EBM Chest Pain Adjunctive Therapies

Pedagogical disambiguation: Emergency Medicine Lecture Notes and Evidence Based emergency medicine principles from Professor A.F.T Brown and the Life in the Fast Lane team.

Myocardial Infarction / Acute Coronary Syndrome (ACS)

Epidemiology

Risk Stratification of Patients with Suspected AMI

Early Management STEMI or NSTEACS

Reperfusion strategies

• Percutaneous coronary intervention (PCI)
• Thrombolysis

Adjunctive anticoagulant therapy

Adjunctive anti-thrombotic therapy

Other therapeutic agents

Adjunctive anticoagulant therapy

Unfractionated (UF) heparin IV

• Traditionally indicated for patients undergoing PCI, front-loaded with plasminogen activators, if lysis is not used, and for some unstable angina / NSTEACS.

Popma JJ et al. Antithrombotic therapy during percutaneous coronary intervention. Chest 2004;126:576S-599S. [Reference]

Low-molecular weight (LMW) heparins SC

• Enoxaparin (dalteparin etc) largely replacing UFH in non-STEACS.
• Also superior to UFH with lysis in STEMI resulting in less re-infarction, but more episodes major bleeding offset by reduction in death or MI.

Murphy S, Gibson M, Morrow D et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007;28:2077-86. [Reference]

Antman E, Morrow D, McCabe C et al. ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. NEJM 2006;354:1477-88. [Reference]

• LMWH reduces re-infarction and death in patients receiving lysis plus aspirin, whereas UFH does not.
• Note dosing difficulty in the elderly, those with renal impairment and the obese.
• Q Health NSTEACS Management Plan still recommends UFH iv if creatinine clearance (CrCl) <30 mL/min measured by Cockcroft Gault calculator; enoxaparin sc if CrCl >50 mL/min; and either if CrCl is somewhere in-between.

Eikelboom J et al. Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation 2005;112:3855-67. [Reference]

• Also occasional recommendation to give LMWH iv front-loaded for STEMI with lysis; or with PCI if last dose > 8-12 hr (NB: does not have a product licence in Australia for IV use at present).
• May be used ‘upstream’ with PCI, particularly if a GP IIb/IIIa inhibitor is used ‘facilitated PCI’.

Harrington RA et al. Antithrombotic treatment for nonST-segment elevation acute coronmary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8e). Chest 2008;133:670S-707S. [Reference]

Kereiakes D, Montalescot G et al. Low- molecular-weight heparin therapy for non ST-elevation acute coronary syndromes and during percutaneous coronary intervention: An expert consensus. Am Heart J 2002; 144:615-24. [Reference]

Fondaparinux and bivalirudin

• Fondaparinux 2.5 mg reduces mortality with less bleeding compared to UFH or no reperfusion therapy in STEMI. Is also ideal for patients with prior HIT (heparin-induced thrombocytopenia).

The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-elevation myocardial infarction.The OASIS 6 Randomised trial.JAMA 2006;295:1519-30. [Reference]

• Fondaparinux and bivalirudin ‘non-inferior’ to standard antithrombin therapy in NSTEACS but with less major bleeding. Not currently licensed for upstream therapy, but consider with GP IIb/IIIa inhibitors for high-risk NSTEACS.

Aroney C, Aylward P, Chew D et al. 2007 addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes 2006. MJA 2008;188:302-3. [Reference]

Adjunctive anti-thrombotic therapy

Glycoprotein IIb/IIIa receptor blockers.

• Intravenous abciximab (irreversibly) and eptifibatide, tirofiban (competitively) completely interrupt final common pathway of platelet aggregation, administered with adjuvant UFH/LMWH.

Vorchheimer DA, Badimon JJ, Fuster V.  Platelet glycoprotein IIb/IIIa receptor antagonists in cardiovascular disease. JAMA 1999; 281:1407-14. [Reference]

• Glycoprotein IIb/IIIa blockers give significant reduction in 30 day death or MI (OR 0.65) and at 6 months (OR 0.70) with PCI, with some increase in risk severe bleeding (OR 1.38; ARI 0.8%).

Bosch X, Marrugat J, Sanchis J. Platelet glycoprotein IIb/IIIa blockers during PCI and as the initial medical treatment of non-STEACS. Cochrane Database of Systematic Reviews 2010;9:CD002130. [Reference]

De Luca G et al. Abciximab as adjunctive therapy to reperfusion in acute ST-elevation myocardial infarction. A meta-analysis of randomised trials. JAMA 2005;293:1759-65. [Reference]

• Reduced lytic dose plus IIb/IIIa inhibitor appeared successful (not better) in ASSENT-3 and GUSTO-V, but must be avoided in the elderly >75 years.

GUSTO V. Lancet 2001; 357:1905-1914. [Reference]

Boden W, McKay R. Optimal treatment of acute coronary syndromes – an evolving strategy. NEJM 2001; 344:1939-42. [Reference]

• TACTICS / ADMIRAL / TARGET trials of ‘upstream’ tirofiban / abciximab favour IIb/IIIa blockers with early angioplasty and stenting in both non-STEMI and STEMI ie. in early invasive management of ACS in general.
• EPIC/EPILOG trials showed reduced morbidity and mortality used with PCI in unstable angina and in routine PCI.

Boersma E, Harrington R et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002; 359:189-98. [Reference]

• Orally are associated with worse outcomes with significantly increased bleeding.

NSW Therapeutic Advisory Group. Antiplatelet therapies: Current issues (Nov 2009). [PDF Reference]

Clopidogrel.

• Slow and variable transformation to active thienopyridine drug, with variable, modest (40-50%), irreversible anti-platelet effect and an increased risk of bleeding.
• Clopidogrel (or IIb/IIIa inhibitor) plus aspirin recommended in early invasive PCI approach to non-STEACS to reduce death, AMI and stroke; and in STEMI including with lysis (COMMIT and CLARITY-TIMI 28 trials). Caution if CABG will be needed (v.rarely).
• Also recommended with aspirin plus anticoagulation if early non-interventional approach to NSTEACS; or if aspirin C/I.
• Early ‘loading dose’ considered anything from 300 – 600 mg, (even 900 mg), with greatest efficacy by 6-15 hours, then 75 mg daily.

Sabatine MC. Something old, something new: β blockers and clopidogrel in acute myocardial infarction. Lancet 2005;366:1587-1589. [Reference]

Prasugrel

• Another thienopyridine prodrug with more consistent and pronounced (> 80% inhibition) irreversible anti-platelet effect than clopidogrel with lower risk of AMI and stent thrombosis, but higher major bleeding in ACS if undergo PCI. Dose 60mg po, then 10mg daily.
• Preferred in patients undergoing PCI who are not at higher risk of bleeding (ie. age <75 yr, weight >60 kg, no prior stroke/TIA).

Mehran R, Pocock S, Stone G et al. Associations of major bleeding and MI with the incidence and timing of mortality in patients presenting with non-ST-elevation ACS. A risk model from the ACUITY trial. Eur Heart J 2009;30:1457-66. [Reference]

Ticagrelor

• Oral reversible P2Y₁₂ direct ADP receptor inhibitor with more rapid onset and more pronounced (> 80% inhibition) anti-platelet effect than clopidogrel.
• Doses of 180 mg then 90 mg bd po in ACS showed reduced rate of vascular /AMI / stroke deaths (RR 0.84) with no increase in overall major bleeding compared to clopidogrel. Thus better option particularly for early invasive strategy approach.
• Dyspnoea and ventricular pauses (on Holter) side-effects rarely symptomatic. Even greater proportional benefit in renal impairment (CrCl <60 mL/min) without any dose reduction.

Cannon C, Harrington R, James S et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for ACS (PLATO): a randomised double-blind study. Lancet 2010;375:283-93 [Reference]. Editorial Stone G. Lancet 2010;375:263-5. [Reference]

James S, Budaz A, Aylward P et al. Ticagrelor versus clopidogrel in ACS in relation to renal function. Circulation 2010;122:1056-67. [Reference]

Wallentin L, Becker R, Budaz A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. NEJM 2009;361:1045-57. [Reference]

Other agents

Beta blockers

• Recommended orally for both STEMI, and non-STEMI (by inference), particularly for hypertension or persistent tachycardia in absence of contraindications, irrespective of other treatment. Give IV if ongoing pain in non-STEMI.
• Should be started after the haemodynamic condition has stabilised if given early with thrombolysis, as although they prevent reinfarction and malignant arrythmias (VF), they increase cardiogenic shock.

COMMIT. Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1622-32. (1250 hospitals in China!). [Reference]

Owen A. Intravenous beta blockade in acute myocardial infarction. BMJ 1998; 317:226-227. [Reference]

ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB).

• Within first 24 hours, in absence significant hypotension with SBP  90 mmHg. Greatest benefit if LV ejection fraction less than 40%, and/or more extensive anterior AMIs.
• May use an ARB when patient is intolerant of an ACEI.
• Then reduce cardiovascular events and diabetic complications in high-risk patients without LV dysfunction if taken long term.

HOPE Study Investigators. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. NEJM 2000; 342:145-53. [Reference]

Statins

• Early statin therapy within 14 days ACS does not reduce death, MI or stroke up to 4 months, except may reduce UA occurrence.

Briel M, Schwartz, Thompson P et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes. JAMA 2006;295:2046-56. [Reference]

• Heart Protection Study showed reduction in death and major cardiovascular events with long term simvastatin use, particularly in diabetics or patients at risk of vascular disease, regardless of lipid levels.

MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes. Lancet 2003; 361:2005-16 [Reference]. (Editorial: Lindholm L. Lancet 2003; 361:2001-2). [Reference]

MRC/BHF Heart Protection Study. Lancet 2002; 360:7-22. [Reference]

Glucose-insulin-potassium (GIK) therapy.

• First suggested in 1962. DIGAMI 1995 – with 30% reduced 1-year mortality in diabetics, then DIGAMI 2 that showed no particular benefit of GIK over any form of ‘aggressive metabolic control’.
• Combined data from OASIS-6 and CREATE-ECLA GIK trials showed infusion of GIK provided no benefit, and may cause early harm following STEMI. Problems with hyperglycaemia, hyperkalaemia and net fluid gain. Avoid !

Diaz R, Goyal A, Mehta S et al. Glucose-insulin-potassium therapy in patients with ST-elevation myocardial infarction. JAMA 2007;298:2399-2405. [Reference]

Malmberg K et al. Intensive metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650-61. [Reference]

O’Connor R, Brady W, Brooks S et al. Part 10. Acute coronary syndromes: 2010 AHA Guidelines for CPR and ECC. Circulation 2010;120(suppl 3):S787-S817. [Reference]