Author + information
- Received July 6, 2017
- Revision received September 5, 2017
- Accepted September 10, 2017
- Published online February 26, 2018.
- aINECO Neurociencias, Rosario, Santa Fe, Argentina
- bDuke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Christopher B. Granger, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27710.
Heart failure (HF) complicating myocardial infarction (MI) is common and may be present at admission or develop during the hospitalization. Among patients with MI, there is a strong relationship between degree of HF and mortality. The optimal management of the patient with HF complicating MI varies according to time since the onset of infarction. Medical therapy for HF after MI includes early (within 24 h) initiation of angiotensin-converting enzyme inhibitors and early (within 7 days) use of aldosterone antagonists. Alternatively, in patients with MI and ongoing HF, early use (<24 h) of beta-blockers is associated with an increased risk of cardiogenic shock and death. Long-term beta-blocker use after MI is associated with a reduced risk of reinfarction and death. Thus, it is critical to frequently re-evaluate beta-blocker eligibility among patients after MI with HF. Cardiogenic shock is an extreme presentation of HF after MI and is a leading cause of death in the MI setting. The only therapy proven to reduce mortality for patients with cardiogenic shock is early revascularization. Several studies are examining new approaches to mitigate the occurrence and adverse impact of post-MI HF. These studies are testing drugs for HF and diabetes and are evaluating mechanical support devices to bridge patients to recovery or transplantation.
Heart failure (HF) complicating acute myocardial infarction (AMI) is common. Among patients with AMI, HF is the most powerful predictor of death (1) and it has important implications for treatment. Whereas cardiogenic shock is widely appreciated as the major complication of hemodynamic compromise, less severe HF states on the spectrum are more common and also have major adverse consequences. This commentary will define the extent of the problem of HF and will discuss treatments that should and that should not be used to limit the impact on outcomes.
Incidence of HF Post-MI
Incidence of HF among patients hospitalized for an AMI varies among studies (2), ranging from 14% to 36%. Although studies have used different definitions of HF, most have at least collected Killip class, with class II (rales and/or third heart sound) and class III (pulmonary edema) representing HF. The Killip classification is a relatively crude descriptor of HF, yet it is a powerful predictor of death (3) that underscores the gravity of HF complicating AMI. HF can be present on admission or develop during hospitalization. Among 483 incident AMI cases recruited from 1992 to 1996, 4% presented with signs of HF on admission and another 39% developed HF during hospitalization (4). In the GRACE (Global Registry of Acute Coronary Events), among 13,707 acute coronary syndrome patients hospitalized from 1999 to 2001, 13% had HF on admission, and another 5.6% developed HF during the hospital stay (5). Spencer et al. (6) found that 20.4% of 123,938 AMI patients hospitalized from 1994 to 2000 presented with signs of HF, whereas another 8.6% developed HF during hospitalization. A more recent study including 187,803 AMI patients hospitalized from 2007 to 2011 found that 12% of patients presented with signs of HF at admission and another 4% developed HF during hospitalization (7). Data from the Cardiovascular Disease in Norway Project that included a total of 86,771 patients with a first AMI from 2001 to 2009 and without previous HF showed that 18.7% of the patients presented with HF or developed HF during hospitalization, and HF occurrence increased with age (8). Comorbidities may play an important role in both the development and management of HF complicating myocardial infarction (MI). Examples of important comorbidities include atrial fibrillation with rapid ventricular rate and hypertensive emergency that often occurs in patients with normal ejection fraction (EF).
The prognostic significance of HF complicating MI has been assessed in many studies. In a registry-based study enrolling 4,825 patients with non–ST-segment elevation myocardial infarction (STEMI) in Canada from 1999 to 2003, the presence of HF on admission increased the odds of in-hospital mortality by 1.87 times (9). Similarly, HF on admission increased the odds of in-hospital mortality by 2.2 times among 13,707 patients enrolled in the GRACE registry from 1999 to 2001 (5). In the GRACE risk score model, Killip class was the most important predictor of mortality when compared with no HF; rales and/or S3 had 2 times, pulmonary edema 3 times, and cardiogenic shock 4 times the risk of death (1). The risk of HF was similar in patients with and without ST-segment elevation. In a pooled analysis of 7 randomized clinical trials including 46,519 non-STEMI patients from 1994 to 2008, compared with patients with no HF, the presence of HF on admission or developing during the hospitalization was associated with an increase in 30-day mortality of 1.74 and 2.34 times, respectively (10). The FAST-MI (French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction) registry showed that 37.5% of AMI patients had HF; these patients, compared with MI patients without HF, had a significantly increased risk of death during index hospitalization (12.2% vs. 3.0%) and at 1 year (26.6% vs. 5.2%) (11). Biomarkers indicative of HF, B-type natriuretic peptide (BNP) and non-terminal pro-BNP, have also been shown to be strong independent predictors of risk (12).
Patients with HF complicating AMI require different treatments than those without HF (Table 1). The evidence and recommendations are summarized next.
The benefits of long-term beta-blockers in the years after MI have been well established (13–16). In a meta-analysis of 31 randomized trials that included approximately 25,000 patients with a history of MI, the long-term use of beta-blockers reduced the risk of reinfarction and death by approximately 20% to 25% after a mean of 2 years of treatment during an average of 2 years of follow-up (17).
The long-term efficacy of carvedilol on morbidity and mortality in patients with left ventricular dysfunction after AMI was assessed in the CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study) (18). A total of 1,959 patients with AMI (3 to 21 days) and a left-ventricular EF of ≤40% were randomly assigned 6.25 mg carvedilol (maximum 25 mg/day) or placebo. The primary outcome (all-cause mortality and cardiovascular hospitalization) was not different between carvedilol (35%) and placebo (37%) cohorts. However, all-cause mortality was lower in the carvedilol group than in the placebo group (12% vs. 15%; hazard ratio: 0.77; 95% confidence interval [CI]: 0.60 to 0.98; p = 0.03). Similarly, in a meta-analysis of 29 randomized trials including more than 40,000 patients with suspected MI, during the first week in the hospital, intravenous followed by oral beta-blocker seemed to reduce the relative risk of death by 13%, reinfarction by 22%, and ventricular fibrillation by 15% (19). However, it is unknown if these findings were related to the use of intravenous beta-blocker.
The COMMIT-CCS 2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study) included 45,852 patients admitted to 1,250 hospitals in China within 24 h of suspected AMI who were randomly assigned to metoprolol (up to 15 mg intravenous then 200 mg oral daily) or placebo (19). One-fifth of the patients presented with Killip class II and nearly 5% Killip class III; approximately one-half of the patients were treated with fibrinolysis. Metoprolol did not show a benefitial effect in neither both co primary endpoints: for death, reinfarction, or cardiac arrest (9.4% metoprolol vs. with 9.9% placebo; odds ratio [OR]: 0.96; 95% CI: 0.90 to 1.01; p = 0.10), and for death alone, 7.7% in the metoprolol group versus 7.8% in the placebo group (OR: 0.99; 95% CI: 0.92 to 1.05; p = 0.69). Metoprolol was associated with 5 fewer people having reinfarction (2.0% vs. 2.5% [OR: 0.82; 95% CI: 0.72 to 0.92; p = 0.001]) and 5 fewer having ventricular fibrillation (2.5% vs. 3.0%; OR: 0.83; 95% CI: 0.75 to 0.93; p = 0.001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1,000 developing cardiogenic shock (5.0% vs. 3.9%; OR: 1.30: 95% CI: 1.19 to 1.41; p < 0.00001). This excess of cardiogenic shock was mainly during days 0 to 1 after admission, whereas the reductions in reinfarction and ventricular fibrillation emerged at day 2 onward. Consequently, the overall effect on death, reinfarction, arrest, or shock was significantly adverse during days 0 to 1 and significantly beneficial thereafter. When assigned to metoprolol as opposed to placebo, patients with pulmonary edema (Killip class III) were more likely to suffer cardiogenic shock (15.6% vs. 9.9%; absolute increase of 6%) and death (19.7% vs. 16.5%; absolute increase 3.2%). This study shows that early use of high-dose beta-blocker appears harmful for patients who present in HF. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have incorporated these results to recommend, as a Class I recommendation (20,21):
1. Oral beta-blockers should be initiated in the first 24 h in patients with STEMI who do not have any of the following: signs of HF, evidence of a low output state, increased risk for cardiogenic shock (age >70 years, systolic BP <120 mm Hg, sinus tachycardia >110 beats/min or heart rate <60 beats/min, and increased time since onset of symptoms of STEMI), or other contraindications to use of oral beta-blockers (PR interval more than 0.24 s, second- or third-degree heart block, active asthma, or reactive airways disease) (Level of Evidence: B);
2. Beta-blockers should be continued during and after hospitalization for all patients with STEMI and with no contraindications to their use (Level of Evidence: B);
3. Patients with initial contraindications to the use of beta-blockers in the first 24 h after STEMI should be re-evaluated to determine their subsequent eligibility (Level of Evidence: C).
Angiotensin-Converting Enzyme Inhibitors
It is well established that angiotensin-converting enzyme inhibitors (ACEIs) should be administered to patients with impaired EFs (≤40%) or those who have experienced HF in the early phase of MI. A systematic overview (22) of 4 trials of ACEIs early (0 to 36 h) in STEMI including more than 98,000 patients, showed a 7% relative reduction in 30-day mortality compared with placebo. The absolute benefit was particularly greater in high-risk groups (such as Killip class II/III, heart rate >100 beats/min at entry) and anterior MI. Importantly, 40% of the survival benefit occurred on the first day of treatment, underscoring the value of initiating ACEIs early, as long as patients have adequate blood pressure.
ACEIs were tested in 5 long-term randomized trials including more than 12,000 patients with left-ventricular dysfunction or HF after MI. A prospective systematic overview (23) with pooled data from individual patients showed long-term benefit of ACEIs. In the 3 post-infarction trials, SAVE (Survival and Ventricular Enlargement) (24), AIRE (Acute Infarction Ramipril Efficacy) (25), and TRACE (TRAndolapril Cardiac Evaluation) (26), ACEIs were started between 3 and 16 days post-MI. Overall, there was a 26% relative risk reduction (RRR) in mortality comparing ACEIs with placebo (OR: 0.74; 95% CI: 0.66 to 0.83). There was also a 27% RRR in readmission for HF (OR: 0.73; 95% CI: 0.63 to 0.85), 20% RRR in reinfarction (OR: 0.80; 95% CI: 0.69 to 0.94), and 25% RRR in the composite of these events. The SOLVD (Studies of Left Ventricular Dysfunction) trials (27,28) evaluated the treatment effect of enalapril on mortality clinical HF in patients with an EF ≤35%. The outcomes were similar, with no apparent heterogeneity in results between symptomatic and asymptomatic patients when the data were examined at the same time point.
The ACC/AHA guidelines recommend (20), based on this evidence, as a Class I, Level of Evidence: A, recommendation: “An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 h to all patients with STEMI with anterior location, HF, or EF ≤0.40%, unless contraindicated.”
Angiotensin Receptor Blockers
Angiotensin receptor blockers as alternatives to ACEIs in the context of STEMI have been evaluated in 2 clinical trials. OPTIMAAL (Optimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan) (29) included 5,477 patients with confirmed AMI and HF during the acute phase or a new Q-wave anterior infarction or reinfarction to receive either losartan 50 mg 3 times a day or captopril 50 mg 3 times a day. The losartan arm failed to show either superiority or noninferiority when compared with captopril for the primary endpoint (18% vs. 16% at 2.7 years follow-up). Conversely, in VALIANT (VALsartan In Acute myocardial iNfarction Trial) (30), 14,703 patients with AMI (0.5 and 10 days) and HF or evidence of left ventricular systolic dysfunction ≤40% were randomly assigned to valsartan alone (160 mg twice daily), full-dose captopril (50 mg 3 times daily), or both (80 mg twice daily and 50 mg 3 times daily). The primary endpoint of all-cause mortality was similar in the 3 groups (valsartan 19.9%, captopril 19.5%, and both 19.3%), but discontinuations were more frequently seen in patients who were administered captopril. Therefore, valsartan, in the dosages used in the trial, represents an alternative to ACEIs (ACC/AHA Class I, Level of Evidence: B recommendation) in patients who have clinical signs of HF and/or an EF ≤40%, particularly in patients who do not tolerate ACEIs.
The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival) study established the benefit of an aldosterone antagonist, eplerenone, added to optimal medical therapy in patients between 3 and 14 days after STEMI with EF ≤0.40 and either symptomatic HF or diabetes mellitus versus placebo. Eplerenone was initiated at 25 mg/day, then titrated to a maximum dose of 50 mg/day. There was a 15% RRR of all-cause mortality with eplerenone compared with placebo. A similar treatment benefit was seen for the other coprimary endpoint of cardiovascular (CV) death or hospitalization for CV events, death from CV causes, and sudden death from cardiac causes. A post hoc analysis of the EPHESUS study (31) assessed the timing of eplerenone initiation and outcomes. Earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (p = 0.001) when compared with the “earlier” placebo. Earlier eplerenone initiation also reduced the risks of CV hospitalization or CV mortality by 24% (p = 0.0001) and sudden cardiac death by 34% (p = 0.0001). In contrast, later eplerenone initiation (≥7 days) had no significant effect on outcomes. Interactions between time-to-randomization and treatment for mortality were significant (p = 0.02).
There have been smaller exploratory trials to assess the role of mineralocorticoid receptor antagonists (MRAs) earlier after MI and in patients with smaller MIs. The ALBATROSS (Aldosterone Lethal effects Blocked in Acute MI Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up) trial investigated the clinical effects of a rapid and prolonged MRA regimen initiated early after the onset of STEMI or high-risk non-STEMI plus standard therapy versus standard therapy alone in 1,603 subjects. Patients assigned to the MRA regimen received a 200-mg intravenous bolus of potassium canrenoate followed by 25-mg oral dose of spironolactone administered 12 to 24 h after the intravenous injection. There was no difference in the combined primary endpoint of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6-month follow-up (11.8% vs. 12.2% for the MRA and control group, respectively). In a non–pre-specified exploratory analysis, the use of MRA was associated with reduction in mortality compared with placebo (0.5% vs. 2.4%; HR: 0.20; 95% CI: 0.06 to 0.70) in the subgroup of STEMI, but not in non-STEMI.
Guidelines recommend that “an aldosterone antagonist should be given to patients with STEMI and no contraindications who are already receiving an ACE inhibitor and beta-blocker and who have an EF ≤0.40 and either symptomatic HF or diabetes mellitus (Level of Evidence: B)” (20).
Cardiogenic shock is the leading cause of in-hospital mortality associated with AMI; the prevalence of cardiogenic shock complicating MI varies between 5% and 15% (32,33). Despite the evolution of medical treatment and technology, in-hospital mortality of patients with cardiogenic shock complicating AMI managed invasively remains stable. An analysis from the National Cardiovascular Data Registry (NCDR) (34) included 56,497 MI patients with cardiogenic shock who were treated with percutaneous coronary intervention (PCI). The analysis showed a mild increase in the adjusted in-hospital mortality (27.6% from 2005 to 2006 vs. 30.6% from 2011 to 2013, adjusted OR: 1.08; 95% CI: 1.00 to 1.17; p = 0.04).
A scientific statement from the AHA has summarized the evidence around treatments for cardiogenic shock (35).
The SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial (36) established early revascularization as the only effective treatment for cardiogenic shock. The SHOCK trial randomized 152 patients to early revascularization and 150 patients to initial medical stabilization; there was a nonsignificant reduction in the primary endpoint of 30-day mortality from 55% for the initial medical stabilization cohort to 46% for the early revascularization group. However, overall mortality 6 months after infarction was significantly lower in the group assigned to revascularization, and long-term follow-up of the study (37) showed a strategy of early revascularization resulted in a 13.2% absolute and a 67% relative improvement in 6-year survival compared with initial medical stabilization. This led to the Class I, Level of Evidence: B, recommendation: “Emergency revascularization with either PCI or CABG is recommended in suitable patients with cardiogenic shock due to pump failure after STEMI irrespective of the time delay from MI onset” (20).
Intra-Aortic Balloon Pump and Other Mechanical Circulatory Support Devices
The mortality rate of patients with cardiogenic shock complicating MI is high even with early revascularization. Intra-aortic balloon pumps (IABPs) are widely used to hemodynamically support cardiogenic shock patients. The IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial (38) was a randomized, open-label, multicenter trial in which 600 patients with cardiogenic shock complicating AMI were randomized to IABP or no IABP. All patients were expected to undergo early revascularization and to receive recommended medical therapy. The study did not show difference in the primary outcome (30-day mortality 39.7% for IABP patients and 41.3% for control group) (39). There were no differences appreciated in secondary endpoints including reinfarction, stroke, stent thrombosis, or in mortality at 6 months and 1 year (40). IABPs have been evaluated in the noncardiogenic shock setting as well; CRISP-AMI (Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction) randomized 337 patients with acute anterior MI without cardiogenic shock to IABP or no IABP. There was no statistically significant difference in the primary endpoint of infarct size 3 to 5 days post-PCI noted on cardiac magnetic resonance imaging or the secondary endpoint of all-cause death at 6 months (41). There is little evidence that the routine use of IABP in cardiogenic shock provides benefit.
The lack of efficacy for routine IABP use in cardiogenic shock has led to an increased use in other short-term mechanical circulatory support devices. A U.S.-based cross-sectional study (42) from 2004 to 2011 showed that percutaneous device use increased by 1,511%. A trend toward decrease in mortality was observed over time for recipients of short-term circulatory assist devices from 41.1% from 2004 to 2007 to 33.4% from 2008 to 2011, and a similar trend was also seen in the subset of patients with cardiogenic shock, decreasing from 51.6% to 43.1%. There are limited randomized data establishing the safety and efficacy of mechanical circulatory support in MI related cardiogenic shock. The IMPRESS trial randomized 48 patients with severe cardiogenic shock requiring mechanical ventilation to IABP versus the Impella (Abiomed, Danvers, Massachusetts) support device. The 30-day mortality rate was 50% for the IABP arm versus 46% for the Impella group (HR: 0.96; 95% CI: 0.42 to 2.18; p = 0.92) (43). Therefore, there is an important need to establish if, for whom, and at what time mechanical circulatory devices may improve clinical outcomes.
Ongoing Research/Future Areas of Development
There is a Class I recommendation to replace ACEIs/angiotensin II receptor blockers with valsartan/sacubitril among chronic symptomatic HF patients with reduced EF and New York Heart Association (NYHA) functional class II or III (44). Valsartan/sacubitril might also reduce the incidence and severity of HF among MI patients. The PARADISE-MI (Prospective ARNI versus ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI) trial (45) aims to address this question. PARADISE-MI will randomize AMI patients with evidence of left ventricular systolic dysfunction to either valsartan/sacubitril, titrated to a target dose of 200 mg twice daily, or ramipril, titrated to a target dose of 5 mg twice daily. In addition to novel HF therapies, new diabetic medications have shown promising results for HF. The EMPA-REG OUTCOME trial randomized 7,020 type 2 diabetic patients to empagliflozin, a sodium-glucose cotransporter-2 inhibitor, or placebo. The empagliflozin group had a 35% RRR in hospitalization for HF and a 38% RRR in death from CV causes (46). These results have prompted interest in the impact of empagliflozin on MI-related HF. The EMMY trial aims to assess the influence of empagliflozin on biomarkers of HF in patients with MI with and without type 2 diabetes (47). From a device perspective, animal-based experiments suggest that unloading the myocardial to reduce myocardial demand before revascularization may attenuate ischemia-reperfusion injury and reduce the infarct size. The DTU (Door to Unloading) trial is a feasibility study among anterior STEMI patients to assess reducing infarct size by unloading the left ventricle with an Impella CP (Cardiac Power) device (48).
Summary and Conclusions
HF complicating acute MI is common and is associated with substantial increased risk of death. Treatments that are proven to improve outcomes are early reperfusion and early use of ACEI and mineralocorticoid receptor antagonists. Beta-blockers are an integral treatment but should be initiated only after HF has resolved. In contrast to the various treatments proven to improve outcome in HF, the only treatment shown to improve outcome in cardiogenic shock is early revascularization. Timing of such treatments (Central Illustration) is also key. There is a strong need to improve implementation of proven treatments and to develop additional treatments to improve outcomes of patients with HF complicating acute MI.
Dr. Granger has received funding from Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Eli Lilly, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Hoffmann-La Roche, Janssen Pharmaceuticals, The Medicines Company, Medtronic Foundation, Medtronic Inc., Novartis, Sirtex, Pfizer, Verseon, and Armetheon. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology
- angiotensin-converting enzyme inhibitor
- American Heart Association
- acute myocardial infarction
- B-type natriuretic peptide
- coronary artery bypass graft
- confidence interval
- ejection fraction
- heart failure
- intra-aortic balloon pump
- myocardial infarction
- mineralocorticoid receptor antagonist
- odds ratio
- percutaneous coronary intervention
- relative risk reduction
- ST-segment myocardial infarction
- Received July 6, 2017.
- Revision received September 5, 2017.
- Accepted September 10, 2017.
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