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

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Editors-In-Chief: Anne-Marie Anagnostopoulos, M.D. and C. Michael Gibson, M.S., 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 myocrdial 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.

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. 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

While RALES and EPHESUS support the long-term administration of an aldosterone antagonists 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.


 * 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.

==ACC / AHA Guidelines- Recommendations for Renin-Angiotensin-Aldosterone System Blockers: ACE Inhibitors (DO NOT EDIT) ==

{{cquote|

Class I
1. ACE inhibitors should be started and continued indefinitely in all patients recovering from STEMI with LVEF less than or equal to 40% and for those with hypertension, diabetes, or chronic kidney disease, unless contraindicated. (Level of Evidence: A)

2. ACE inhibitors should be started and continued indefinitely in patients recovering from STEMI who are not lower risk (lower risk defined as those with normal LVEF in whom cardiovascular risk factors are well controlled and revascularization has been performed), unless contraindicated. (Level of Evidence: B)

Class IIa
1. Among lower risk patients recovering from STEMI (i.e., those with normal LVEF in whom cardiovascular risk factors are well controlled and revascularization has been performed) use of ACE inhibitors is reasonable. (Level of Evidence: B) }}

==ACC / AHA Guidelines- Recommendations for Renin-Angiotensin-Aldosterone System Blockers: Angiotensin Receptor Blockers (DO NOT EDIT) ==

{{cquote|

Class I
1. Use of angiotensin receptor blockers is recommended in patients who are intolerant of ACE inhibitors and have HF or have had an MI with LVEF less than or equal to 40%. (Level of Evidence: A)

2. It is beneficial to use angiotensin receptor blocker therapy in other patients who are ACE-inhibitor intolerant and have hypertension. (Level of Evidence: B)

Class IIb
1. Considering use in combination with ACE inhibitors in systolic dysfunction HF may be reasonable. (Level of Evidence: B) }}

==ACC / AHA Guidelines- Recommendations for Renin-Angiotensin-Aldosterone System Blockers: Aldosterone Blockade (DO NOT EDIT) ==

{{cquote|

Class I
1. Use of aldosterone blockade in post-MI patients without significant renal dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, have an LVEF of less than or equal to 40%, and have either diabetes or HF. (Level of Evidence: A) }}