ST elevation myocardial infarction aspirin therapy: Difference between revisions
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==Overview== | ==Overview== | ||
Antiplatelet therapy 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 42%) when compared to the administration of neither agent. <ref name="pmid2903874">{{cite journal |author= |title=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 |journal=J. Am. Coll. Cardiol. |volume=12 |issue=6 Suppl A |pages=3A–13A |year=1988 |month=December |pmid=2903874 |doi= |url=}}</ref> | 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 42%) when compared to the administration of neither agent. <ref name="pmid2903874">{{cite journal |author= |title=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 |journal=J. Am. Coll. Cardiol. |volume=12 |issue=6 Suppl A |pages=3A–13A |year=1988 |month=December |pmid=2903874 |doi= |url=}}</ref> | ||
==Clinical trials 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: | |||
#[[Streptokinase]] (1.5 million units) administered via the intravenous route over 1 hour or | |||
#Aspirin (enteric coated at a dose of 160 mg/day) for one month or | |||
#Both streptokinase and aspirin treatments or | |||
#Neither treatemnt | |||
Both [[streptokinase]] alone and aspirin alone were associated with a similar significant reduction in 5 week vascular mortality: | |||
791/8592 (9.2%) vascular deaths among streptokinase versus 1029/8595 (12.0%) among placebo infusion (odds reduction: 25% +/- 4; 2p less than 0.00001); | |||
804/8587 (9.4%) vascular deaths among aspirin versus 1016/8600 (11.8%) among placebo tablets (odds reduction: 23% +/- 4; 2p less than 0.00001). | |||
The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular death appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents versus 568/4300 (13.2%) among those allocated neither (odds reduction: 42% +/- 5; 95% confidence limits 34% to 50%). There was evidence of benefit rom each agent even for patients treated late after pain onset (odds reduction at 0-4, 5-12, and 13-24 h: 35% +/- 6, 16% +/- 7 and 21% +/- 12 for streptokinase alone; 25% +/- 7,21% +/- 7 and 21% +/- 12 for aspirin alone; and 53% +/- 8,32% +/- 9 and 38% +/- 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5% versus 0.2%) and of confirmed cerebral hemorrhage (0.1% versus 0.0%), but with fewer other strokes (0.6% versus 0.8%). These "other" strokes may have included a few undiagnosed cerebral hemorrhages, but still there was no increase in total strokes (0.7% streptokinase versus 0.8% placebo infusion). Aspirin significantly reduced nonfatal reinfarction (1.0% versus 2.0%) and nonfatal stroke (0.3% versus 0.6%), and was not associated with any significant increase in cerebral hemorrhage or in bleeds requiring transfusion. An excess of nonfatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% versus 2.9%), strokes (0.6% versus 1.1%), and deaths (8.0% versus 13.2%) than those allocated neither. | |||
==History== | ==History== | ||
Revision as of 21:46, 15 February 2009
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
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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 42%) when compared to the administration of neither agent. [1]
Clinical trials 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:
- Streptokinase (1.5 million units) administered via the intravenous route over 1 hour or
- Aspirin (enteric coated at a dose of 160 mg/day) for one month or
- Both streptokinase and aspirin treatments or
- Neither treatemnt
Both streptokinase alone and aspirin alone were associated with a similar significant reduction in 5 week vascular mortality:
791/8592 (9.2%) vascular deaths among streptokinase versus 1029/8595 (12.0%) among placebo infusion (odds reduction: 25% +/- 4; 2p less than 0.00001);
804/8587 (9.4%) vascular deaths among aspirin versus 1016/8600 (11.8%) among placebo tablets (odds reduction: 23% +/- 4; 2p less than 0.00001).
The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular death appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents versus 568/4300 (13.2%) among those allocated neither (odds reduction: 42% +/- 5; 95% confidence limits 34% to 50%). There was evidence of benefit rom each agent even for patients treated late after pain onset (odds reduction at 0-4, 5-12, and 13-24 h: 35% +/- 6, 16% +/- 7 and 21% +/- 12 for streptokinase alone; 25% +/- 7,21% +/- 7 and 21% +/- 12 for aspirin alone; and 53% +/- 8,32% +/- 9 and 38% +/- 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5% versus 0.2%) and of confirmed cerebral hemorrhage (0.1% versus 0.0%), but with fewer other strokes (0.6% versus 0.8%). These "other" strokes may have included a few undiagnosed cerebral hemorrhages, but still there was no increase in total strokes (0.7% streptokinase versus 0.8% placebo infusion). Aspirin significantly reduced nonfatal reinfarction (1.0% versus 2.0%) and nonfatal stroke (0.3% versus 0.6%), and was not associated with any significant increase in cerebral hemorrhage or in bleeds requiring transfusion. An excess of nonfatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% versus 2.9%), strokes (0.6% versus 1.1%), and deaths (8.0% versus 13.2%) than those allocated neither.
History
Aspirin, or acetylsalicylic acid, was first synthesized in 1897 at Friedrich Bayer & Company as a more palatable formulation of salicylic acid—a pain reliever used in some form dating back to ancient Egypt. Aspirin was initially sold to pharmacists in 250-g bottles and was dispensed to patients as a powder. Imitators and adulterated versions of the powder led Bayer to develop an aspirin tablet in 1900. [2]
In the United States, this was sold as a 5 grain (approximately 325-mg) pill, the genesis of the dose commonly used today. The 81-mg/d children's dosage, which is one quarter of the adult dosage and was arbitrarily determined, first became available in 1922.[3][4]
Mechanism(s) of Benefit
Acetylation of platelet cyclooxygenase-1 (COX-1) begins to occur in the portal circulation prior to any measurable systemic level; thus, the measurement of plasma levels of the inactive form of acetylsalicylic acid may be an incomplete measure of efficacy. Nonetheless, peak plasma levels are achieved rapidly, within approximately 30 minutes, followed by rapid clearance with a half-life of 15-20 minutes. The systemic bioavailability of aspirin is about 50% for single oral doses ranging from 20-1300 mg.[5]
Both the beneficial and detrimental effects of aspirin are believed to be primarily due to inhibition of prostanoid biosynthesis, in particular the inhibition of of thromboxane A2 (TXA2) and prostaglandins (e.g., PGE2 and PGI2).
Aspirin irreversibly inhibits platelet cyclooxygenase 1 (COX-1) through acetylation of the amino acid serine at position 529, thereby preventing arachidonic acid's access to the COX-1 catalytic site through steric hindrance. By inhibiting COX-1, the platelet is unable to synthesize prostaglandin H2, which, under normal circumstances, is then converted to thromboxane A2 (TXA2) via the enzyme Thromboxane synthase. Although anucleate platelets possess some capacity for protein synthesis, they are incapable of overcoming COX-1 inhibition with new protein synthesis, and the aspirin-induced defect spans the 8 to 10 day life span of the platelet. Because of platelet turnover, approximately 10% of platelets with normal COX activity will be recovered daily following cessation of aspirin therapy. Therefore, up to 10 days can be required for complete recovery of platelet COX activity; however, it may require only 20% of normal COX activity to exhibit normal hemostasis.[6][7][8][9]
COX-1 is constitutively expressed in most cells and plays important roles beyond TXA2 production in platelets. Of particular importance is the production of the cytoprotective prostaglandins by gastric mucosa. Unlike platelets, gastric mucosal cells possess the biosynthetic machinery necessary to overcome COX-1 inhibition and, therefore, recover the ability to synthesize prostaglandins within a few hours after exposure to aspirin. COX-2, a second cyclo oxygenase isoenzyme primarily responsible for synthesis of the platelet inhibitor PGI2 by endothelial cells and induced in response to inflammatory stimuli, is less sensitive to the effects of aspirin. Aspirin is 170 fold less effective at inhibiting COX-2 than COX-1.
At higher doses, aspirin suppresses vascular endothelial cell production of prostacyclin, which, if unopposed, results in inhibition of platelet aggregation and induces vasodilatation.
It has been postulated that aspirin’s anti-inflammatory properties may explain at least part of its mechanism of benefit in CVD. However, with aspirin’s much greater selectivity for COX-1 and the central role of COX-2 in inflammation, dosages that achieve measurable anti-inflammatory activity (up to several grams daily) are much higher than those proven clinically effective in the prevention of atherothrombotic events. Consistent with this is the lack of an effect on high sensitivity C-reactive protein levels in most studies.
Currently, there is no gold standard measure of aspirin’s pharmacodynamics.
There has been only 1 randomized study that directly compared aspirin dose in STEMI. The Duke University Clinical Cardiology Group Study-II (DUCCS-II) compared the efficacy of 81 and 325 mg aspirin doses in 162 patients with STEMI treated with front loaded tissue plasminogen activator or an isolated plasminogen streptokinase activator complex. No effect of aspirin dose on clinical outcomes was noted; however, because of its early termination, the study was severely underpowered. The majority of data supporting the use of aspirin in the setting of acute myocardial infarction are from ISIS-2. In this study, 162.5 mg aspirin reduced vascular mortality, re-infarction, and stroke without substantially increasing the risk of major bleeding. Other studies of aspirin in the acute setting of myocardial infarction have been severely underpowered to address the clinical efficacy and safety profile of aspirin in this setting.
A wide range of aspirin doses, preparations, and methods of ingestion have been evaluated to determine the best way to achieve maximal antiplatelet activity in the acute setting. In a study that evaluated the acute antiplatelet effects of 40 mg, 100 mg, 300 mg, and 500 mg doses of aspirin, the 300 mg and 500 mg doses were found to achieve equal levels of platelet inhibition 2 hours following ingestion, suggesting that there is no added benefit for doses of more than 300 mg. However, at very low doses (0.45 mg/kg, corresponding to about 30 mg in an adult), it may take 10 days to effectively suppress TXA2 production. [10]
Aspirin absorption and the onset of antiplatelet activity are significantly shortened by chewing or drinking soluble aspirin, with maximal inhibition of serum Thromboxane B2 (TXB2) production achieved within 20 to 30 minutes compared with swallowing a whole pill that required approximately 60 minutes.
In another study of 18 volunteers, chewing an 81 mg, 162 mg, or 324 mg aspirin pill led to equivalent reduction in TXB2 production, but maximal inhibition by 15 minutes after ingestion was achieved only with the 162 mg and 324 mg doses. The results of these and other studies suggest that to rapidly (within 15 minutes) achieve the maximal effects of aspirin, at least 162 mg should be chewed or dissolved, then swallowed.[11][12]
The major risk of aspirin, as with other non steroidal anti inflammatory drugs (NSAIDs), is the risk of bleeding. Although the antiplatelet effects of aspirin likely contribute to an increase in the risk of bleeding, as highlighted by an increased risk of hemorrhagic stroke of 0.2 events per 1000 patient years, the majority of the increased bleeding has a gastrointestinal tract etiology.
Although this increased risk of gastrointestinal bleeding is more commonly attributed to non aspirin NSAIDs, a recent evaluation of patients hospitalized for ulcer bleeding found that low-dose aspirin therapy was responsible for as much ulcer bleeding as all other NSAIDs combined. In another prospective evaluation of 18 820 hospitalized patients, 1225 were admitted as a result of adverse drug reactions, and low-dose aspirin was identified as one of the most common causal agents, with 18% of the hospitalizations and 61% of the fatal cases associated with aspirin.[13][14][15][16]
An analysis of aspirin-treated patients from the UKTIA trial found almost double the risk of gastrointestinal bleeding among patients randomized to 1200 mg/day of aspirin compared with 300 mg/day. In the Dutch-TIA trial, where the higher aspirin dose was more reflective of contemporary dosing, a trend toward less bleeding was noted in the 30 mg group (2.6%) than the 283 mg group (3.2%).
Observational data from the BRAVO (Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trials also demonstrated an increased risk of bleeding with higher doses of aspirin, even when doses no greater than 325 mg were used.[17][18]
Dosing
If not given prior to hospital admission, Aspirin should be administered to all patients at a dose of 162 to 325 mg to chew and swallow, unless there is a compelling contraindication (e.g., history of anaphylactic reaction). Aspirin is generally administered orally and is rapidly absorbed in the stomach and upper intestine. Enteric coating may delay the absorption, and it is for this reason that not enteric coated aspirin is often administered in the setting of ST elevation MI. It should also be noted that aspirin can also be administered via the intravenous route.[19]
162 mg versus 325 mg
A recent study from Duke University compared the acute mortality and bleeding risks associated with the initial use of 162 mg versus 325 mg aspirin among patients with STEMI treated with thrombolytic therapy. A total of 48,422 patients with acute ST segment elevation myocardial infarction from the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) were studied. The association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding was compared. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 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. Mortality rates at 7 and 30 days 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 adjustment, aspirin dose was not associated with 2]]4-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 myocardial infarction or the composite of death or myocardial infarction between 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, 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 study demonstrates two major findings on the dose of aspirin. First, in the acute setting of STEMI, there is no significant association between initial aspirin dose (162 mg versus 325 mg) and risk of death, myocardial infarction, or stroke. [20][21]
Second, the initial dose of 325 mg aspirin is associated with a significant increase in the risk of moderate or severe bleeding compared with 162 mg in the initial treatment of STEMI.
This study 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.
Side Effects and Contraindications
The use of aspirin is contraindicated in those with a hypersensitivity to salicylate.
Aspirin suppositories (300 mg) can be used safely and are the recommended route of administration for patients with severe nausea and vomiting or known upper-gastrointestinal disorders.
In patients with true aspirin allergy (hives, nasal polyps, bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be substituted.[22]
Guidelines (DO NOT EDIT)
Class I
- For all post Percutaneous Coronary Interventions (PCI) stented STEMI 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 bare metal stent (BMS) implantation, 3 months after Sirolimus eluting stent implantation (SES), and 6 months after Paclitaxel eluting stent implantation (PES), after which long term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily. Class I (Level of Evidence: B)[23]
Class IIa
- 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. Class IIa (Level of Evidence: C)[23]
References
- ↑ "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) - ↑ Zundorf U. 100 Years of Aspirin: The Future Has Just Begun. Leverkusen, Germany: Bayer AG; 1997.
- ↑ Ajani UA, Ford ES, Greenland KJ, Giles WH, Mokdad AH (2006). "Aspirin use among U.S. adults: Behavioral Risk Factor Surveillance System". Am J Prev Med. 30 (1): 74–7. doi:10.1016/j.amepre.2005.08.042. PMID 16414427. Unknown parameter
|month=ignored (help) - ↑ National Disease and Therapeutic Index [database]. Norwalk, Conn: IMS Health; September 2006.
- ↑ Campbell CL, Smyth S, Montalescot G, Steinhubl SR (2007). "Aspirin dose for the prevention of cardiovascular disease: a systematic review". JAMA. 297 (18): 2018–24. doi:10.1001/jama.297.18.2018. PMID 17488967. Unknown parameter
|month=ignored (help) - ↑ Roux S, Christeller S, Lüdin E (1992). "Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis". J. Am. Coll. Cardiol. 19 (3): 671–7. PMID 1531663. Unknown parameter
|month=ignored (help) - ↑ "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) - ↑ Sagar KA, Smyth MR (1999). "A comparative bioavailability study of different aspirin formulations using on-line multidimensional chromatography". J Pharm Biomed Anal. 21 (2): 383–92. PMID 10703994. Unknown parameter
|month=ignored (help) - ↑ 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) - ↑ Patrignani P, Filabozzi P, Patrono C (1982). "Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects". J. Clin. Invest. 69 (6): 1366–72. PMC 370209. PMID 7045161. Unknown parameter
|month=ignored (help) - ↑ Dabaghi SF, Kamat SG, Payne J; et al. (1994). "Effects of low-dose aspirin on in vitro platelet aggregation in the early minutes after ingestion in normal subjects". Am. J. Cardiol. 74 (7): 720–3. PMID 7942533. Unknown parameter
|month=ignored (help) - ↑ Feldman M, Cryer B (1999). "Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution". Am. J. Cardiol. 84 (4): 404–9. PMID 10468077. Unknown parameter
|month=ignored (help) - ↑ Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV (2007). "Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review". Am. Heart J. 153 (2): 175–81. doi:10.1016/j.ahj.2006.10.040. PMID 17239674. Unknown parameter
|month=ignored (help) - ↑ Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V (2005). "Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases". Eur. Heart J. 26 (16): 1585–95. doi:10.1093/eurheartj/ehi397. PMID 15996977. Unknown parameter
|month=ignored (help) - ↑ Becker DM, Segal J, Vaidya D; et al. (2006). "Sex differences in platelet reactivity and response to low-dose aspirin therapy". JAMA. 295 (12): 1420–7. doi:10.1001/jama.295.12.1420. PMID 16551714. Unknown parameter
|month=ignored (help) - ↑ Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL (2006). "Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials". JAMA. 295 (3): 306–13. doi:10.1001/jama.295.3.306. PMID 16418466. Unknown parameter
|month=ignored (help) - ↑ Topol EJ, Easton D, Harrington RA; et al. (2003). "Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease". Circulation. 108 (4): 399–406. doi:10.1161/01.CIR.0000084501.48570.F6. PMID 12874182. Unknown parameter
|month=ignored (help) - ↑ Quinn MJ, Aronow HD, Califf RM; et al. (2004). "Aspirin dose and six-month outcome after an acute coronary syndrome". J. Am. Coll. Cardiol. 43 (6): 972–8. doi:10.1016/j.jacc.2003.09.059. PMID 15028352. Unknown parameter
|month=ignored (help) - ↑ 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. doi:10.1161/CIRCULATIONAHA.107.729558. PMID 18086929. Unknown parameter
|month=ignored (help) - ↑ 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. doi:10.1161/01.STR.0000106763.46123.F6. PMID 14671242. Unknown parameter
|month=ignored (help) - ↑ 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. doi:10.1016/j.amjcard.2005.01.049. PMID 15877994. Unknown parameter
|month=ignored (help) - ↑ 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. doi:10.1136/bmj.329.7456.15. PMC 443443. PMID 15231615. Unknown parameter
|month=ignored (help) - ↑ 23.0 23.1 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. doi:10.1161/CIRCULATIONAHA.107.188209. PMID 18071078. Unknown parameter
|month=ignored (help)