View source for ST elevation myocardial infarction inhibition of the renin-angiotensin-aldosterone system at discharge

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{{ST elevation myocardial infarction}}
'''Editors-In-Chief:'''  [[C. Michael Gibson, M.S., M.D.]] and Anne-Marie Anagnostopoulos, M.D.

==Overview==
[[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 <<sub>_</sub>= 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-blocker]]s 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 factor]]s controlled and revascularized).  It is a Class IIa recommendation to initiate ACE inhibitors  in patients with low risk STEMI.

==Aldosterone Inhibition==
Data regarding the safety and efficacy [[aldosterone]] inhibition is derived from trials of [[heart failure]] that enrolled patients with a prior [[MI]].

'''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. <ref>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.</ref>  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 inhibitor]]s 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 <ref> 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.</ref>

While RALES and EPHESUS support the long-term administration of an [[aldosterone antagonist]]s in post_MI patients with an EF < 40% or [[heart failure]], the following are contraindications:
* [[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. <ref>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. </ref>

'''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. <ref> 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.</ref> 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)<ref name="pmid23256913">{{cite journal| author=American College of Emergency Physicians. Society for Cardiovascular Angiography and Interventions. O'Gara PT, Kushner FG, Ascheim DD, Casey DE et al.| title=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. | journal=J Am Coll Cardiol | year= 2013 | volume= 61 | issue= 4 | pages= 485-510 | pmid=23256913 | doi=10.1016/j.jacc.2012.11.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23256913  }} </ref>==

==='''Renin-Angiotensin-Aldosterone System Inhibitors (DO NOT EDIT)'''===

{|class="wikitable" style="width:80%"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' An [[angiotensin]]-converting [[enzyme inhibitor]] should be administered within the first 24 hours to all patients with STEMI with anterior location, [[Heart Failure|HF]], or [[ejection fraction]] less than or equal to 0.40, unless contraindicated''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' An angiotensin receptor blocker should be given to patients with STEMI who have indications for but are intolerant of angiotensin-converting enzyme inhibitors''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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]]''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
|}

{|class="wikitable" style="width:80%"
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no contraindications to their use ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki>
|-
|}

==2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (DO NOT EDIT)<ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD, ''et al.'' |title=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 |journal=Circulation |volume=|issue= |pages= |year=2012 |month=December |pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84|url=}}</ref>==

===Renin-Angiotensin-Aldosterone System Blockers: ACE Inhibitors <ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD, ''et al.'' |title=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 |journal=Circulation |volume=|issue= |pages= |year=2012 |month=December |pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84|url=}}</ref>===

{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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.<ref name="pmid1386652">{{cite journal |author=Pfeffer MA, Braunwald E, Moyé LA, ''et al.'' |title=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 |journal=N. Engl. J. Med. |volume=327 |issue=10 |pages=669–77 |year=1992 |month=September |pmid=1386652 |doi=10.1056/NEJM199209033271001 |url=}}</ref><ref name="pmid8076659">{{cite journal |author=Ball SG, Hall AS, Murray GD |title=ACE inhibition, atherosclerosis and myocardial infarction--the AIRE Study in practice. Acute Infarction Ramipril Efficacy Study |journal=Eur. Heart J. |volume=15 Suppl B |issue= |pages=20–5; discussion 26–30 |year=1994 |month=May |pmid=8076659 |doi= |url=}}</ref><ref name="pmid7477219">{{cite journal |author=Køber L, Torp-Pedersen C, Carlsen JE, ''et al.'' |title=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 |journal=N. Engl. J. Med. |volume=333 |issue=25 |pages=1670–6 |year=1995 |month=December |pmid=7477219 |doi=10.1056/NEJM199512213332503 |url=}}</ref><ref name="pmid9193433">{{cite journal |author=Pfeffer MA, Greaves SC, Arnold JM, ''et al.'' |title=Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial |journal=Circulation |volume=95 |issue=12 |pages=2643–51 |year=1997 |month=June |pmid=9193433 |doi= |url=}}</ref> ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki>
|}

{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Angiotensin-converting enzyme inhibitors are reasonable for all patients with [[STEMI]] and no contraindications to their use.<ref name="pmid9631869">{{cite journal |author= |title=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 |journal=Circulation |volume=97 |issue=22 |pages=2202–12 |year=1998 |month=June |pmid=9631869 |doi= |url=}}</ref><ref name="pmid7910229">{{cite journal |author= |title=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 |journal=Lancet |volume=343 |issue=8906 |pages=1115–22 |year=1994 |month=May |pmid=7910229 |doi= |url=}}</ref><ref name="pmid7661937">{{cite journal |author= |title=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 |journal=Lancet |volume=345 |issue=8951 |pages=669–85 |year=1995 |month=March |pmid=7661937 |doi= |url=}}</ref> ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki>
|}

===Renin-Angiotensin-Aldosterone System Blockers: Angiotensin Receptor Blockers <ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD, ''et al.'' |title=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 |journal=Circulation |volume=|issue= |pages= |year=2012 |month=December |pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84|url=}}</ref>===

{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' An angiotensin receptor blocker should be given to patients with [[STEMI]] who have indications for but are intolerant of angiotensin-converting enzyme inhibitors.<ref name="pmid14610160">{{cite journal |author=Pfeffer MA, McMurray JJ, Velazquez EJ, ''et al.'' |title=Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both |journal=N. Engl. J. Med. |volume=349 |issue=20 |pages=1893–906 |year=2003 |month=November |pmid=14610160 |doi=10.1056/NEJMoa032292 |url=}}</ref><ref name="pmid15794740">{{cite journal |author=Maggioni AP, Fabbri G |title=VALIANT (VALsartan In Acute myocardial iNfarcTion) trial |journal=Expert Opin Pharmacother |volume=6 |issue=3 |pages=507–12 |year=2005 |month=March |pmid=15794740 |doi=10.1517/14656566.6.3.507 |url=}}</ref> ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|}

===Renin-Angiotensin-Aldosterone System Blockers: Aldosterone Blockade<ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD, ''et al.'' |title=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 |journal=Circulation |volume=|issue= |pages= |year=2012 |month=December |pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84|url=}}</ref>===

{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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]].<ref name="pmid12668699">{{cite journal |author=Pitt B, Remme W, Zannad F, ''et al.'' |title=Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction |journal=N. Engl. J. Med. |volume=348 |issue=14 |pages=1309–21 |year=2003 |month=April |pmid=12668699 |doi=10.1056/NEJMoa030207 |url=}}</ref> ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki>
|}

==Sources==
*2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (DO NOT EDIT)<ref name="pmid23247303">{{cite journal |author=O'Gara PT, Kushner FG, Ascheim DD, ''et al.'' |title=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 |journal=Circulation|volume=|issue= |pages= |year=2012 |month=December |pmid=23247303 |doi=10.1161/CIR.0b013e3182742c84|url=}}</ref>

==References==
{{Reflist|2}}

[[Category:Disease]]
[[Category:Cardiology]]
[[Category:Ischemic heart diseases]]
[[Category:Intensive care medicine]]
[[Category:Emergency medicine]]
[[Category:Mature chapter]]

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