Cardiology

Acute Coronary Syndromes Management/CAD Management: Post-Discharge Considerations

General (including evidence of efficacy)

What classes of antiplatelet drugs should be prescribed after an acute coronary syndrome?

1. Aspirin

Mechanism of action:

  • Irreversibly inhibits the platelet COX-1 enzyme leading to reduced thromboxane A2 (TXA2) production. In turn, this inhibits platelet activation and aggregation via TXA2-dependent pathways and blocks TXA2-dependent vasoconstriction.

Efficacy of aspirin:

  • In patients with acute myocardial infarction (MI), aspirin has been shown to reduce the odds of vascular death by 23% [see ISIS-2 trial].

  • Aspirin reduced the risk of death or MI by 64% at 3 months in patients with non-ST-elevation acute coronary syndrome (ACS) and has been shown to reduce post-percutaneous coronary intervention (PCI) ischemic complications.

2. P2Y12 Receptor Blockers:

Overview:

  • Dual antiplatelet therapy (DAPT) with aspirin in combination with a P2Y12 receptor inhibitor is recommended in patients during and after ACS and in those undergoing PCI.

  • This class of drug blocks the P2Y12 receptor on the platelet cell surface, thereby preventing platelet activation and downstream platelet aggregation. Platelets may still be activated via alternate pathways.

  • Ticlopidine, clopidogrel, and prasugrel are all thienopyridines and have irreversible effects on the platelet. In contrast, ticagrelor and intravenous cangrelor are nonthienopyridines and bind reversibly to the P2Y12 receptor. To date, cangrelor is the only approved P2Y12 inhibitor with an intravenous formulation.

  • Ticagrelor and prasugrel are faster in onset, more potent, and have less interpatient variability in pharmacodynamic response, as compared with clopidogrel. However, both ticagrelor and prasugrel increase the risk of major and minor non-CABG-related bleeding.

  • Intravenous cangrelor demonstrates very rapid and offset kinetics. When compared to clopidogrel administered at the time of PCI (elective or urgent), cangrelor reduces the risk of cardiovascular events with a trend toward increased bleeding when administered for the duration of the procedure.

  • It is recommended that all oral P2Y12 receptor blockers be stopped for at least 5 days prior to coronary artery bypass grafting (CABG), whenever possible. A recommendation of 7 days is provided for prasugrel. There is interest in the use of cangrelor for bridging patients at increased risk of cardiovascular events while off of dual antiplatelet therapy since the drug has rapid onset and offset kinetics; however, it is not currently approved for this indication.

Option 1: Ticlopidine

  • Overall has similar efficacy to clopidogrel, but has a less favorable safety profile and therefore is not considered the drug of choice.

  • Risks include neutropenia, thrombocytopenia, gastrointestinal side effects, and thrombotic thrombocytopenic purpura (TTP).

Option 2: Clopidogrel

  • Now available as a generic drug in the United States.

  • Pro-drug; requires hepatic metabolism to form its active metabolite.

  • After 300 mg load, requires approximately 6 hours to achieve steady-state.

  • TTP has been reported, but less frequently than with ticlopidine.

Efficacy and safety of clopidogrel:

  • In the CURE trial, clopidogrel and aspirin reduced cardiovascular (CV) death, MI, or stroke by 20% versus aspirin alone in patients after non-ST-elevation ACS. Benefit was seen regardless of whether patients were managed medically, or by PCI or CABG [see CURE trial]. Clopidogrel increased the risk of major and minor bleeding as compared with placebo.

  • In patients undergoing PCI, clopidogrel and aspirin reduced CV events by 27%. The benefit appeared early and was sustained over the first year [see CREDO trial].

  • In patients with ST segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy, the addition of clopidogrel improved infarct-related artery patency and reduced mortality as compared with placebo [see CLARITY-TIMI 28 and COMMIT/CCS-2 trials].

Clopidogrel Response Variability (Clopidogrel “Resistance”)

  • There exists marked interpatient variability in pharmacodynamic response to clopidogrel.

  • Approximately 30% of individuals demonstrate <20% inhibition in platelet aggregation (IPA) after a 300 mg loading dose of clopidogrel. In turn, patients with high on-treatment platelet reactivity are at increased risk of CV events.

  • A fraction of this variability in pharmacodynamic response is explained by genetic polymorphisms in the CYP2C19 enzyme. This isoenzyme is involved in the transformation of clopidogrel to its active form.

  • Individuals who carry at least one copy of a reduced-function CYP2C19 allele (approximately 30% of the population) have reduced pharmacokinetic/dynamic response to clopidogrel and are at increased risk of CV events if treated with clopidogrel after PCI.

  • Some proton pump inhibitors (PPIs), including omeprazole, inhibit the CYP2C19 enzyme and have been shown to attenuate the pharmacodynamic response to clopidogrel. However, there is no clear evidence that combining clopidogrel and PPIs increases the risk of CV events [see COGENT trial].

Option 3: Prasugrel

  • Advantages over clopidogrel include:

    • Faster onset (initial antiplatelet effects seen within 30 minutes)

    • Reduced interpatient variability

    • Increased potency

    • Efficacy not significantly influenced by genetic polymorphisms in the CYP2C19 enzyme

Efficacy and safety of prasugrel:

  • In phase III testing, prasugrel significantly reduced CV death, MI, or stroke by 19% versus clopidogrel in patients with ACS undergoing PCI [see TRITON-TIMI 38 trial].

  • Prasugrel significantly reduced stent thrombosis by 52% compared with clopidogrel.

  • Although bleeding rates were low, prasugrel significantly increased major and minor bleeding, including fatal bleeding. Prasugrel did not increase intracranial hemorrhage overall.

  • Prasugrel should NOT be administered to patients with a history of stroke or TIA and should be used with caution in patients >75 years or <60 kg (see Prasugrel dosing).

  • The balance of efficacy and safety seems most favorable in patients with diabetes mellitus and those with STEMI.

    • There is no clear benefit for prasugrel in patients with ACS who are medically managed and do not go for cardiac catheterization [TRILOGY-ACS].

    • Pre-treatment with prasugrel 30 mg prior to angiography in patients with NSTE-ACS (followed by an additional 30 mg at the time of PCI) does not reduce the rate of major ischemic events, but increases the rate of major bleeding (including bleeding unrelated to CABG) [see ACCOAST trial]. Therefore, in patients with NSTE-ACS and a short delay from admission to angiography, pre-treatment with prasugrel should be avoided and prasugrel should only be administered once the coronary anatomy is known and PCI will be performed. However, prasugrel can be administered upstream to coronary angiography in patients with STEMI who are intended for primary PCI.

Option 4: Ticagrelor

  • Binds reversibly to the P2Y12 receptor.

  • Not a pro-drug therefore does not require hepatic biotransformation to form its active metabolite.

  • As with prasugrel, ticagrelor has rapid onset of action, reduced interpatient variability and enhanced potency as compared with clopidogrel and is not influenced by genetic polymorphisms in the CYP2C19 enzyme.

  • Although the drug is reversible, the antiplatelet effects of the drug persist for approximately 72 hours [see ONSET/OFFSET trial]. Per FDA, the recommendations remain to wait 5 days off drug prior to CABG.

Efficacy and safety of ticagrelor:

  • In phase III testing, ticagrelor significantly reduced CV death, MI or stroke by 16% as compared with clopidogrel in patients with ACS [see PLATO trial].

  • Ticagrelor also significantly reduced all-cause mortality by 22% and stent thrombosis by 25% compared with clopidogrel.

  • Ticagrelor did not increase CABG-related bleeding compared with clopidogrel.

  • Ticagrelor significantly increased the risk of non-CABG-related major bleeding.

  • Adverse effects included dyspnea and ventricular pauses. These may be related to off-target effects of ticagrelor on adenosine reuptake. The dyspnea appears to be subjective and the drug has not been shown to affect pulmonary function tests.

  • A small increase in uric acid and creatinine has been reported with ticagrelor, but without clear clinical implications.

  • Ticagrelor (90 mg twice daily or 60 mg twice daily) has also been shown to reduce the risk of CV events in stable patients who are 1 to 3 years post MI, but with increased bleeding when compared to placebo [see PEGASUS-TIMI 54]. In these stable patients, the lower dose of 60 mg twice daily appeared to have as much efficacy with less bleeding as the previously approved dose of 90 mg twice daily.

  • In patients with presumed STEMI, pre-hospital administration of ticagrelor does not significantly improve pre-PCI coronary reperfusion as measured by ECG or TIMI flow grade criteria compared to in-hospital administration, but may reduce the risk of stent thrombosis [see ATLANTIC trial].

  • In patients with NSTE-ACS, ticagrelor can be given upstream or at the time of PCI.

Option 5: Cangrelor

  • Intravenous adenosine triphosphate (ATP) analog that binds reversibly and directly inhibits the P2Y12 receptor.

  • Like ticagrelor, it is not a pro-drug and therefore does not require hepatic biotransformation to form its active metabolite.

  • Cangrelor has immediate onset of action, with short duration of effect (30-60 min) and short half-life (3-5 min). Like prasugrel and ticagrelor, its effect has less interpatient variability compared with clopidogrel and is not influenced by genetic polymorphisms in the CYP2C19 enzyme.

Efficacy and safety of cangrelor:

  • Three phase III trials have investigated the efficacy and safety of cangrelor in patients undergoing PCI; cangrelor is now approved for use during PCI in patients with ACS or stable CAD who have not been pretreated with an oral P2Y12 receptor blocker and are not receiving a glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitor.

  • In patients undergoing urgent or elective PCI, cangrelor significantly reduced the risk of death, MI, ischemia driven revascularization or stent thrombosis by 22% and stent thrombosis by 38% when compared to patients who received clopidogrel at the time of PCI. The risk of severe bleeding was 0.16% for patients treated with cangrelor and 0.11% for patients treated with clopidogrel (OR 1.50, 95% CI 0.43-4.22) [see CHAMPION PHOENIX trial].

What doses of antiplatelet drugs should be prescribed?

Aspirin dosing

  • To date, there is no evidence that high-dose aspirin is superior to low-dose aspirin after day 1 of treatment.

  • A randomized clinical trial demonstrated that high-dose (300 to 325 mg daily) and low-dose (75 to 100 mg daily) aspirin had similar efficacy, but high-dose aspirin increased the risk of minor and gastrointestinal bleeding [see CURRENT-OASIS 7 trial].

  • The 2011 ACCF/AHA/SCAI PCI Guidelines for PCI recommend the following:

    • Class I indication: Prior to PCI, patients should take non-enteric ASA 81-325 mg (325 mg if not already on aspirin therapy); after PCI, ASA should be continued indefinitely.

    • Class IIa: Low-dose (81 mg) is a reasonable alternative to higher maintenance doses.

  • Of note, ticagrelor should only be used in combination with an aspirin dose of <100 mg daily based on data that suggested potential harm when higher doses of aspirin were used.

Clopidogrel dosing

  • A 600 mg loading dose is recommended for clopidogrel-naïve patients who are <6 hours pre-PCI. A 300 mg loading dose requires 6 hours to achieve steady state.

  • In a randomized clinical trial, a high-dose regimen of clopidogrel (600 mg LD, 150 mg QD x7 days) was not superior to standard dosing (300 mg LD, 75 mg daily). In those patients who required PCI, the higher dose regimen reduced CV events, but increased major bleeding [see CURRENT-OASIS 7 trial].

  • In patients who carry a single copy of a reduced function CYP2C19 allele, clopidogrel 225 mg daily appears to be bioequivalent to 75 mg daily [see ELEVATE-TIMI 56 trial].

  • A clopidogrel dose of 150 mg daily has not been shown to be superior to 75 mg daily in patients with an inadequate response to clopidogrel by platelet function testing [see GRAVITAS trial].

Prasugrel dosing

  • 60 mg loading dose, then 10 mg daily was evaluated in phase III testing.

  • A maintenance dose of 5 mg daily can be used in patients at increased risk of bleeding, including those older than 75 or weighing less than 60 kg.

  • Caution should be used in prescribing prasugrel in patients at increased risk of bleeding and should not be used in patients with a history of stroke or TIA.

Ticagrelor dosing

  • 180 mg loading dose, then 90 mg twice daily was evaluated in phase III testing and is recommended during the first year after an ACS event. Beyond one year after MI, a reduced dose of 60 mg twice daily can be considered.

  • Ticagrelor should only be used in combination with low-dose aspirin.

Cangrelor dosing

  • 30 μg/kg bolus prior to PCI, followed by a 4 μg/kg/min infusion for at least 2 hours or the duration of the procedure, whichever is longer (up to a maximum of 4 hours).

  • An oral P2Y12 platelet inhibitor should be administered to maintain platelet inhibition after discontinuation of the cangrelor infusion. Clopidogrel 600 mg PO or prasugrel 60 mg PO may be administrated immediately after discontinuation of the infusion, while ticagrelor 180 mg PO may be administered anytime during the infusion or immediately after discontinuation.

Administration

How long should DAPT be continued?

  • Aspirin should be continued lifelong in patients with coronary artery disease (CAD).

  • The optimal duration of P2Y12 inhibition remains disputed. However, the largest randomized trial of prolonged DAPT to date suggests that continuation of DAPT through 30 months reduces the risk of CV events by 29% and the risk of stent thrombosis by 71% but with increased bleeding [see DAPT trial]. An increase in the risk of CV events is observed during the first few months after discontinuation of DAPT.

  • For patients with ACS managed without PCI, the ACC/AHA guidelines recommend that P2Y12 inhibitors should be continued for at least 12 months.

  • For patients treated with PCI after ACS, the 2016 ACC/AHA guidelines support at least 12 months of DAPT (regardless of stent type).

  • In those treated with a DES who are at high risk of bleeding, who develop a high risk of bleeding or who develop overt bleeding, discontinuation of DAPT after 6 months may be reasonable.

  • Regardless of treatment strategy, for those who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk, continuation of DAPT for longer than 12 months may be reasonable.

What other classes of drugs should be considered post-ACS?

Beta-blockers

Mechanism of action:

  • Block catecholamine effects via β-adrenergic receptors throughout the body (β1 subtype in heart and kidneys; β2 subtype in lungs and vascular smooth muscle). Some beta-blockers also block α1 receptors.

  • Effects may include:

    • Reduced myocardial demand due to negative inotropy and chronotropy

    • Decreased automaticity and risk of ventricular arrhythmias

    • Improved coronary perfusion due to prolongation of diastole

    • Reduced adverse remodeling

Efficacy of beta-blockers:

  • Beta-blockers reduce long-term mortality by 23% after acute MI. Although some obsevational studies have raised into question the need for long-term treatment with beta blockers in patients with stable CAD, beta blockers remain routinely administered.

  • Treatment with beta-blockers after successful primary PCI is associated with reduced six-month mortality, with the greatest benefit in patients with a low ejection fraction or multi-vessel CAD.

  • In patients with reduced ejection fractions, only metoprolol, carvedilol, and bisoprolol have established benefit.

Contraindications:

  • Should not be used in patients with decompensated heart failure or cardiogenic shock. Relative contraindications include severe bronchospasm, high-grade AV block, bradycardia (hr <50 bpm) or hypotension (SBP <90 mm Hg).

  • Should not be used in patients with decompensated heart failure or cardiogenic shock. Relative contraindications include severe bronchospasm, high-grade AV block, bradycardia (hr <50 bpm) or hypotension (SBP <90 mm Hg).

Statins

Mechanism of action:

  • Statins inhibit the HMG CoA reductase enzyme, thereby reducing cholesterol biosynthesis by the liver.

  • Efficacy and risks of statins:

    • Atorvastatin 80 mg daily has been shown to reduce early recurrent ischemic events by 16% when administered early after ACS, as compared with a placebo [see MIRACL trial].

    • In patients after ACS, high-potency statins (atorvastatin 80 mg daily) have been shown to significantly reduce the risk of CV events by 16%, as compared with moderate-potency statins (pravastatin 40 mg daily). The benefit appeared early and persisted over time. Median achieved low density lipoproteins (LDL) concentration for patients on atorvastatin 80 mg daily was approximately 70 mg/dl [see PROVE IT-TIMI 22 trial].

    • Administration of high-potency statins prior to PCI has been shown to reduce periprocedural myonecrosis.

    • Adverse effects: myalgias, hepatoxicity, rhabdomyolysis (risk of rhabdomyolysis appears to be highest for patients on simvastatin 80 mg daily).

Dosing considerations:

  • High-potency statin therapy is recommended for patients early after diagnosis of ACS.

  • Ideally, atorvastatin 80 mg daily or rosuvastatin 40 mg daily should be prescribed regardless of baseline LDL and use of preexisting statin therapy.

  • Due to increased risk of rhabdomyolysis, simvastatin 80 mg daily should no longer be newly prescribed to patients.

  • Although there is no clear evidence that events are not further reduced by further LDL reduction, most guidelines suggest that the optimal target LDL is <70 mg/dl in patients after ACS; all patients should be targeted to <100 mg/dl.

  • If a patient develops an adverse effect that is not severe, consideration can be given to changing statin type or reducing dose rather than discontinuation.

  • Combining statins with fibrates or niacin may increase the risk of muscle toxicity.

  • Lipophilic statins (excludes rosuvastatin and pravastatin) may interact with drugs that interfere with CYP3A4 enzyme activity.

Ezetemibe

Mechanism of action:

  • Ezetemibe inhibits NPC1L1 protein located on the epithelial brush border of the GI tract, thereby reducing cholesterol transportation and absorption.

  • Efficacy and risks of ezetemibe:

    • In patients after ACS with well controlled LDL levels at baseline, the addition of ezetemibe (10 mg daily) to simvastatin 40 mg daily significantly reduced the risk of CV events by 6% when compared to simvastatin alone. The mean achieved LDL was 53.7 mg/dl in patients treated with ezetimibe with simvastatin versus 69.5 mg/dl in patients on statin alone [see IMPROVE-IT trial].

    • Overall ezetimibe appears to be well tolerated without notable adverse effects.

Dosing considerations:

  • In patients hospitalized with ACS, if a high potency statin is not tolerated or response to therapy is inadequate, ezetemibe may be added to a moderate potency statin.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers

Mechanism of action:

  • ACE inhibitors inhibit the angiotensin-converting enzyme, thereby reducing formation of angiotensin II (that binds to both AT1 and AT2 receptors); angiotensin receptor blockers (ARBs) inhibit the AT1 angiotensin receptor.

  • In addition to reducing blood pressure, ACE-Is and ARBs are believed to have favorable effects of ventricular remodeling post-MI.

Efficacy of ACE-Is and ARBs:

  • ACE-Is have been shown to reduce mortality when administered early after MI [see ISIS-4 and GISSI-3 trials].

  • ACE-Is significantly reduce death by 17% to 30% in patients with reduced ejection fractions with or without overt heart failure [see SAVE and AIRE trials].

  • ARBs are considered noninferior to ACE-Is and are preferred for patients with ACE-I-induced cough.

  • ACE-Is may not offer significant benefit in low-risk patients with stable CAD [see PEACE trial].

  • Adverse effects: Cough with ACE-Is, angioedema, hyperkalemia, hypotension, renal failure.

Dosing considerations:

  • ACE-Is or ARBs should be prescribed in patients with CAD with reduced ejection fractions, diabetes mellitus, chronic renal insufficiency, hypertension, or following STEMI (in particular anterior STEMI). May have benefit in all high-risk patients with CAD.

  • Dose should be uptitrated as tolerated.

Contraindications:

  • History of anaphylaxis or angioedema, bilateral renal artery stenosis, hypotension, and advanced renal dysfunction.

Aldosterone blockade

Mechanism of action:

  • Inhibit aldosterone at the mineralocorticoid receptor, thereby inhibiting sodium and water reabsorption, while reducing urinary potassium excretion.

  • Prevents adverse ventricular remodeling and collagen formation in patients after MI.

Efficacy and safety of aldosterone blockade:

  • In patients after MI with left ventricular ejection fraction (LVEF) <40% and clinical heart failure and/or diabetes mellitus, eplerenone significantly reduced all-cause mortality by 15% versus a placebo [see EPHESUS trial].

  • Eplerenone increases the risk of hyperkalemia. Individuals with a creatinine >2.5 mg/dl were not enrolled in the EPHESUS trial.

  • Aldosterone blockers may also have endocrine effects including gynecomastia, menstrual irregularities, and impotence.

Dosing considerations:

  • Start at 25 mg daily and uptitrate to 50 mg daily.

  • Eplerenone is believed to have fewer endocrine side effects than spironolactone.

  • Should be used with caution in patients with renal dysfunction and has not been evaluated in patients with a creatinine >2.5 mg/dl.

Anticoagulant therapy

  • Although clinical trial evidence is lacking, warfarin is often prescribed to patients following a large anterior or apical MI to help reduce the risk of stroke.

  • Although warfarin is not routinely prescribed to all patients after ACS, a meta-analysis of clinical trials demonstrated that warfarin reduced the risk of recurrent MI by 44%, but increased bleeding 2.5-fold. A very low dose of the novel factor Xa inhibitor rivaroxaban (2.5 mg PO BID) was shown to significantly reduce the risk of CV death, MI, or stroke by 16% and reduced all-cause mortality by 32% as compared with a placebo. The benefit was consistent regardless of the background use of a P2Y12 inhibitor. However, rivaroxaban also increased the risk of major bleeding and intracranial hemorrhage [see ATLAS ACS 2-TIMI 51].

  • Apixaban, a direct factor Xa inhibitor, at a dose of 5 mg BID has not been shown to be beneficial for patients after ACS.

Protease-activated receptor (PAR)-1 Receptor Antagonists

  • Vorapaxar is a PAR-1 receptor antagonist that has been evaluated in the setting of ACS, as well as in patients with stable atherosclerotic disease.

  • Vorapaxar does not reduce the risk of CV events when administered early post ACS.

  • In patients with stable CAD (>14 days post MI), the addition of vorapaxar (2.5mg daily) to existing therapies (with or without background dual antiplatelet therapy) significantly reduced the risk of recurrent CV events by 20% [see TRA2P-TIMI 50 trial].

  • Vorapaxar increases the risk of bleeding, including intracranial hemorrhage. It should not be administered to patients with a history of TIA or stroke.

What lifestyle and risk factor modifications should be encouraged?

  • Aggressive treatment of underlying risk factors

    • Blood pressure: Goal <140/90 mm Hg or <130/80 mm Hg for patients with diabetes mellitus (DM) or chronic kidney disease (CKD). More aggressive goals have not been shown to be beneficial.

    • Low cholesterol (<200 mg/day) and low fat (<7% saturated fat) diet.

    • Weight loss (target BMI 18.5 to 25 kg/m2).

    • Smoking cessation:

      • Substantial reduction in risk of recurrent MI.

      • Education during hospitalization and referral to smoking cessation on discharge.

    • Vaccination: pneumococcal prior to discharge, influenza annually. Cardiac rehabilitation: Exercise training, psychosocial intervention, emphasis on risk factor reduction noted above.

    • Regular exercise routine.

When should patients be considered for ICD implantation?

  • Secondary prevention: Sustained VT/VF >2 days post-MI and not due to reversible ischemia

  • Primary prevention:

    • ICD implantation for primary prevention should not be considered until at least 40 days post-MI or 3 months post-elective CABG

    • The ACC/AHA guidelines recommend consideration for ICD implantation in the following high-risk groups:

      • LVEF <30% and NYHA class I heart failure

      • LVEF <35% and NYHA class II or III heart failure

      • LVEF <40% with nonsustained ventricular tachycardia (NSVT) and inducible ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) during an electrophysiology study (EP) study

Additional citations

Freemantle, N, Cleland, J, Young, P. "Beta blockade after myocardial infarction: systematic review and meta regression analysis". BMJ. vol. 318. 1999. pp. 1730-1737.

Kernis, SJ, Harjaj, KJ, Stone, GW. "Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty". J Am Coll Cardiol. vol. 43. 2004. pp. 1773-1779.

Schwartz, GG, Olsson, AG, Ezekowitz, MD. "Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: at randomized controlled trial". JAMA. vol. 285. 2001. pp. 1711-1708.

Briguori, C, Visconti, G, Focaccio, A. "Novel approaches for preventing or limiting events (Naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction". J Am Coll Cardiol. vol. 54. 2009. pp. 2157-2163.

Patti, G, Pasceri, V, Colonna, G. "Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial". J Am Coll Cardiol. vol. 49. 2007. pp. 1272-1278.

"ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Grou. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction". Lancet. vol. 345. 1995. pp. 669-685.

"Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction". Lancet. vol. 343. 1994. pp. 1115-1122.

Pfeffer, MA, Braunwald, E, Moyé, LA. "Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial". N Engl J Med. vol. 327. 1992. pp. 669-677.

"The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure". Lancet. vol. 342. 1993. pp. 821-828.

Braunwald, E, Domanski, MJ, Fowler, SE. "Angiotensin-converting-enzyme inhibition in stable coronary artery disease". N Engl J Med. vol. 351. 2004. pp. 2058-2068.

Rothberg, MB, Celestin, C, Fiore, LD. "Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit". Ann Intern Med. vol. 143. 2005; 16. pp. 241-250.

Dickstein, K, Kiekshus, J. "Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan". Lancet. vol. 360. 2002. pp. 752-760.

Pitt, B, Remme, W, Zannad, F. "Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction". N Engl J Med. vol. 348. 2003. pp. 1309-1321.

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