Quinto Sprint

STEMI. (Level of Evidence: A)

by guest on April 2, 2018

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lowering medications (69%), and beta-blockers (63%). Given the results of the HOPE trial and the secondary analy- sis from the initial ACE inhibitor trials, ACE inhibitor thera- py is recommended for all patients after STEMI unless oth- erwise contraindicated.

The results of the VALIANT study evaluating the ARB val- sartan are discussed in Section 7.4.3. The series of CHARM studies (Candesartan in Heart Failure Assessment in Reduction of Mortality, although focusing on the evaluation of the ARB candesartan in patients with chronic heart failure, provides information that can be extrapolated to the long- term management of the STEMI patient, because 50% to 60% of the patients studied had ischemic heart disease as the cause of heart failure. In patients with symptomatic heart failure and LVEF 0.40 or less who were intolerant of ACE inhibitors (CHARM-Alternative trial), candesartan (target dose 32 mg once daily) was more effective than placebo in preventing cardiovascular death or hospital admission for heart failure (7% ARD; 23% RRR) (1263). In patients with symptomatic heart failure and LVEF 0.40 or less who were being treated with an ACE inhibitor (CHARM-Added trial), candesartan (target dose 32 mg) was more effective than placebo in preventing cardiovascular death or hospital admission for heart failure (4% ARD; 15% RRR) (1264). In patients with symptomatic heart failure but with a preserved LVEF (greater than 0.40; CHARM-Preserved trial), can- desartan had no impact on cardiovascular death compared with placebo but was associated with a trend toward fewer admissions for heart failure (1265).

Given the extensive randomized trial and routine clinical experience with ACE inhibitors, they remain the logical first agent for inhibition of the renin-angiotensin-aldosterone sys- tem in the long-term management of patients with STEMI (726). The ARBs valsartan and candesartan should be admin- istered over the long term to patients with STEMI with symptomatic heart failure who are intolerant of ACE inhibitors. As described in Section 7.4.3, the choice between an ACE inhibitor and an ARB in patients who are tolerant of ACE inhibitors over the long term will vary with individual physician and patient preference, as well as cost and antici- pated side-effect profile (726).

The results of the most relevant clinical trials testing com- binations of ACE inhibitors and ARBs have subtly different but clinically relevant results. Whereas the CHARM-Added (1264) trial demonstrated a reduction in the combined end point of heart failure hospitalization and death over ACE inhibition alone, the VALIANT study (725) reported that the combination of captopril and valsartan was equivalent to either alone, but with a greater number of adverse effects. Thus, when combination ACE inhibition and angiotensin receptor blockade is considered, the preferred ARB is can- desartan. Although there is evidence that the combination of an ACE inhibitor and an aldosterone inhibitor is effective at reducing mortality and is well tolerated in patients with a serum creatinine less than or equal to 2.5 mg/dL and serum potassium concentration less than or equal to 5.0 mmol/L (see Section 7.4.3), much less experience exists with the Similarly, the TRACE trial, in which patients with LV dys-

function on echocardiogram were randomly assigned to receive either trandolapril or placebo a median of 4 days after onset of infarction, demonstrated a significant reduction in mortality (7.6% ARD; 22% RRR) (1258).

The SOLVD trial evaluated the ACE inhibitor enalapril in 4228 asymptomatic patients with LVEF less than 0.35, 80% of whom had experienced a prior MI (1259). However, randomization was performed considerably later on the aver- age than in the SAVE and AIRE trials. This prevention arm of the SOLVD trial revealed a trend toward improved mor- tality but not a statistically significant difference (1260). On the other hand, SOLVD did demonstrate a significant risk reduction of 20% for the combined end points of death or development of CHF requiring hospitalization.

In secondary analyses of the initial ACE inhibitor trials, the benefit of treatment appeared to be primarily in patients with anterior infarctions or LVEF below 0.40. However, based on post hoc analysis of the SAVE trial, in which the likelihood of recurrent MI was reduced by approximately 25% in treat- ed patients, studies were initiated to determine the benefits of ACE inhibitor therapy among patients with known CHD but no clinical evidence for CHF (1261). Compelling evidence now supports the broad chronic use of ACE inhibitors after STEMI. The HOPE trial evaluated the effect of long-term (4 to 6 years) ACE inhibition therapy with ramipril 10 mg per day in 9297 high-risk patients, 2480 of whom were women. Fifty-two percent of the patients had a history of MI, and in 10%, the MI was within 1 year. Overall, there was a highly significant reduction in the combined end point of MI, stroke, and all-cause cardiovascular mortality (3.8% ARD; 22% RRR; p less than 0.001). Significant reductions were seen for each individual component of the primary end point: MI 2.4% ARD, RRR 20%; stroke 1.5% ARD, RRR 32%; and death of any cause 1.8% ARD, RRR 16%. Importantly, the study was performed in patients who were not known to have low ejection fraction or heart failure. The European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) evaluated the use of the ACE inhibitor perindopril given 8 mg per day among 13 655 patients (age range 26 to 89 years, mean 60 years) with known CHD but no history of clinical heart failure (1262). Nearly two thirds (64%) of the patients had a history of pre- vious MI (more than 3 months before screening). After a mean follow-up of 4.2 years, treatment with perindopril was associated with a significant reduction (2% ARD; 20% RRR; p equals 0.0003) in the combined end point of nonfatal MI, cardiovascular mortality and resuscitated cardiac arrest. The benefit began to appear at 1 year and gradually progressed throughout the trial. Patients in EUROPA all had CHD but a lower risk than those in HOPE, in which the enrollment age was 55 years or older and 39% had diabetes. In EUROPA, nearly one third of the patients were younger than 55 years, and fewer had diabetes and hypertension. Moreover, the ben- efits of ACE inhibitor therapy with perindopril were observed in spite of relatively high use of other secondary prevention therapies such as platelet inhibitors (91%), lipid-

by guest on April 2, 2018

http://circ.ahajournals.org/

combination of an ARB and an aldosterone inhibitor (24% of 2028 patients in the CHARM-Alternative trial) and the triple combination of an ACE inhibitor, ARB, and an aldosterone antagonist (17% of 2548 patients in the CHARM-Added trial) (1263,1264).

The combination of an ACE inhibitor and an ARB (valsar- tan 20 mg orally per day initially, titrated up to 160 mg oral- ly twice per day, or candesartan 4 to 8 mg orally per day ini- tially, titrated up to 32 mg orally per day) or an ACE inhibitor and an aldosterone inhibitor may be considered for the long- term management of patients with STEMI with symptomatic heart failure and ejection fraction less than 0.40, provided the serum creatinine is less than or equal to 2.5 mg/dL in men and less than or equal to 2.0 mg/dL in women and serum potassium concentration is less than or equal to 5.0 mEq/L. (See Sections 7.4.3 and 7.6.4.)

7.12.7. Beta-Blockers

1. All patients after STEMI except those at low risk