Pharmacological and Device-Based Intervention for Preventing Heart Failure After Acute Myocardial Infarction　― A Clinical Review ―

Abstract

In patients with acute myocardial infarction (MI), heart failure (HF) is one of the most common complications that is associated with a significant burden of mortality and healthcare resources. The clinical benefits of key HF drugs, the so-called “4 pillars” or “fantastic 4”, namely β-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitor, and sodium-glucose cotransporter 2 inhibitors, have been established in patients with HF with reduced ejection fraction, whereas the effects of these drugs are not comprehensively appreciated in patients with acute MI. This review summarizes current evidence on pharmacological and device-based interventions for preventing HF after acute MI.

Ischemic heart disease (IHD), represented by acute myocardial infarction (MI), is one of the leading causes of mortality and morbidity worldwide.¹ Due to recent advances in early reperfusion with primary percutaneous coronary intervention (PCI) and pharmacological therapies, the short-term prognosis after acute MI has improved considerably in decades.^2–5 Even in patients with cardiogenic shock (CS), mechanical circulatory support (MCS) devices, such as a percutaneous microaxial ventricular assist device (Impella; Abiomed, Danvers, USA), have emerged as a treatment option to reduce mortality in a setting of ST-segment elevation MI (STEMI).⁶ In the current era, clinical attention has shifted, at least partially, from short-term mortality to long-term adverse outcomes, of which heart failure (HF) is one of the most common complications after acute MI.⁷ The prevalence of a background history of IHD accounted for approximately 50% of patients with HF in Eastern and Western populations,^8,9 whereas HF is also a common presentation in a setting of acute coronary syndrome (ACS) and MI, with a prevalence of up to 40% and accrues thereafter in around 10%.^10,11 Because the development of HF is a strong predictor of mortality, multidisciplinary efforts, including an early reperfusion strategy, advances in pharmacological therapy, care system improvements, and identification of vulnerable subsets, are required to prevent HF after acute MI.¹² Of these treatment strategies, there has been a rapid evolution in the pharmacological treatment of HF. In patients with HF with reduced ejection fraction (HFrEF), the clinical benefits of key anti-HF drugs, the so-called “4 pillars” or “fantastic 4”,^13,14 namely β-blockers, mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, have been established, although the effects of these medications on HF prevention in patients with acute MI has been a matter of debate. This narrative review summarizes the clinical evidence for pharmacological and device-based interventions for preventing HF after acute MI.

Mechanisms and Timing of HF Following MI

Following acute MI, various pathophysiological mechanisms contribute to cardiac remodeling and HF, including mechanical and non-mechanical pathways.⁷ Increases in afterload and subsequently in preload (pressure and volume overload) promote mechanical cardiac stretching and activate prohypertrophic pathways for the development of left ventricular remodeling. Disorders in energy metabolism, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, and proinflammatory responses also promote chronic remodeling.⁷ In patients with acute MI, HF occurs at 3 different time points after the heart attack: (1) HF onset at the time of presentation for MI; (2) HF that develops during hospitalization for MI; and (3) HF onset after discharge.¹⁵ In this context, we previously developed a risk-scoring system, the “HF time-points”, to estimate the risk of developing HF after discharge based on the presence or absence of HF on admission, during hospitalization, and at short-term follow-up (approximately 1 month) in patients with acute MI undergoing primary PCI, resulting in successful risk stratification.¹¹ Previous studies have demonstrated that, HF is found in approximately 10–20% of patients with ACS at the time of presentation and accrues 5% to 10% during hospitalization and after discharge, respectively.¹⁰ The presence of HF following the acute phase of MI is associated with increased mortality,^10,11 and thus early initiation of pharmacological intervention may prevent HF and improve clinical outcomes. The results of key randomized control trials (RCTs) of the 4 pillars in the setting of acute MI are summarized in Table 1 and in the Figure.¹⁶

Table 1.

Key Randomized Controlled Trials of HF Drugs in Patients With AMI

	CAPRICORN20	EPHESUS33	SAVE41	VALIANT45	PARADISE-MI47	EMPACT-MI57
Intervention	β-blocker	MRA	ACEi	ARB	ARNI	SGLT2-i
Publication year	2001	2003	1992	2003	2021	2024
Sample size	1,959	6,632	2,231	14,703	5,661	6,522
Drugs tested	Carvedilol vs. placebo	Eplerenone vs. placebo	Captopril vs. placebo	Valsartan vs. captoprilA	Sac/Val vs. ramipril	Empagliflozin vs. placebo
Time from AMI (days)	NRB	7.3	11	4.9	4.3	5.0
LVEF (%)	32.8	33	31	35.3	36.5	40.0
PCI (%)	46C	45C	17	34.6	88.0	89.3
Medications (%)
RAS modulatorD	97	87	NA	NA	NA	82.0
β-blocker	NA	75	36	70.4	85.3	86.0
MRA	NR	NA	NR	9.0	41.3	47.2
SGLT2-i	NR	NR	NR	NR	NR	NA
Follow-up duration	1.3 years	16 months	42 months	24.7 months	22 months	17.9 months
Mortality (%)	12 vs. 15 (P=0.031)	14.4 vs. 16.7 (P=0.008)	20.4 vs. 24.6 (P=0.019)	19.9 vs. 19.5 (P=0.98)	7.5 vs. 8.5 (P=NS)	5.2 vs. 5.5 (P=NS)
Primary or other outcomes	35% vs. 37% (P=0.296)E	26.7% vs. 30.0% (P=0.002)F	32.2% vs. 40.1% (P<0.001)G	32.8% vs. 33.4% (P=0.25)H	11.9% vs. 13.2% (P=0.17)I	8.2% vs. 9.1% (P=0.21)J

^AThe study included another comparison with a combination of valsartan and captopril. ^BAcute myocardial infarction (AMI) occurred 3–21 days before randomization. ^CPercutaneous coronary intervention (PCI) or thrombolysis. ^DAngiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI). ^EAll-cause death or cardiovascular (CV)-related hospital admission. ^FCV death and hospitalization. ^GCV death, heart failure (HF) requiring ACEi therapy and hospitalization, or recurrent AMI. ^HCV death, AMI, HF, cardiac arrest, or stroke. ^ICV death, HF hospitalization, and outpatient symptomatic HF. ^JAll-cause death or first hospitalization for HF. LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NA, not applicable; NR, not reported; RAS, renin-angiotensin system; Sac/Val, sacubitril/valsartan; SGLT2-i, sodium-glucose cotransporter 2 inhibitor.

Figure.

Key knowledge of the “4 pillars” (“fantastic 4”) for preventing heart failure (HF) after acute myocardial infarction (MI). All 4 HF drugs have been established to prevent cardiac remodeling and to improve clinical outcomes in patients with HF with reduced ejection fraction (EF). Key knowledge of the drugs is briefly summarized. ACEi, angiotensin-converting enzyme inhibitor; ARNI, angiotensin receptor-neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose cotransporter 2.

Pharmacological Treatment With the 4 Pillars

β-Blockers

Blockade of β-adrenergic receptors can directly interfere with the harmful effects of sustained sympathetic nervous system activation and indirectly inhibit the renin-angiotensin-aldosterone system pathway, thereby preventing myocardial fibrosis and cardiac remodeling.¹⁷ In patients with chronic HFrEF, a survival benefit of β-blockers has been established in pivotal RCTs, all of which stopped early owing to the reduction in mortality.¹⁸ A meta-analysis published in 1999 included 31 RCTs with 54,234 patients with acute or past MI and revealed a survival benefit of β-blockers when used over a long term (≥6 months).¹⁹

The CAPRICORN study tested the efficacy of the β-blocker carvedilol in acute MI in patients with left ventricular ejection fraction (LVEF) ≤40% in (Table 1). In this landmark RCT, β-blocker use successfully reduced all-cause mortality, cardiovascular mortality, and non-fatal MI, although no significant benefit of carvedilol was observed on HF hospitalization.²⁰ The subsequent COMMIT-CCS2 study was performed across 1,250 hospitals in China and randomized 45,852 patients with acute MI to either metoprolol treatment (administered intravenously and then orally) or placebo, within 24 h of onset.²¹ In that study, metoprolol did not reduce the primary outcome, a composite of death, reinfarction, ventricular fibrillation, or other cardiac arrest, compared with placebo (9.4% vs. 9.9%, respectively; P=0.10).²¹ Nonetheless, reinfarction and ventricular arrhythmias were significantly reduced in the metoprolol group, but the beneficial effects of the drug were counterbalanced by an increased risk of CS, particularly when used on the first day of admission for acute MI.²¹

The potential for acute intravenous β-blocker administration to decrease infarct size, preserve LVEF, and improve survival has been investigated in STEMI patients in dedicated RCTs.²² Although intravenous β-blocker administration possibly improved some surrogate markers, no significant benefit in clinical outcomes was found.²³ Based on the clinical evidence, guidelines recommend the use of β-blockers in patients with ACS and LVEF ≤40% (Class I, level of evidence [LOE] A) in a hemodynamically stable condition unless contraindicated, whereas routine β-blockers for all ACS patients regardless of LVEF may be considered (Class IIa, LOE B in European guidelines; Class IIb, LOE C in Japanese guidelines).^24,25

Because most RCTs showing a benefit of β-adrenergic receptor blockade after acute MI have included patients with large infarctions in an era before modern diagnostic and therapeutic strategies, such as high-sensitivity troponin, primary PCI, potent antithrombotic therapy, statins, and other HF medications), whether β-blockers should be used routinely in patients with small MI and no HF is uncertain. Indeed, several observational studies have demonstrated that β-blocker use was not associated with survival benefits in acute MI patients with preserved LVEF and no HF.²⁶ To fill the evidence gap, the large-scale, registry-based, randomized, open-label REDUCE-AMI trial was conducted, in which 5,020 patients with acute type 1 MI and LVEF ≥50% were randomly assigned to β-blocker treatment (metoprolol or bisoprolol) or no β-blockers.²⁷ Coronary revascularization with PCI was performed in >95% of participants and contemporary medical therapies included an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) in 80.2% of patients, statins in 98.5% of patients, aspirin in 97.4% of patients, and a P2Y12 inhibitor in 95.8% of patients. In this pragmatic RCT, β-blocker treatment did not result in a significantly lower incidence of the composite primary outcome of death or recurrent MI compared with no β-blocker treatment (7.9% vs. 8.3%, respectively; P=0.64).²⁷ Therefore, β-blockers may not be necessarily indicated for all patients with acute MI, particularly when HF is absent and LVEF is preserved, in current clinical practice. Upcoming RCTs in this field, including DANBLOCK (ClinicalTrials.gov ID NCT03778554), BETAMI (NCT03646357), REBOOT (NCT03596385), AβYSS (NCT03498066), SMART-DECISION (NCT04769362), and ABBREVIATE (NCT05081999), will provide further evidence to tailor β-blocker therapy in patients with acute MI.¹²

MRAs

MRAs prevent adverse cardiac remodeling by suppressing myocardial fibrosis and hypertrophy.²⁸ The landmark RALES trial demonstrated that spironolactone reduced mortality in patients with severe HFrEF (LVEF ≤35%), in which an ischemic etiology accounted for >50%.²⁹ The EMPHASIS-HF trial also tested whether eplerenone, another MRA, can improve clinical outcomes in patients with chronic HFrEF and mild HF symptoms. More than two-thirds of participants in the EMPHASIS-HF trial had IHD as a principal cause of HF, with 93.4% receiving ACE inhibitor or ARB treatment and 86.7% receiving β-blockers.³⁰ In that study, eplerenone, compared with placebo, reduced the risk of death and HF hospitalization during a median follow-up period of 21 months (18.3% vs. 25.9%, respectively; P<0.001).³⁰ The TOPCAT trial investigated whether spironolactone can reduce cardiovascular death, cardiac arrest, and HF hospitalization in patients with chronic HF with preserved ejection fraction (HFpEF; LVEF ≥45%) across 6 countries (the US, Canada, Brazil, Argentina, Russia, and Georgia).³¹ TOPCAT was initially reported as a “negative” RCT, but subsequent scrutiny shed light on a significant effect of irregular and unreliable data from Russia and Georgia. Using data from the Americas only, TOPCAT finally suggested the potential benefit of spironolactone in patients with HFpEF.³² The upcoming SPIRIT-HF (NCT04727073) and SPIRRIT-HFpEF (NCT02901184) trials will hopefully provide definitive results regarding the clinical benefits of MRAs across a spectrum of LVEF.

The EPHESUS trial addressed the potential of eplerenone to reduce all-cause mortality and adverse cardiovascular events (HF hospitalization, ventricular arrhythmia) and showed clinical benefit of eplerenone compared with placebo in patients with acute MI and LVEF ≤40% (Table 1).³³ Although eplerenone was initiated 3–14 days after the onset of acute MI, no severe safety concerns were identified. Interestingly, a post hoc analysis of the EPHESUS trial indicated that early initiation of eplerenone within 3–6 days after acute MI was more beneficial, and eplerenone initiation ≥7 days after MI did not show a statistically significant effect of eplerenone compared with placebo,³⁴ suggesting that MRAs should be introduced early in the setting of acute MI.

In the open-label, randomized ALBATROSS trial, patients with acute MI (n=1,603), regardless of the presence of HF or LVEF, were randomized to receive either an MRA regimen with a single intravenous bolus of potassium canrenoate followed by oral spironolactone for 6 months on top of standard therapy or standard therapy alone.³⁵ Overall, the intervention failed to show the benefit of early MRA use compared with standard care alone in patients with acute MI, with no significant difference in the incidence of the composite of death, resuscitated cardiac arrest, ventricular arrhythmia, indication for implantable defibrillator, and new or worsening HF between the 2 groups (11.8% vs. 12.2%, respectively; P=0.81).³⁵ However, a significant treatment interaction was found in patients with STEMI and non-ST-segment elevation MI, favoring MRA in STEMI.³⁵

The double-blind REMINDER trial (n=1,012) randomly assigned STEMI patients with no HF and no reduced LVEF to receive either eplerenone or placebo.³⁶ The initiation of eplerenone within 24 h (preferably within 12 h) of STEMI onset resulted in lower B-type natriuretic peptide (BNP) or N-terminal pro BNP (NT-proBNP concentrations) at 1 month.³⁶ Although whether the changes in BNP and NT-proBNP concentrations, surrogates of HF, can be translated into clinical outcomes remains uncertain,³⁷ these results may be promising. However, robust evidence of the benefit of MRAs in acute MI is lacking when LVEF is preserved. Hence, current international guidelines recommend MRA use in ACS patients with LVEF ≤40% and HF or diabetes.^24,25 Although not yet established, the early initiation of MRAs in patients with acute MI across a spectrum of LVEF is likely to convey clinical benefits in reducing HF-related events.

ARNI

ACE inhibitors are the first anti-HF drugs, with established RCT data showing improved outcomes in patients with chronic HFrEF or acute MI. Beneficial effects of ACE inhibitors are secondary to the prevention of myocardial fibrosis and cardiac remodeling, and afterload reduction.³⁸ A systematic review of 4 RCTs including 98,496 patients presenting with acute MI demonstrated that early initiation of an ACE inhibitor within 0–36 h resulted in a 7% relative reduction in short-term mortality and was associated with a lower incidence of HF but a higher risk of hypotension compared with control.³⁹ A survival benefit of ACE inhibitors was established in the SOLVD trial and in other studies in patients with chronic HFrEF,⁴⁰ and was tested in the pivotal SAVE trial in an acute MI population (Table 1). SAVE was the first large-scale RCT of HF drugs to show positive results in this field of acute MI, and thus few such drugs were used (with β-blockers used in only 36% of patients) and PCI was rarely performed (in 17% of participants; Table 1).⁴¹ As a result, captopril treatment was associated with an approximate 4% absolute risk reduction (ARR) in mortality and 5% ARR in HF over a mean follow-up period of 42 months,⁴¹ establishing robust evidence for the survival benefit of ACE inhibitors after acute MI, along with other RCTs such as the AIRE and TRACE trials in the early 1990s.^42,43 Based on subsequent RCT results, including the OPTIMAAL and VALIANT trials (Table 1),^44,45 ARBs have been established as a non-inferior alternative to ACE inhibitors in patients with acute MI.

There was a gap in the timeline of the chronological development of HF drugs for a decade until the PARADIGM-HF trial was unveiled. The RCT that provided new paradigms in HF treatment included a total of 8,442 patients with chronic HFrEF and randomized them to either the ARNI (sacubitril/valsartan) or ACE inhibitor (enalapril) group. After a median follow-up period of 27 months, ARNI reduced the rate of the primary endpoint, a composite of death or HF hospitalization, compared with ACE inhibitor treatment (21.8% vs. 26.5%, respectively; P<0.001).⁴⁶ ARNI was also associated with a reduction in all-cause mortality with 2.8% ARR in the PARADIGM-HF trial. Several years later, the PARADISE-MI trial examined whether ARNI also conveys another paradigm shift in the setting of acute MI.⁴⁷ The trial randomized 5,661 patients with acute MI (within 7 days) and newly depressed LVEF <40% and/or signs of congestive HF to either ARNI or an ACE inhibitor (ramipril). Over a median follow-up period of 22 months, the rates of the primary outcome, a composite of cardiovascular death or HF, did not differ significantly between the 2 study groups (11.9% vs. 13.2%, respectively; P=0.17).⁴⁷ In addition, hypotension was more frequent in the ARNI group. Unlike preceding RCTs reported decades ago (Table 1), most patients in the PARADISE-MI trial underwent contemporary therapeutic strategies, including PCI and other pharmacological treatments, leading to “only” 8% mortality at 2 years in this modern trial and making it challenging to show the superiority of newer drugs. Despite the overall neutral results, potentially positive effects of ARNI have been subsequently reported for total HF events and coronary outcomes.⁴⁸ In addition, subgroup analyses in the PARADISE-MI trial identified patients undergoing PCI as potential candidates for ARNI.⁴⁷ Given that the LIFE trial demonstrated no benefit or possible harm of ARNI in patients with highly advanced HFrEF,⁴⁹ some patient groups may benefit from early initiation of sacubitril/valsartan after acute MI. To date, however, the routine use of ARNI is not indicated. Still, ACE inhibitors are recommended in patients with ACS and LVEF ≤40% (Class I, LOE A) and all ACS patients unless contraindicated (Class IIa, LOE A), and ARBs are an alternative to ACE inhibitors.^24,25

SGLT2 Inhibitors

SGLT2 inhibitors have become an integral part of guideline-directed medical therapy for patients with HF,⁵⁰ regardless of the presence of diabetes and across a broad range of LVEF. Although the underlying mechanisms remain to be elucidated, the benefit of SGLT2 inhibition is presumably derived from multifactorial effects, such as natriuresis, a rise in a hematocrit level, improved vascular function, suppression of advanced glycation end-product signaling, a shift towards ketone bodies as a metabolic substrate for the heart and kidneys, and reductions in blood pressure, serum uric acid concentrations, adipose tissue-mediated inflammation, glomerular hyperfiltration and albuminuria, and oxidative stress.⁵¹ Numerous RCTs have shown that SGLT2 inhibitors improve clinical outcomes in several patient populations, including those with diabetes, HF, and chronic kidney disease.⁵²

In this context, the potential role of SGLT2 inhibitors has been investigated in the setting of acute MI. An experimental study with pigs showed a relative improvement in cardiac remodeling by empagliflozin over placebo after the induction of MI at 2 months, with the possible mechanism due to changes in energy consumption of myocytes, replacing glucose with free fatty acids, ketone bodies, and branched-chain amino acids to improve the metabolic profile of the heart after MI.⁵³ From a clinical perspective, the proof-of-concept EMMY trial randomized 476 patients with acute MI accompanied by a large creatine kinase elevation (>800 U/L) to empagliflozin or placebo within 72 h of PCI.⁵⁴ During a median follow-up period of 26 weeks, the primary outcome of NT-proBNP was significantly reduced in the empagliflozin group compared with the placebo group. In addition, echocardiographic parameters, such as LVEF, E/e′, and left ventricular end-systolic and diastolic volumes, favored empagliflozin. In addition to the EMMY trial, which demonstrated promising results of early initiation of SGLT2 inhibitors without any safety concerns in patients with acute MI,⁵⁴ a subanalysis of an RCT in patients with diabetes showed that dapagliflozin reduced major adverse cardiovascular events in patients with previous MI, whereas no significant effect was found in those without a history of MI.⁵⁵

The DAPA-MI trial, originally designed to evaluate the effect of dapagliflozin on clinical outcome, a composite of cardiovascular death and HF hospitalization, randomized 4,017 patients hospitalized for acute MI within 7–10 days to receive dapagliflozin or placebo.⁵⁶ However, due to the lower than anticipated event rate during the course of the RCT, the trial endpoint was modified from an event-driven time-to-event approach to a hierarchical composite outcome approach, including all-cause death, HF hospitalization, recurrent MI, atrial fibrillation or flutter, new diagnosis of type 2 diabetes, New York Heart Association class, and weight decrease >5%, to be analyzed with the win ratio method. The overall results of DAPA-MI were positive, but the better outcomes with dapagliflozin for the hierarchical composite outcome were predominantly driven by differences in new diagnoses of diabetes and weight loss. The rates of the original endpoint (cardiovascular death and HF hospitalization) were similar between the dapagliflozin and placebo groups (4.1% vs. 4.3%, respectively) during the median follow-up of 11.6 months.⁵⁶ Similar to the PARADISE-MI trial but more evident, the mortality rate in the DAPA-MI trial was very low, at <2% at about 1 year, potentially precluding the study completion upon the original protocol and the identification of the benefits of SGLT2 inhibition in reducing clinical events in patients with acute MI. Nonetheless, the DAPA-MI trial confirmed the safety of the early initiation of an SGLT2 inhibitor.⁵⁶

In contrast to the DAPA-MI trial, the EMAPCT-MI trial completed its primary endpoint of time to first HF hospitalization or all-cause death in patients with acute MI. The EMPACT-MI trial randomly assigned 6,522 patients with spontaneous MI who had clinical evidence of congestion and/or LVEF <45% with at least 1 additional risk factor (age ≥65 years, LVEF <35%, elevated NT-proBNP) within 14 days (Table 1).¹⁶ During a median follow-up of 17.9 months, the incidence of the primary outcome did not differ significantly between the empagliflozin and placebo (8.2% vs. 9.1%, respectively; P=0.21).⁵⁷ The annualized mortality rate in the EMPACT-MI trial was nearly 4%, without a significant between-group difference, which was approximately twice as high as that in DAPA-MI and similar to PARADISE-MI. Until the early 2000s, all-cause mortality rates were around 10% per year in previous RCTs (Table 1), suggesting therapeutic advances in this field of acute MI. No safety concerns were again observed, and the risk related to HF hospitalization was significantly lower in the empagliflozin group across a spectrum of LVEF than in the placebo group, as shown in subanalyses of the EMPACT-MI trial,⁵⁸ indicating the potential roles of empagliflozin in preventing HF development in high-risk post-MI patients, although recommendations for the routine initiation of early SGLT inhibition in all patients with acute MI in future guidelines are unlikely.

Other Therapeutic Interventions for HF

Although antiplatelet agents and statins are established as cornerstones to reduce atherosclerotic cardiovascular events after acute MI,^24,25,59,60 some possible mechanisms by which these drugs prevent HF have been reported. In the recently reported ULTIMATE-DAPT trial, 1-month dual antiplatelet therapy followed by ticagrelor monotherapy was superior over 12-month dual antiplatelet therapy with ticagrelor plus aspirin in reducing major bleeding events without an increase in thrombotic events in patients with ACS who had PCI with contemporary drug-eluting stents.⁶¹ Beyond an antithrombotic effect, ticagrelor, compared to clopidogrel, reportedly improved coronary microvascular function in STEMI and ACS,⁶² which may contribute to protecting cardiac function and preventing future HF events.

In an experimental study in a rat MI model, statins improved cardiac remodeling compared with placebo,⁶³ although such an effect has not been proven in patients with chronic HF in a clinical setting.⁶⁴

Although ivabradine has negative chronotropic effects without affecting inotropy and is a guideline-recommended treatment option in patients with HFrEF who are in sinus rhythm with a heart rate ≥70 beats/min at rest,⁵⁰ the role in IHD is unclear. The randomized BEAUTIFUL trial included a total of 10,917 patients with chronic coronary artery disease and LVEF <40% and showed no significant benefit of ivabradine.⁶⁵ However, in a subgroup of patients with a heart rate ≥70 beats/min, the incidence of MI and coronary revascularization was reduced in the ivabradine group. A pilot RCT indicated a safety signal in patients with STEMI,⁶⁶ and an experimental study in mice with induced acute MI suggested a cardioprotective effect of ivabradine,⁶⁷ but an indication for ivabradine in patients with acute MI has not yet been established.

Although vericiguat, a soluble guanylyl cyclase stimulator, is another guideline-recommended option for HFrEF,⁵⁰ the evidence for its use is limited in the setting of acute MI. To date, only experimental studies with MI models have alluded to some positive results.⁶⁸

Here, we also briefly summarize several potentials and possibilities of device-based HF interventions moving forward (Table 2).⁶⁹ Reperfusion injury is still a strong predictor after acute MI, even in the current era where PCI technologies have evolved considerably.^70–104 Because infarct size is strongly associated with mortality and HF risks, endeavors for cardioprotective therapies to attenuate reperfusion injury and decrease the size of MI are appreciated; of these, intracoronary hypothermia during primary PCI may have potential as a viable therapeutic option.¹⁰⁵ Despite conflicting results from clinical trials so far, hypothermia theoretically attenuates myocardial reperfusion injury, as shown in animal studies, and selective intracoronary hypothermia using a dedicated system will possibly be a part of the armamentarium of interventional cardiologists.^105,106

Table 2.

Adjunctive Device-Based Therapies With Reperfusion in AMI

Approach	Mechanisms	Key trials	Status
Hypothermia	Intracoronary hypothermia may diminish metabolic demand on the ischemic myocardium	EURO-ICE106	Conflicting clinical trial results have been reported
SSO2	SSO2 (760–1,000 mmHg) may prevent severe endothelial edema and allow better perfusion	AMIHOT107 ISO-SHOCK	Reduced infarct size was previously shown in a selected population
PiCSO	Balloon inflation in the coronary sinus may remotely redistribute blood flow to the ischemic myocardium	PiCSO-AMI-I109	The PiCSO-AMI-I trial failed to show a benefit of PiCSO
RIC	Serial inflations and deflations of a pneumatic cuff on the arm or leg may protect against myocardial damage	Bøtker, et al.110 CONDI-2/ERIC-PPCI111	Conflicting clinical trial results have been reported
LV unloading	LV unloading with the Impella before primary PCI may reduce infarct size	DTU-STEMI112	The key RCT results will be published

AMI, acute myocardial infarction; LV, left ventricular; PCI, percutaneous coronary intervention; PiCSO, pressure-controlled intermittent coronary sinus occlusion; RCT, randomized control trial; RIC, remote ischemic conditioning; SSO₂, super-saturated oxygen.

Super-saturated oxygen therapy is another adjunctive treatment option in patients with STEMI to reduce infarct size. Super-saturated oxygen therapy has already been approved by the US Food and Drug Administration, with the proposed mechanism being that the delivery of supersaturated oxygen (760–1,000 mmHg) to the infarct area prevents severe endothelial edema and allows better perfusion in the small blood vessels.^107,108 Other adjunctive therapies with reperfusion include pressure-controlled intermittent coronary sinus occlusion and remote ischemic conditioning.^109–111 Immediate left ventricular unloading before coronary reperfusion with Impella devices is another area for investigation.¹¹² None of these technologies for better myocardial salvage are ready for routine use in current daily practice and require further evaluation with adequately powered clinical trials; however, they will potentially improve the prognosis of the growing population with HF after acute MI.

Short-term mortality remains high at up to 50% in patients with acute MI when complicated by CS.^6,113 Immediate coronary angiography and PCI of the infarct-related artery are necessary in patients with ACS and CS but are not sufficient to achieve better clinical outcomes. In this patient subset, MCS devices may be indicated.²⁴ The intra-aortic balloon pump (IABP) is a frequently used MCS device that increases coronary blood flow and reduces afterload by aortic counterpulsation. However, the IABP-SHOCK II trial failed to show a mortality benefit of the device,¹¹⁴ and the routine use of IABP is currently not recommended.²⁴ Nevertheless, some select patients with acute MI and CS may benefit from IABP treatment.¹¹⁵

Veno-arterial extracorporeal membrane oxygenation (ECMO) provides temporary cardiac and/or pulmonary support to hemodynamically unstable patients with CS.¹¹⁶ The randomized ECLS-SHOCK trial included 420 patients with acute MI complicated by CS for whom early coronary revascularization was planned and tested whether the routine use of ECMO leads to lower mortality.¹¹⁷ In that pragmatic RCT, all-cause mortality was not significantly different between patients allocated to the ECMO group and those allocated to standard care alone.¹¹⁷

Although the left-sided Impella has the theoretical potential as a superior MCS device over others, observational studies have counterintuitively shown increased risks of complications including major bleeding, stroke, and all-cause mortality with the Impella.^118,119 In this context, the DanGer Shock trial randomized 360 patients with STEMI complicated by CS (systolic blood pressure <100 mmHg or an ongoing need for vasopressor support, arterial lactate concentration ≥2.5 mmol/L, and LVEF <45%) to receive the Impella CP plus standard care or standard care alone, with an enrollment period from January 2013 to July 2023.⁶ Cardiac arrest occurring in the ambulance or after arrival to a hospital was not an exclusion criterion, but patients with out-of-hospital cardiac arrest with a persistent Glasgow Coma Scale score <8 after return of spontaneous circulation were excluded. In the end, all-cause mortality at 180 days was lower in the Impella than standard-care group, with approximately 10% ARR (45.8% vs. 58.5%; P=0.04), whereas safety outcome events were more frequently observed in the Impella group.⁶

Given the substantial barriers to performing adequately sized randomized trials of MCS devices in patients with acute MI, the completion of large RCTs including the IABP-SHOCK II, ECLS-SHOCK, and DanGer Shock trials is a remarkable accomplishment. However, the inclusion and exclusion criteria, along with the potential external generalizability of such trials, should be acknowledged when managing and treating patients with CS in real-world practice. Ongoing RCTs, including the PROTECT IV (NCT04763200) and STEMI-DTU (NCT03947619) trials, will improve our understanding of the clinical applicability of Impella in acute MI.

Conclusions

Owing to advances in therapeutic strategies in recent decades, the prognosis after acute MI has improved. However, HF is a major consequence after MI that is associated with a significant burden of mortality and healthcare resources, and there is still considerable room for further improvement. Pharmacological interventions established in patients with HFrEF, particularly with the 4 pillars, may be beneficial to patients with acute MI for preventing HF. All 4 HF drugs are likely to improve clinical outcomes but have some uncertainness from the perspective of clinical evidence. In addition, whether comprehensive early initiation and up-titration of HF drugs conveys better outcomes, as shown in the STRONG-HF trial,¹²⁰ remains unknown in the setting of acute MI. Future studies will shape our understanding of therapeutic interventions to prevent HF in patients with acute MI.

Sources of Funding

None.

Disclosures

Y.K., K.T., K. Kuwahara, Y.I., H.T., K. Kinugawa, and K. Kozuma are members of Circulation Journal’s Editorial Team. Y.S. has received lecture fees from Daiichi Sankyo. Y.K. has received lecture fees from Abbott Medical Japan and Daiichi Sankyo and research grants from Abbott Medical Japan, Win International, Otsuka Pharmaceutical, Boehringer Ingelheim, Nipro, and Japan Lifeline. K.T. has received lecture fees from Abbott Medical, Amgen, Bayer, Daiichi Sankyo, Kowa Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, and TERUMO; research grants from Bayer, Bristol-Myers, Daiichi Sankyo, Mochida Pharmaceutical, EA Pharma, Novo Nordisk Pharma, and PRA Health Sciences; and scholarship funds from Abbott Medical, Boehringer Ingelheim, Otsuka Pharmaceutical, and Boston Scientific Japan; and belongs to endowed departments donated to by Abbott Japan, Boston Scientific Japan, Fides-one, GM Medical, ITI, Kaneka Medix, NIPRO, TERUMO, Philips Japan, Getinge Group Japan, Orbusneich Medical, Abbott Medical, Biotronik Japan, Boston Scientific Japan, Fukuda Denshi, Japan Lifeline, Medtronic Japan, and Nippon Boehringer Ingelheim. K. Kuwahara has received lecture fees from Alnylam, Astellas Pharma, AstraZeneca, MSD, Otsuka Pharmaceutical, Ono Pharmaceutical, Kyowa Kirin, Kowa, Sanofi, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk Pharma, Bayer, Pfizer Japan, and Janssen Pharmaceutical; funded research or joint research expenses from Japan Academic Research Forum, Kowa, AstraZeneca, Daiichi Sankyo, Novo Nordisk Pharma, Amgen, Janssen Pharmaceutical, Parexel International, and Astellas Pharma. K. Kuwahara’s affiliated institution (Shinshu University School of Medicine) has received grants from Otsuka Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Taisho Pharmaceutical, Fukuda Denshi, and Kyowa Kirin, and his department has endowed chairs from Medtronic Japan, Boston Scientific Japan, Abbott Medical Japan, Japan Lifeline, Biotronik Japan, Terumo Corporation, Nipro Corporation, and Cordis Japan. Y.I. has received research grants from Boston Scientific. H.T. has received remuneration from MSD, Astellas Pharma, Pfizer Japan, Bristol-Myers Squibb, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Bayer Yakuhin, Novartis Pharma, Kowa Pharmaceutical, and Teijin Pharma; research funding from Actelion Pharmaceuticals Japan, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, IQVIA Services Japan, and Omron Healthcare; scholarship funds from Astellas Pharma, Novartis Pharma, Daiichi Sankyo, Takeda Pharmaceutical Company, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and MSD; consultancy fees from Nippon Boehringer Ingelheim, Bayer Yakuhin, Novartis Pharma, and Ono Pharmaceutical; and manuscript fees from Medical View and Nippon Rinsho. K. Kinugawa has received lecture fees from Otsuka, Abiomed, Novartis, Medtronic, Boehringer Ingelheim, Abbott, Daiichi Sankyo, Alnylam, Nipro, AstraZeneca, Ono, and Bayer; research grants from Ono, Kowa, and Boehringer Ingelheim; scholarship funds from Otsuka and Ono; consultancy fees from Otsuka, Abiomed, Novartis, Medtronic, Boehringer Ingelheim, Abbott, and Bayer; and manuscript fees from Otsuka. K. Kozuma has received lecture fees from Boston Scientific, Abbott Medical, Medtronic, Otsuka, Daiichi Sankyo, Amgen, Novartis, Boehringer Ingelheim, Bayer, Life Science Institute, Mochida, and Novo Nordisk, as well as scholarship funds from Abbott Medical.

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