ST elevation myocardial infarction aspirin therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Antiplatelet therapy with aspirin is a mainstay of pharmacotherapy in STEMI. In the International Study of Infarct Survival 2 (ISIS 2), aspirin reduced mortality in STEMI as much as streptokinase (by approximately 25%) when compared to the administration of neither agent. [1] Full doses of non-enteric coated aspirin should be administered as soon as possible to patients with STEMI if there are no contraindications.

Indications

All STEMI patients should receive a full dose of non-enteric coated or intravenous aspirin (162 to 325 mg) within the first 24 hours of presentation. Aspirin should be administered irrespective of the reperfusion strategy selected (either primary PCI, fibrinolytic administration, or no reperfusion therapy).

Contraindications

It should be noted that prior to hospital discharge, these patients with hypersensitivity can be treated with aspirin desensitization.

  • Active major bleeding at a non compressible site is another contraindication.

Clinical Trial Data Supporting the Administration of Aspirin in STEMI

ISIS 2 was a landmark trial which randomized a total of 17,187 patients from 417 hospitals who presented within 24 hours (median 5 h) of STEMI symptom onset to one of 4 strategies:

  1. Streptokinase (SK) (1.5 million units) administered via the intravenous route over 1 hour or
  2. Aspirin (ASA) (enteric coated at a dose of 160 mg/day) for one month or
  3. Both streptokinase and aspirin treatments or
  4. Neither treatment

Both streptokinase alone and aspirin alone were associated with a similar significant reduction in 5 week cardiovascular mortality:

9.2% (791/8592) incidence of cardiovascular deaths among streptokinase versus 12.0% (1029/8595) among placebo infusion patients (odds reduction: 25% +/- 4; p < 0.00001)
9.4% (804/8587) incidence of cardiovascular deaths among aspirin versus 11.8% (1016/8600) among placebo tablet patients (odds reduction: 23% +/- 4; p < 0.00001)

The combination of streptokinase and aspirin was associated with a significant reduction in cardiovascular mortality when compared to the administration of either agent alone (p < 0.0001). Furthermore, the effect of SK and ASA appeared to be additive as the mortality was only 8.0% (343/4292) among patients treated with both SK and ASA vs 13.2% (568/4300) among those treated with neither agent (42% +/- 5 relative risk reduction; 95% confidence limits 34% to 50%).

Streptokinase was associated with an increased risk of bleeding requiring transfusion (0.5% versus 0.2%) and intracranial hemorrhage (ICH) (0.1% versus 0.0%). Streptokinase was, however, associated with fewer non-ICH strokes (0.6% versus 0.8%).

Aspirin was associated with a significant reduction in nonfatal reinfarction (1.0% versus 2.0%) as well as nonfatal stroke (0.3% versus 0.6%). In contrast to streptokinase, aspirin was not associated with a significant increase in intracranial hemorrhage or bleeding requiring transfusion. Furthermore, while streptokinase alone was associated with an increased risk of reinfarction, the addition of aspirin to streptokinase reduced the increased risk of reinfarction associated with streptokinase administration.

Mechanism(s) of Action

Suppression of Prostaglandins and Thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. It should be noted that NSAIDs compete with aspirin to bind to this serine residue, and this is the mechanism by which a prior dose of a NSAID inhibits the efficacy of aspirin. While inhibition of thromboxane inhibits platelet aggregation, inhibition of prostaglandins may increase the risk of vasoconstriction. Given the potential for vasoconstriction with increasing doses, higher doses of aspirin (325 mg and greater) may not be more effective than doses of 162 to 75 mg.

COX-1 and COX-2 Inhibition

There are at least two different types of cyclooxygenase (COX): COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side-effects.

However, several of the new COX-2 selective inhibitors, such as Vioxx, have been withdrawn recently, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are down-regulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors. Utilization of NSAIDs is contraindicated in STEMI, and NSAIDs therapy should be withdrawn in patients with STEMI because of a heightened risk of recurrent MI and congestive heart failure.

Aspirin Dosing

Full dose aspirin should be administered as soon as possible in the setting of STEMI, including in the pre-hospital setting if there are no contraindications. There are studies that suggest enteric coating may delay aspirin absorption. [4] Therefore, non-enteric coated aspirin is recommended in the setting of ST elevation MI. It should also be noted that aspirin can also be administered via the intravenous route.

Efficacy and Safety of Low Dose (162 mg) Aspirin versus High Dose (325 mg) Aspirin in STEMI Patients

Large, prospective, randomized trials randomizing STEMI patients to either low vs high doses of aspirin in STEMI are lacking. The 30 day mortality and bleeding risks associated with the administration of 162 mg versus 325 mg aspirin among patients with STEMI treated with thrombolytic therapy has been compared in a non-randomized retrospective analysis. [5][6][7] Data for the largest analysis was drawn from a total of 48,422 patients with acute ST segment elevation myocardial infarction in the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). [7] 24.4% of patients (n=11 828) were treated in a non-randomized fashio with an initial aspirin dose of 325 mg, and 75.6% (n=36 594) were treated with 162 mg. 24-hour mortality did not differ between the two doses: 2.9% for those receiving an initial aspirin dose of 325 mg versus 2.8% (P=0.894) for those receiving an initial aspirin dose 162 mg. 7 and 30 day mortality rates were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin respectively. After multivariate adjustment for imbalances in baseline characteristics, the initial aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for reinfarction or the composite of death or reinfarction between the two aspirin dose groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). However, after adjustment for imbalances in baseline characteristics, an initial dose of 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003) compared to an initial does of 162 mg.

This non-randomized data from trials conducted many years ago with a substantial use of streptokinase demonstrates that the initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST elevation myocardial infarction. These findings require confirmation in large randomized trials of fibrin specific agents before a firm recommendation can be made regarding the optimal initial dose of aspirin in STEMI patients.

2013 Revised and 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (DO NOT EDIT)[8] [9][10]

Class I
"1. Aspirin 162 to 325 mg should be given before primary PCI.[11][12][13] (Level of Evidence: B)"
"2. After PCI, aspirin should be continued indefinitely.[14][15][16] (Level of Evidence: A)"
"3. For all post-PCI STEMI stented patients without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily. (Level of Evidence: B) "
"4. Aspirin (162- to 325-mg loading dose) and clopidogrel (300-mg loading dose for patients <75 years of age, 75-mg dose for patients >75 years of age) should be administered to patients with STEMI who receive fibrinolytic therapy.[17][18][19](Level of Evidence: A) "
"5. Aspirin should be continued indefinitely [17][18][19](Level of Evidence: A) and clopidogrel (75 mg daily) should be continued for at least 14 days [18][19](Level of Evidence: A) and up to 1 year (Level of Evidence: C) in patients with STEMI who receive fibrinolytic therapy."
Class IIa
"1. It is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses after primary PCI.[14][13][6][20](Level of Evidence: B)"
"2. In patients for whom the physician is concerned about risk of bleeding lower-dose 75 mg to 162 mg of aspirin is reasonable during the initial period after stent implantation. (Level of Evidence: C) "
"3. It is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses after fibrinolytic therapy.[14][16][6][20](Level of Evidence: B) "

Antiplatelet Therapy to Support PCI After Fibrinolytic Therapy (DO NOT EDIT)[8]

Class I
"1. After PCI, aspirin should be continued indefinitely.[13][14][16][21][18][19](Level of Evidence: A) "
Class IIa
"1. After PCI, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses.[13][21][6][20](Level of Evidence: B) "

See Also

Sources

  • The 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction [22]
  • The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction [10]
  • 2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction[8]

References

  1. "Randomized 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". J. Am. Coll. Cardiol. 12 (6 Suppl A): 3A–13A. 1988. PMID 2903874.  Unknown parameter |month= ignored (help)
  2. Pirmohamed M, James S, Meakin S; et al. (2004). "Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients". BMJ. 329 (7456): 15–9. PMC 443443Freely accessible. PMID 15231615. doi:10.1136/bmj.329.7456.15.  Unknown parameter |month= ignored (help)
  3. "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. Retrieved 2010-07-01.  Unknown parameter |month= ignored (help)
  4. Sagar KA, Smyth MR. Acomparative bioavailability study of different aspirin formulations using on-line multidimensional chromatography. J Pharm Biomed Anal 1999;21:383-92.
  5. Alberts MJ, Bergman DL, Molner E, Jovanovic BD, Ushiwata I, Teruya J (2004). "Antiplatelet effect of aspirin in patients with cerebrovascular disease". Stroke. 35 (1): 175–8. PMID 14671242. doi:10.1161/01.STR.0000106763.46123.F6.  Unknown parameter |month= ignored (help)
  6. 6.0 6.1 6.2 6.3 Serebruany VL, Steinhubl SR, Berger PB; et al. (2005). "Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials". Am. J. Cardiol. 95 (10): 1218–22. PMID 15877994. doi:10.1016/j.amjcard.2005.01.049.  Unknown parameter |month= ignored (help)
  7. 7.0 7.1 Berger JS, Stebbins A, Granger CB; et al. (2008). "Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy". Circulation. 117 (2): 192–9. PMID 18086929. doi:10.1161/CIRCULATIONAHA.107.729558.  Unknown parameter |month= ignored (help)
  8. 8.0 8.1 8.2 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. PMID 23247303. doi:10.1161/CIR.0b013e3182742c84.  Unknown parameter |month= ignored (help)
  9. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M; et al. (2004). "ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).". Circulation. 110 (5): 588–636. PMID 15289388. doi:10.1161/01.CIR.0000134791.68010.FA. 
  10. 10.0 10.1 Antman EM, Hand M, Armstrong PW; et al. (2008). "2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee". Circulation. 117 (2): 296–329. PMID 18071078. doi:10.1161/CIRCULATIONAHA.107.188209.  Unknown parameter |month= ignored (help)
  11. Jolly SS, Pogue J, Haladyn K; et al. (2009). "Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study". Eur. Heart J. 30 (8): 900–7. PMID 18819961. doi:10.1093/eurheartj/ehn417.  Unknown parameter |month= ignored (help)
  12. Barnathan ES, Schwartz JS, Taylor L; et al. (1987). "Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty". Circulation. 76 (1): 125–34. PMID 2954724.  Unknown parameter |month= ignored (help)
  13. 13.0 13.1 13.2 13.3 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. PMID 20818903. doi:10.1056/NEJMoa0909475.  Unknown parameter |month= ignored (help)
  14. 14.0 14.1 14.2 14.3 "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 64503Freely accessible. PMID 11786451.  Unknown parameter |month= ignored (help)
  15. Schömig A, Neumann FJ, Kastrati A; et al. (1996). "A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents". N. Engl. J. Med. 334 (17): 1084–9. PMID 8598866. doi:10.1056/NEJM199604253341702.  Unknown parameter |month= ignored (help)
  16. 16.0 16.1 16.2 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. PMID 22052934. doi:10.1161/CIR.0b013e318235eb4d.  Unknown parameter |month= ignored (help)
  17. 17.0 17.1 "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)
  18. 18.0 18.1 18.2 18.3 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. PMID 16271642. doi:10.1016/S0140-6736(05)67660-X.  Unknown parameter |month= ignored (help)
  19. 19.0 19.1 19.2 19.3 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. PMID 15758000. doi:10.1056/NEJMoa050522.  Unknown parameter |month= ignored (help)
  20. 20.0 20.1 20.2 Steinhubl SR, Bhatt DL, Brennan DM; et al. (2009). "Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding". Ann. Intern. Med. 150 (6): 379–86. PMID 19293071.  Unknown parameter |month= ignored (help)
  21. 21.0 21.1 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. PMID 20817281. doi:10.1016/S0140-6736(10)61088-4.  Unknown parameter |month= ignored (help)
  22. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK (2004). "ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction)". Circulation. 110 (9): e82–292. PMID 15339869.  Unknown parameter |month= ignored (help)

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