (PCI) or coronary artery bypass grafting (CABG). Thus, after an initial loading dose of 162 to 325 mg, a dose of 75 to 100 mg daily appears sufficient. In patients who have an allergy or who cannot tolerate aspirin, use of clopidogrel is recommended. On the basis of current available data, lifelong continuation of aspirin should be encouraged unless a contraindication develops.
Thienopyridines
This class of drugs inhibits platelet aggregation and reduces blood viscosity by inhibiting adenosine diphosphate (ADP) action on platelet receptors, specifically the P2Y12 component of the ADP receptor. Ticlopidine, one of the first agents studied in this class, has become less popular now because of its role in causing neutropenia, thrombotic thrombocytopenic purpura and gastrointestinal side effects. Clopidogrel is another extensively studied drug which has been shown to improve outcomes in UA/NSTEMI patients. Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial[2] led to widespread use of Clopidogrel in ACS and stroke patients. Trial enrolled a total of 19,185 patients who were randomized to receive ASA 325 mg per d or clopidogrel 75 mg per d in patients with atherosclerotic vascular disease(manifested as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease). Follow up ranged from 1-3 yrs. Results showed that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The results of the CURE trial[3] further reinforced the benefits of Clopidogrel in patients with UA/NSTEMI. A loading dose of 300mg is typically used, although some studies have used higher dose(600-900mg) and shown improved outcomes, but also increase incidence of side effects.
A limiting factor in the use of Clopidogrel is its inter-individual variability in response(hyporesponders) which has growing concern in patients with PCI and its impact on the incidence of stent thrombosis. A number of drugs are currently being studies for use in ACS patients. Most recently, Prasugrel has been approved by FDA for use in patients undergoing PCI. It has similar mechanism of action but more potent antiplatelet effect. TRION-TIMI 38 trial[4] which was a multicenter, randomized, double blind study enrolling 13,608 patients with moderate to high-risk ACS led to the FDA approval and its inclusion in ACC/AHA guidelines for PCI as one of the recommended thienopyridine agent. Results of this study showed that in patients with acute coronary syndromes with scheduled percutaneous coronary intervention,Prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. Prasugrel is being increasingly used in high risk patients with ACS undergoing PCI and also in patients with failed Clopidogrel therapy.
Another drug in this class which is pending FDA approval is Ticagrelor. This drug was investigated in a multicenter, double-blind, randomized PLATO trial[5] which enrolled 18,624 patients with ACS. This trial compared Clopidogrel with Ticagrelor and showed improved outcomes in patients on Ticagrelor in both STEMI and NSTEMI group with regards to death from vascular causes, MI and stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.
CHAMPION PCI[6] and CHAMPION PLATFORM[7] trials have studied the role of IV platelet inhibition with Cangrelor and both trials did not show superiority of Cangrelor over Clopidogrel or Placebo, respectively.
Glycoprotein IIb/IIIa Inhibitors
GP IIb/IIIa inhibitors inhibit the fibrinogen-mediated cross linkage of platelets, which is the final common pathway of platelet aggregation. Three agents currently available are Abciximab, Eptifibatide and Tirofiban, all three of which are now included by the ACC/AHA guidelines for use in PCI. All three agents are for intravenous usage and are given by bolus and continuous infusion. ISAR-REACT 2 trial[8] studied Abciximab in NSTEMI patients. This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 2022 patients with non-ST-segment elevation ACS undergoing PCI. Results showed that Abciximab reduces the risk of adverse events in patients with non-ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level.
ACC / AHA Guidelines for Antiplatelet therapy in Unstable Angina/NSTEMI (DO NOT EDIT) [9]
| “ |
Class I1. Aspirin should be administered to UA / NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients not known to be intolerant of that medication. (Level of Evidence: A) 2. Clopidogrel (loading dose followed by daily maintenance dose) should be administered to UA / NSTEMI patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A) 3. In UA / NSTEMI patients with a history of gastrointestinal bleeding, when ASA and clopidogrel are administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton pump inhibitors) should be prescribed concomitantly. (Level of Evidence: B) 4. For UA / NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose) or an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B) 5. For UA / NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose) should be added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B) 6. For UA / NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, HF, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (Level of Evidence: A) Either an intravenous GP IIb/IIIa inhibitor (eptifibatide or tirofiban; Level of Evidence: A) or clopidogrel (loading dose followed by daily maintenance dose; Level of Evidence: A) should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream).(Level of Evidence: C) Class IIa1. For UA / NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with clopidogrel, ASA, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C) 2. For UA / NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to initiate antiplatelet therapy with both clopidogrel (loading dose followed by daily maintenance dose) and an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: B) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to coronary angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B) 3. For UA / NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an intravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI. (Level of Evidence: B) Class IIb1. For UA / NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. (Level of Evidence: B) Class III1. Abciximab should not be administered to patients in whom PCI is not planned. (Level of Evidence: A) |
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See Also
Sources
- The ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction [9]
References
- ↑ "Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group". Lancet. 2 (8607): 349–60. 1988. PMID 2899772. Unknown parameter
|month=ignored (help) - ↑ "A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee". Lancet. 348 (9038): 1329–39. 1996. PMID 8918275. Unknown parameter
|month=ignored (help) - ↑ Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001). "Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation". N. Engl. J. Med. 345 (7): 494–502. PMID 11519503. Unknown parameter
|month=ignored (help) - ↑ 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) - ↑ Wallentin L, Becker RC, Budaj A; et al. (2009). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". N. Engl. J. Med. 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. PMID 19717846. Unknown parameter
|month=ignored (help) - ↑ Harrington RA, Stone GW, McNulty S; et al. (2009). "Platelet Inhibition with Cangrelor in Patients Undergoing PCI". N. Engl. J. Med. doi:10.1056/NEJMoa0908628. PMID 19915221. Unknown parameter
|month=ignored (help) - ↑ Bhatt DL, Lincoff AM, Gibson CM; et al. (2009). "Intravenous Platelet Blockade with Cangrelor during PCI". N. Engl. J. Med. doi:10.1056/NEJMoa0908629. PMID 19915222. Unknown parameter
|month=ignored (help) - ↑ Kastrati A, Mehilli J, Neumann FJ; et al. (2006). "Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial". JAMA. 295 (13): 1531–8. doi:10.1001/jama.295.13.joc60034. PMID 16533938. Unknown parameter
|month=ignored (help) - ↑ 9.0 9.1 Anderson JL, Adams CD, Antman EM; et al. (2007). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". JACC. 50 (7): e1–e157. PMID 17692738. Text "doi:10.1016/j.jacc.2007.02.013 " ignored (help); Unknown parameter
|month=ignored (help)