ST elevation myocardial infarction inhibition of the renin-angiotensin-aldosterone system at discharge
ST Elevation Myocardial Infarction Microchapters
ST elevation myocardial infarction inhibition of the renin-angiotensin-aldosterone system at discharge On the Web
Editors-In-Chief: C. Michael Gibson, M.S., M.D. and Anne-Marie Anagnostopoulos, M.D.
Angiotensin Converting Enzyme (ACE) Inhibition remains first line therapy among STEMI patients, particularly those with poor left ventricular function following ST elevation myocardial infarction. The benefits of ACE inhibition are clear among patients with an anterior myocardial infarction and are less clear among patients with non-anterior myocardial infarction. Patients who cannot tolerate an ACE inhibitor (for example they develop a cough) can be treated with an Angiotensin Receptor Blocker (ARB). In addition to an ACE inhibitor, if a patient has symptomatic heart failure or a left ventricular ejection fraction < 40% and does not have impaired renal function or hyperkalemia, then long-term aldosterone blockade should be administered.
Benefits of ACE Inhibitors in Congestive Heart Failure
Studies have established a mortality benefit and a reduction in hospitalizations among patients with heart failure who were administered ACE inhibitors. The two major trials establishing these benefits were the SOLVD and CONSENSUS trials. While these two studies both used enalapril; an overview of 32 ACE inhibitor trials in the treatment of heart failure using various ACE inhibitors showed similar benefit among different ACE inhibitors suggesting a class effect.
Benefits of Early Angiotensin Converting Enzyme (ACE) Inhibition in Acute ST Segment Elevation MI (STEMI)
While the above studies focused upon the improvement in clinical outcomes among patients with congestive heart failure, the clinical benefits of both the early and late initiation of ACE inhibitors has been studied among patients with ST elevation MI, regardless of LV function. With respect to early initiation, there have been multiple randomized and non-randomized trials performed in the mid to late 1990’s. Four large randomized trials (each with >1000 patients) addressed the specific question of whether starting ACE inhibitors early in the acute phase of an STEMI improved morbidity and mortality. These studies were: CONSENSUS-II (Enalapril as active comparator), GISSI-2 (Lisinopril as active comparator), ISIS-4 (Captopril as active comparator), and CCS-1 (Captopril as active comparator). They were included in a systematic overview, performed by the ACE Inhibitor Myocardial Infarction Collaborative Group in 1998, whose goal it was to determine the overall benefit of early (within 36 hours of symptom onset) ACE inhibition, particularly in various subgroups of acute MI patients. The study included the four trials mentioned above and analyzed 98,000 patients who presented with a diagnosis of a STEMI, within 36 hours of symptom onset and were randomized in this time period, and were treated for 4-6 weeks). Patients who received early ACE inhibition had statistically better mortality rates at 30 days compared to the control group (7.11% vs. 7.59% respectively, with a relative risk reduction of 7%, p 0.004). The relative risk reduction in mortality in the first 7 days after STEMI was higher than in days 8-30 indicating that much of the survival advantage of early initiation of ACE inhibition was seen in the first week post-MI, when the risk of dying is highest.
While ACE inhibitor-treated subgroups in general sustained similar relative risk reductions in 30-day mortality, the benefit in 30-day mortality was greater among two subgroups: anterior ST segment elevation MI and patients with heart rate >100 beats per minute. It should be noted that patients with cardiogenic shock and hypotension were excluded from the trials analyzed and therefore the results are not applicable to these patients.
Benefits of Angiotensin Converting Enzyme (ACE) Inhibition in LV Dysfunction After the Acute Phase of ST Segment Elevation MI (STEMI)
Three important trials established the mortality benefit of ACE inhibitor use in patients with MI and clinical or echocardiographic heart failure when started after the acute phase of the MI. The trials, SAVE, AIRE, and TRACE, initiated ACE inhibitors at a later time point after a myocardial infarction (an average of 11 days, 5.4 days, and 4.5 days respectively). All three trials demonstrated a significant mortality benefit when ACE inhibitors were added to standard therapies of aspirin, thrombolytics, and beta-blockers among patients with a reduced ejection fraction.
The SAVE trial randomized 2,200 patients 3-16 days post-MI with an LVEF <40% to forced dose titration of captopril or placebo with a mean follow up of 42 months. There was a 19% relative risk reduction in the ACE inhibitor-treated group compared to the placebo group (mortality of 20% and 25% respectively, p = 0.019).
The AIRE trial randomized 2,000 patients 3-10 days after MI who had clinical or radiographic evidence of left heart failure to receive ramipril or placebo for a mean follow-up of 15 months. Again, the results were significant for a mortality rate of 17% in the ramipril group and 23% in the placebo group, resulting in a 27% relative risk reduction (p = 0.002). There was also a 21% relative risk reduction in progression to severe heart failure.
Lastly, the TRACE trial randomized 1,700 patients, 3-7 days post-MI, with an EF by echocardiography of <_= 35% to receive trandolapril or placebo. All-cause mortality in the ACEI group was 34.7% versus 42.3% in the placebo group. This resulted in a 22% relative risk reduction (p = 0.001). This study, as well as SAVE and AIRE, showed that those patients with reduced LV function who received ACE inhibitor therapy on top of aspirin, thrombolytic therapy or beta-blockers experienced additional benefits beyond that provided by these other, standard therapies.
In summary, these studies established that ACE inhibitors initiated following the acute phase of ST elevtion MI provide a unique survival benefit in high-risk patients with STEMI and clinical heart failure or objective radiographic LV dysfunction.
Recommendations Regarding Initiation of ACE Inhibitors in the Setting of ST Elevation MI (STEMI)
Early initiation of ACE inhibitors during acute ST elevation MI has not only been found to be safe (barring a contraindication), but has also resulted in a significant short-term mortality benefit. As a result, the ACC-AHA guidelines now include Class Ia recommendations for ACE inhibitor initiation in patients with STEMI and a left ventricular ejection fraction (LVEF)<40% or hypertension, diabetes, or chronic kidney disease and these agents should be continued indefinitely (unless contraindicated). It is a Class Ib recommendation to initiate and continue ACE inhibitors in STEMI patients who are not at low risk (low risk defined as normal EF with all cardiovascular risk factors controlled and revascularized). It is a Class IIa recommendation to initiate ACE inhibitors in patients with low risk STEMI.
RALES study (Randomized Aldactone Evaluation Study)
Among patients with New York Heart Association class III to IV heart failure, treatment with spironolactone at an initial dose of 25 mg daily with an increase to 50 mg PO daily was associated with a 11% ARD (24% RRR) in all-cause mortality over 2 years despite co-administration of an ACE inhibitor in 95% of the patients.  In so far as 55% of the patients developed heart failure on the basis of ischemic heart disease, these results may be applicable to patients with STEMI.
EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study)
In contrast to RALES, this study focused specifically on post-MI patients (n=6632). Despite co-administration of ACE inhibitors to these post-MI patients with either a ejection fraction < 40% or diabetes, eplerenone at a dose of 50 mg daily was associated with a significant reduction in all cause mortality, cardiovascular mortality, and cardiac hospitalizations 
- Creatinine > 2.5 mg/dl in men
- Creatinine (Cr) > 2.0 mg/dl in women
- Potassium (K+) > 5.0 mEq/L.
- A relative contraindication is a creatinine clearance < 50 mL/min.
Angiotensin Receptor Blockade (ARB)
The safety and efficacy of Angiotensin Receptor Blockade (ARB) in the setting of STEMI has not been as extensively evaluated as ACE inhibitors.
OPTIMAAL (Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan)
Losartan 50 mg once daily did not differ from captopril at a dose of 50 mg PO three times daily with respect to all cause mortality. Numerically but not significantly significant results were found in favor of captopril. 
VALIANT trial (Valsartan in Acute Myocardial Infarction Trial)
Post MI patients with LV dysfunction were randomized to receive either valsartan at a dose of 160 mg PO twice daily versus captopril 50 mg 3 times daily versus the combination of the two agents at doses of valsartan 80 mg twice daily plus captopril 50 mg 3 times daily plus.  Two year mortality did not differ between the three arms 19.9% for valsartan, 19.5% for captopril, and 19.3% in the combination arm (p=NS). Valsartan was associated with a higher rate of hypotension and renal dysfunction.
ACE Versus ARB Inhibition
ACE inhibitors remain the first line of therapy given the large randomized trial data demonstrating their safety and efficacy following STEMI. Among STEMI patients with poor LV function who are intolerant to ACE inhibitors, Valsartan monotherapy at a dose 160 mg twice daily. Side effects and cost should be taken into consideration if a decision is made to administer valsartan instead of an ACE inhibitor.
2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary(DO NOT EDIT)
Renin-Angiotensin-Aldosterone System Inhibitors (DO NOT EDIT)
|"1. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated(Level of Evidence: A)"|
|"2. An angiotensin receptor blocker should be given to patients with STEMI who have indications for but are intolerant of angiotensin-converting enzyme inhibitors(Level of Evidence: B)"|
|"3. An aldosterone antagonist should be given to patients with STEMI and no contraindications who are already receiving an angiotensin-converting enzyme inhibitor and beta blocker and who have an ejection fraction less than or equal to 0.40 and either symptomatic HF or diabetes mellitus(Level of Evidence: B)"|
|"1. Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no contraindications to their use (Level of Evidence: A)"|
2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (DO NOT EDIT)
Renin-Angiotensin-Aldosterone System Blockers: ACE Inhibitors 
|"1. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated. (Level of Evidence: A)"|
|"1. Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no contraindications to their use. (Level of Evidence: A)"|
Renin-Angiotensin-Aldosterone System Blockers: Angiotensin Receptor Blockers 
|"1. An angiotensin receptor blocker should be given to patients with STEMI who have indications for but are intolerant of angiotensin-converting enzyme inhibitors. (Level of Evidence: B)"|
Renin-Angiotensin-Aldosterone System Blockers: Aldosterone Blockade
|"1. An aldosterone antagonist should be given to patients with STEMI and no contraindications who are already receiving an angiotensin-converting enzyme inhibitor and beta blocker and who have an ejection fraction less than or equal to 0.40 and either symptomatic HF or diabetes mellitus. (Level of Evidence: A)"|
- 2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (DO NOT EDIT)
- Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone: Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.
- Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.
- Dickstein K, Kjekshus J, for the OPTIMAAL Steering Committee of the OPTIMAAL Study Group. 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 2002;360:752-60.
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.
- American College of Emergency Physicians. Society for Cardiovascular Angiography and Interventions. O'Gara PT, Kushner FG, Ascheim DD, Casey DE; et al. (2013). "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.". J Am Coll Cardiol. 61 (4): 485–510. PMID 23256913. doi:10.1016/j.jacc.2012.11.018.
- 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.
- Pfeffer MA, Braunwald E, Moyé LA; et al. (1992). "Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators". N. Engl. J. Med. 327 (10): 669–77. PMID 1386652. doi:10.1056/NEJM199209033271001.
- Ball SG, Hall AS, Murray GD (1994). "ACE inhibition, atherosclerosis and myocardial infarction--the AIRE Study in practice. Acute Infarction Ramipril Efficacy Study". Eur. Heart J. 15 Suppl B: 20–5; discussion 26–30. PMID 8076659.
- Køber L, Torp-Pedersen C, Carlsen JE; et al. (1995). "A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group". N. Engl. J. Med. 333 (25): 1670–6. PMID 7477219. doi:10.1056/NEJM199512213332503.
- Pfeffer MA, Greaves SC, Arnold JM; et al. (1997). "Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial". Circulation. 95 (12): 2643–51. PMID 9193433.
- "Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group". Circulation. 97 (22): 2202–12. 1998. PMID 9631869.
- "GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico". Lancet. 343 (8906): 1115–22. 1994. PMID 7910229.
- "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. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group". Lancet. 345 (8951): 669–85. 1995. PMID 7661937.
- Pfeffer MA, McMurray JJ, Velazquez EJ; et al. (2003). "Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both". N. Engl. J. Med. 349 (20): 1893–906. PMID 14610160. doi:10.1056/NEJMoa032292.
- Maggioni AP, Fabbri G (2005). "VALIANT (VALsartan In Acute myocardial iNfarcTion) trial". Expert Opin Pharmacother. 6 (3): 507–12. PMID 15794740. doi:10.1517/14656518.104.22.1687.
- Pitt B, Remme W, Zannad F; et al. (2003). "Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction". N. Engl. J. Med. 348 (14): 1309–21. PMID 12668699. doi:10.1056/NEJMoa030207.