Long-term Management of Patients with Myocardial Infarction: An Updated Review

Abstract

The outcomes of patients with myocardial infarction (MI) have substantially improved given the rapid progress that has occurred in revascularization techniques and secondary prevention, and the majority of MI patients subsequently enter a chronic stable phase. Therefore, the long-term management of patients with MI has become a core issue in daily clinical practice for cardiologists. The long-term incidence of adverse events can be further reduced using newly developed medications and therapies ranging from lipid-lowering agents (eg, proprotein convertase subtilisin/kexin type 9 inhibitors) to anti-thrombotic treatments (eg, shortened dual anti-platelet therapy). However, a considerable number of patients still experience adverse events, as some residual risk can remain despite intensive secondary prevention, such as continuously elevated cholesterol levels, chronic cardiovascular inflammation, and rapid atherosclerosis progression due to increased plaque instability. Therefore, the present review sought to summarize and discuss recent advances in several key aspects regarding the long-term management of MI patients, with the expectation of clarifying the available treatment strategies for various clinical scenarios, examining the gaps between trial evidence and clinical practice, and providing possible directions for future research.

Introduction

With the development of revascularization techniques and intensive secondary prevention measures, the outcomes of patients with myocardial infarction (MI) have greatly improved in the past few decades. In recent clinical trials, stable MI patients receiving optimal treatment experience a mortality rate of 1% to 3% beyond 1 year,^[1–4] suggesting that most MI patients enter a stable and chronic phase of coronary heart disease (CHD) after the index acute event, which is now defined as a category of chronic coronary syndrome.^[5] MI patients in the chronic phase of disease may be generally classified into the following 2 sub-types: (1) asymptomatic and symptomatic patients with stabilized symptoms <1 year after MI and (2) asymptomatic and symptomatic patients >1 year after the initial diagnosis or revascularization despite the stability of ischemic symptoms. However, recurrent adverse events, restenosis after emergent revascularization, and decreased cardiac function still occur despite optimal treatment and rigorous follow-up.^[2,6–8] Meanwhile, some newly developed medications and therapies have shown greater potential for further reducing lipid levels, inflammation, and thrombotic risk,^[7,9–12] while other conventional drugs have demonstrated an attenuated efficacy and reduced clinical benefit for the long-term management of MI patients,^[13,14] leading to updated recommendations and evidence gaps in clinical guidelines.^[5,15–17] Therefore, this review sought to discuss the latest evidence of several major topics concerning the long-term management of patients with MI, including anti-thrombotic treatments, lipid-lowering medications, residual inflammation suppression, cardiac function preservation, revascularization strategies, and cardiac rehabilitation.

Long-term anti-thrombotic treatment after MI

Reducing the risk of recurrent myocardial ischemia is a key issue in long-term management after MI. The use of dual anti-platelet therapy (DAPT), consisting of aspirin and P2Y12 inhibitors, for up to 1 year is currently the mainstream anti-thrombotic strategy for the majority of MI patients as recommended by most guidelines.^[15,16] However, in recent years, some studies have demonstrated the advantages of shortened DAPT, including a reduced bleeding risk with adequate prevention of ischemic events,^[1–4] while others indicate that extended DAPT and the addition of oral anti-coagulants are also clinically beneficial approaches.^[18,19] Evidence from numerous clinical trials posed question of whether “one size could fit all,” and has highlighted the need for tailored risk-stratification to identify patients suitable for certain combinations and durations of anti-thrombotic agents [Table 1].^{[1–4,18–23]}

Table 1 - Randomized clinical trials dedicated to patients with MI or ACS comparing different anti-thrombotic treatment strategies.

Study (year)	Key inclusion/exclusion criteria	Clinical presentations	Anti-platelet/anti-thrombotic treatment and sample size	Clinical endpoints
Shortened DAPT + aspirin monotherapy vs. standard DAPT
REDUCE (2019)[1]	ACS patients; Successful implantation of coronary stents (TIMI 3 flow with residual stenosis <20% on CAG); and No clinical adverse event during hospitalization (death, stent thrombosis, stroke, TVR, BARC 2/3/5 bleeding)	STEMI: 47.2% NSTEMI: 38.3% UA: 14.5%	3 months vs. 12 months: 751 vs. 745	Primary endpoint (12 months): All-cause mortality, MI, stent thrombosis, stroke, TVR, or bleeding (BARC 2/3/5): 8.2% vs. 8.4% (P non-inferiority < 0.001) Secondary endpoints (24 months): All-cause mortality, MI, stent thrombosis, stroke, TVR, or bleeding (BARC 2/3/5): 11.6% vs. 12.1% (P = 0.764) BARC 2/3/5 bleeding: 3.3% vs. 4.0% (P = 0.465) All-cause mortality: 3.1% vs. 2.2% (P = 0.267) Cardiac mortality: 1.8% vs. 1.1% (P = 0.280) MI: 3.5% vs. 3.0% (P = 0.577) Stent thrombosis: 1.6% vs. 0.8% (P = 0.160) TVR: 4.9% vs. 4.7% (P = 0.834) Stroke: 0.3% vs. 0.6% (P = 0.450)
SMART-DATE (2018)[2]	ACS patients; Culprit lesion in a native coronary artery with significant stenosis (>50% by CAG); Diameter ≥2.25 and ≤4.25 mm; and Coronary lesion amenable for PCI	STEMI: 37.7% NSTEMI: 31.5% UA: 30.8%	6 months vs. 12 months: 1357 vs. 1355	Primary endpoint (18 months): All-cause death, MI, or stroke: 4.7% vs. 4.2% (P non-inferiority= 0.03) Secondary endpoints (18 months): All-cause mortality: 2.6% vs. 2.9% (P = 0.90) Cardiac mortality: 1.4% vs. 1.8% (P = 0.36) MI: 1.8% vs. 0.8% (P = 0.02) Stroke: 0.8% vs. 0.9% (P = 0.84) Stent thrombosis: 1.1% vs. 0.7% (P = 0.32) BARC 2–5 bleeding: 2.7% vs. 2.9% (P = 0.09)
DAPT-STEMI (2018)[3]	STEMI patients; Treated by primary PCI with a second-generation DES; and Event-free on DAPT at 6 months.	STEMI: 100%	6 months vs. 12 months: 433 vs. 437	Primary endpoint (18 months): All-cause mortality, MI, any revascularization, stroke, and TIMI major bleeding: 4.8% vs. 6.6% (P non-inferiority = 0.004) Secondary endpoints (18 months): All-cause mortality, MI, stent thrombosis, any revascularization, and TIMI major bleeding: 3.2% vs. 4.3% (P = 0.40) All-cause mortality: 0.7% vs. 1.4% (P = 0.33) Cardiac mortality: 0.5% vs. 0.9% (P = 0.43) MI: 1.8% vs. 1.8% (P = 0.97) Revascularization: 3.0% vs. 3.9% (P = 0.72) Stent thrombosis: 0.7% vs. 0.9% (P = 0.72) Target lesion failure (cardiac death, target lesion revascularization, and target lesion MI): 1.2% vs. 1.8% (P = 0.42) Stroke: 0.7% vs. 0.7% (P = 0.99) TIMI major bleeding: 0.2% vs. 0.5% (P = 0.58)
Shortened DAPT + P2Y12 inhibitors (ticagrelor) monotherapy vs. standard DAPT
TICO (2020)[4]	ACS patients; and Successfully treated by bioresorbable polymer sirolimus-eluting stent.	STEMI: 36.1% NSTEMI: 33.6% UA: 30.3%	3 months vs. 12 months: 1527 vs. 1529	Primary endpoint (12 months): All-cause death, MI, stent thrombosis, stroke, TVR, and TIMI major bleeding: 3.9% vs. 5.9% (P = 0.01) Secondary endpoints (12 months): All-cause death, MI, stent thrombosis, stroke, and TVR: 2.3% vs. 3.4% (P = 0.09) All-cause mortality: 1.1% vs. 1.5% (P = 0.27) MI: 0.4% vs. 0.7% (P = 0.24) Stent thrombosis: 0.4% vs. 0.3% (P = 0.53) TVR: 0.5% vs. 0.7% (P = 0.64) Stroke: 0.5% vs. 0.7% (P = 0.50) TIMI major bleeding: 1.7% vs. 3.0% (P = 0.02) TIMI major or minor bleeding: 3.6% vs. 5.5% (P = 0.01)
Extended DAPT vs. standard DAPT
PEGASUS-TIMI 54 (2015)[18]	Spontaneous MI 1–3 years prior, plus any one of the following: Age ≥65 years; Diabetes mellitus on medication; A second prior MI; Multivessel CAD with ≥50% stenosis in ≥2 coronary territories; and Chronic renal dysfunction	STEMI: 53.6% NSTEMI: 40.6% Unknown: 5.8%	Ticagrelor 90 mg vs. 60 mg vs. placebo beyond 1 year: 7050 vs. 7045 vs. 7067	Primary efficacy endpoint (3 years): Cardiovascular death, MI, or stroke: 7.85% vs. 7.77% vs. 9.04% (P 90 mg vs. placebo = 0.008, P 60 mg vs. placebo = 0.004, P 90/60 mg vs. placebo = 0.001) Primary safety endpoint (3 years): TIMI major bleeding: 2.60% vs. 2.30% vs. 1.06% (P 90 mg vs. placebo < 0.001, P 60 mg vs. placebo < 0.001) Bleeding requiring transfusion: 2.43% vs. 2.09% vs. 0.72% (P 90 mg vs. placebo < 0.001, P 60 mg vs. placebo < 0.001) Bleeding led to study drug discontinuation: 7.81% vs. 6.15% vs. 1.50% (P 90 mg vs. placebo < 0.001, P 60 mg vs. placebo < 0.001) Fatal bleeding and non-fatal intracranial hemorrhage: 0.63% vs. 0.71% vs. 0.60% (P 90 mg vs. placebo = 0.43, P 60 mg vs. placebo = 0.47) Secondary endpoints (3 years): Cardiovascular death: 2.94% vs. 2.86% vs. 3.39% (P 90 mg vs. placebo = 0.15, P 60 mg vs. placebo = 0.07, P pooled= 0.06) MI: 4.40% vs. 4.53% vs. 5.25% (P 90 mg vs. placebo = 0.01, P 60 mg vs. placebo = 0.03, P pooled= 0.005) Stroke: 1.61% vs. 1.47% vs. 1.94% (P 90 mg vs. placebo = 0.14, P 60 mg vs. placebo = 0.03, P pooled= 0.03)
Oral anti-coagulants + P2Y12 inhibitors vs. standard DAPT
GEMINI-ACS-1 (2017)[19]	ACS within 48 hours of hospitalization or while hospitalized.	STEMI: 48.8 % NSTEMI: 40.3% UA: 10.9%	Rivaroxaban vs. aspirin on top of P2Y12 inhibitors: 1518 vs. 1519 Ticagrelor: 56.1% Clopidogrel: 43.9%	Primary endpoint (390 days): TIMI non-CABG significant bleeding: 5.3% vs. 4.9% (P = 0.584) Secondary endpoints (390 days): Bleeding events: TIMI major bleeding: 0.7% vs. 0.5% (P = 0.643) GUSTO life-threatening or severe bleeding: 0.2% vs. 0.1% (P = 0.657) ISTH major bleeding: 2.0% vs. 1.1% (P = 0.042) BARC 3a and higher bleeding: 1.4% vs. 0.9% (P = 0.126) Ischemic events: Cardiovascular death, MI, stroke, or definite stent thrombosis: 5.0% vs. 4.7% (P = 0.732) Cardiovascular death: 1.3% vs. 1.1% (P = 0.740) All-cause death: 1.4% vs. 1.5% (P = 0.877) MI: 3.7% vs. 3.2% (P = 0.487) All stent thrombosis: 1.1% vs. 1.1% (P = 0.858) Definite stent thrombosis: 0.07% vs. 0.05% (P = 0.492)
PFT-guided escalated and de-escalated DAPT vs. standard DAPT
ANTARCTIC (2016)[20]	ACS patients; Age ≥75 years; and Treated by PCI stent	STEMI: 34.4% NSTEMI: 47.7% UA: 17.9%	PFT monitoring-guided vs. traditional DAPT: 435 vs. 442	Primary endpoint (12 months): Cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and BARC 2/3/5 bleedings: 28% vs. 28% (P = 0.98) Secondary endpoints (12 months): Ischemic events: Cardiovascular death, MI, stent thrombosis, or urgent revascularization: 10% vs. 9% (P = 0.80) Cardiovascular death and MI: 8% vs. 7% (P = 0.60) Cardiovascular death: 3% vs. 2% (P = 0.81) All-cause death: 4% vs. 5% (P = 0.22) Definite thrombosis: 1% vs. 1% (P = 0.98) Bleeding events: BARC 2/3/5 bleedings: 21% vs. 20% (P = 0.77) TIMI major bleeding: 3% vs. 3% (P = 0.70) GUSTO severe bleeding: 2% vs. 3% (P = 0.39) STEEPLE major bleeding: 7% vs. 7% (P = 0.82) ISTH major bleeding: 7% vs. 9% (P = 0.48)
TROPICAL-ACS (2017)[21]	Troponin-positive ACS patients; and Successfully treated by PCI (ie, a post-PCI diameter stenosis <20% and TIMI flow ≥2)	STEMI: 55.7% NSTEMI: 45.3%	PFT-guided de-escalation vs. traditional DAPT: 1304 vs. 1306	Primary endpoint (1 year): Cardiovascular death, MI, stroke, and BARC 2+ bleeding: 7% vs. 9% (P non-inferiority= 0.0004) Secondary endpoints (1 year): Cardiovascular death, MI, stroke, and any bleedings (BARC 1–5): 11% vs. 13% (P = 0.06) Ischemic events: Cardiovascular death, MI, or stroke: 3% vs. 3% (P non-inferiority= 0.0115) Cardiovascular death: 1% vs. 1% (P = 0.63) All-cause death: 1% vs. 1% (P = 0.85) MI: 2% vs. 2% (P = 0.59) Stroke: 0.3% vs. 0.5% (P = 0.22) Stent thrombosis: 0.2% vs. 0.2% (P = 0.66) Bleeding events: BARC 2+ bleeding: 5% vs. 6% (P = 0.23) BARC 3/5 bleeding: 1% vs. 2% (P = 0.63) Any BARC bleeding: 9% vs. 11% (P = 0.14)
Genotype-guided de-escalated DAPT vs. standard DAPT
POPular Genetics (2019)[22]	STEMI patients with symptoms lasting 30 minutes to 12 hours; and Underwent primary PCI with stent implantation.	STEMI: 100%	• Genotype-guided DAPT (1242 patients):  LOF+, ticagrelor/prasugrel + aspirin  LOF−, clopidogrel + aspirin Standard DAPT (1246 patients): ticagrelor/prasugrel + aspirin	Primary endpoints (12 months): Net adverse clinical events (death, MI, definite stent thrombosis, stroke, or major bleeding): 5.1% vs. 5.9% (P non-inferiority< 0.001) PLATO major or minor bleeding: 9.8% vs. 12.5% (P = 0.04) Secondary endpoints (12 months): Ischemic events: Death: 1.5% vs. 1.5% (HR, 1.00; 95% CI, 0.53–1.89) MI: 1.5% vs. 2.1% (HR, 0.73; 95% CI, 0.41–1.32) Stroke: 0.6% vs. 0.9% (HR, 0.73; 95% CI, 0.29–1.82) Definite stent thrombosis 0.2% vs. 0.2% (HR, 0.67; 95% CI, 0.11–4.01) Bleeding events: PLATO major bleeding: 2.3% vs. 2.3% (HR, 0.97; 95% CI, 0.58–1.63) BARC 2–5 bleeding: 10.1% vs. 13.1% (HR, 0.77; 95% CI, 0.61–0.97) TIMI major bleeding: 1.2% vs. 1.3% (HR, 0.94; 95% CI, 0.47–1.90)
TAILOR-PCI (2020)[23]	Carriers of CYP2C19*2 or CYP2C19*3 LOF variants; and Undergoing PCI due to SCAD or ACS.	SCAD: 14% UA: 37% NSTEMI: 28% STEMI: 21%	• Genotype-guided DAPT (903 patients):  LOF+, ticagrelor + aspirin  LOF−, clopidogrel + aspirin Standard DAPT (946 patients): clopidogrel + aspirin	Primary endpoint (12 months): Cardiovascular death, MI, stroke, stent thrombosis, and severe recurrent ischemia: 4.0% vs. 5.9% (P = 0.06) Secondary endpoint (12 months): Ischemic events: Cardiovascular death: 0.5% vs. 0.9% (P = 0.24) MI: 1.3% vs. 1.5% (P = 0.62) Stroke: 0.2% vs. 0.4% (P = 0.42) Severe recurrent ischemia: 2.2% vs. 3.2% (P = 0.19) Stent thrombosis: 0.2% vs. 0.9% (P = 0.05) Bleeding events: BARC 2/3/5 bleedings: 3.0% vs. 1.8% (P = 0.08) BARC 3/5 bleedings: 2.0% vs. 1.5% (P = 0.50) TIMI major or minor bleedings: 1.9% vs. 1.6% (P = 0.58)

ACS: Acute coronary syndromes; BARC: Bleeding Academic Research Consortium; CABG: Coronary bypass graft; CAD: Coronary artery disease; CAG: Coronary angiography; CI: Confidence interval; DAPT: Dual anti-platelet treatment; DES: Drug-eluting stents; GUSTO: Global Use of Strategies to Open Occluded Arteries; HR: Hazard ratio; ISTH: International Society on Thrombosis and Haemostasias; LOF: Loss-of-function; MI: Myocardial infarction; NSTEMI: Non-ST-elevation myocardial infarction; PCI: Percutaneous coronary intervention; PFT: Platelet function test; PLATO: PLATelet inhibition and patient Outcomes; SCAD: Stable coronary artery disease; STEMI: ST-segment-elevation myocardial infarction; STEEPLE: Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients (trial); TIMI: Thrombolysis in myocardial infarction; TVR: Target-vessel revascularization; UA: Unstable angina.

Shortened DAPT followed by aspirin monotherapy

Shortened DAPT followed by aspirin monotherapy is a major substitute for standard DAPT with abundant evidence.^[1–3] Three randomized clinical trials (RCTs) have evaluated the use of this strategy specifically in patients with MI or acute coronary syndrome (ACS). Although all of these trials demonstrated non-inferiority for their primary composite endpoints, clinical decisions should be made with caution considering the variations in risk profiles and the breakdown of secondary outcomes. The REDUCE (Randomised Evaluation of Short-Term Dual Anti-platelet Therapy in Patients with Acute Coronary Syndrome Treated with the Combo Dual-therapy Stent) trial is an open-label non-inferiority randomized study comparing 3-month DAPT followed by aspirin and 12-month DAPT.^[1] The results showed that a shortened DAPT was non-inferior to standard DAPT for the composite endpoint of all-cause mortality, MI, stent thrombosis, stroke, target-vessel revascularization, or Bleeding Academic Research Consortium (BARC) 2/3/5 bleeding events (8.2% vs. 8.4%, P_{non-inferiority} < 0.001), while the event rate for each component endpoint was also similar between the 2 groups. However, this study recruited only patients who were successfully treated with percutaneous coronary intervention (PCI) with no in-hospital adverse events, leading to concerns of selection bias among low-risk patients. The study’s non-inferiority margin (5%) also appears to be too large, considering the primary endpoint event rate of 8.2%, while the incidence rates of death and stent thrombosis were numerically high, although without statistical significance. Therefore, the researchers concluded that the 3-month DAPT strategy should only be considered if clinically mandated.

Following the REDUCE trial, the SMART-DATE (Smart Angioplasty Research Team—Safety of 6-month Duration of Dual Anti-platelet Therapy after Percutaneous Coronary Intervention in Patients with ACS) trial took a less progressive step to compare 6- and 12-month or longer DAPT regimens.^[19] Although this open-label non-inferiority randomized trial demonstrated that a shortened DAPT is non-inferior to standard treatment for the primary endpoint of all-cause death, MI, or stroke (4.7% vs. 4.2%, P_{non-inferiority} = 0.03), the incidence of MI was substantially higher in the shortened DAPT group (1.8% vs. 0.8%, P = 0.02) when analyzed separately, which became more significant after excluding events that occurred during the first 6 months. Again, the wide non-inferiority margin (2%) versus the primary event rate (4.5%) further impairs the conclusiveness.^[24] It should be noted that patients in the SMART-DATE trial had a higher risk profile than those in the REDUCE trial, since the former did not exclude patients with acute adverse events or those with procedural failure during the index PCI. Therefore, shortened DAPT followed by aspirin is not suitable for all patients, while standard or prolonged treatment is of clinical benefit for those with a higher ischemic risk.

The DAPT-STEMI (DAPT after Drug-eluting Stent Implantation in the ST-Segment Elevation MI) trial offers a more reasonable design for prescribing shortened DAPT treatment.^[3] This open-label non-inferiority randomized trial demonstrated that the discontinuation of P2Y12 inhibitors was non-inferior to standard DAPT in patients with ST-segment-elevation myocardial infarction (STEMI) without adverse events in the first 6 months for the primary composite endpoint of death, MI, revascularization, stroke, and thrombolysis in myocardial infarction (TIMI) major bleeding (4.8% vs. 6.6%, P_{non-inferiority} = 0.004). Although the trial was penalized for its low enrollment and high withdrawal rates, the DAPT-STEMI trial remains unique as it has demonstrated that de-escalated anti-platelet treatment could be achieved in high-risk STEMI patients by identifying those at low risk of ischemia, since randomization at 6 months enabled a more specific and accurate assessment to rule out high-risk patients already suffering from recurrent events.

Shortened DAPT followed by P2Y12 inhibitor monotherapy

Substitution of aspirin monotherapy with P2Y12 inhibitors has gained more interest in recent years, as aspirin has been criticized for increasing the gastroenteric bleeding risk,^[25] while the aforementioned trials present differing efficacies for the prevention of re-infarction in high-risk MI patients. In addition, the more stable and reversible inhibition of the P2Y12 receptors with new-generation P2Y12 inhibitors (ie, ticagrelor) offers the possibility of monotherapy with more complete inhibition of platelets and better control of the bleeding risk.^[26] To date, only TICO (Ticagrelor Monotherapy after 3 Months in Patients Treated with a New-Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome Trial) study has compared shortened DAPT followed by P2Y12 inhibitors to traditional DAPT.^[4] In this open-label superiority randomized study, 3-month DAPT followed by ticagrelor significantly reduced the rate of 1-year net adverse clinical events (3.9% vs. 5.9%, P = 0.01), a result which was mainly driven by the decrease in TIMI major bleeding (1.7% vs. 3.0%, P = 0.02). However, the composite of cardiac death, acute MI, stent thrombosis, and target-vessel revascularization showed a marginal decrease in the monotherapy group (1.2% vs. 2.0%, P = 0.09). Notably, the trial recruited only patients who were successfully treated with bioabsorbable stents, while only 34.4% of patients underwent primary PCI, therefore constituting a lower risk profile. Recent research has demonstrated that ticagrelor more effectively reduces major adverse cardiovascular events (MACEs) in patients with late stent thrombosis,^[27] making it a suitable choice for patients at greater ischemic risk. A sub-group analysis of the ACS population from several randomized trials also demonstrated that long-term monotherapy with a P2Y12 inhibitor is a safe and effective alternative to standard DAPT. The ACS sub-group analysis of the SMART-CHOICE (Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs. Dual Anti-platelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents) trial showed that switching to P2Y12 inhibitor monotherapy at 3 months resulted in similar risks of death, MI, or stroke (3.0% vs. 2.9%; hazard ratio (HR), 1.06; 95% confidence interval (CI), 0.61–1.85) and BARC 2–5 bleeding events (1.8% vs. 3.2%; HR, 0.56; 95% CI, 0.30–1.05) at 12 months compared to standard DAPT.^[28] For the TWILIGHT (Ticagrelor with Aspirin or Alone in High-risk Patients after Coronary Intervention) trial, the sub-group analysis of the non-ST-elevation ACS population suggested that a 3-month DAPT regimen followed by ticagrelor monotherapy is associated with a lower risk of BARC 2/3/5 bleeding (3.6% vs. 7.6%, P < 0.001) and similar risks of death, MI, and stroke (4.3% vs. 4.4%, P = 0.84) within 1 year compared with standard DAPT.^[29]

Although findings from these analyses are hypothesis-generating and could be underpowered, they generally suggest that a 3-month DAPT regimen followed by P2Y12 inhibitor monotherapy is feasible and safe, paving the way for its future validation among MI populations with various clinical features and risk profiles in randomized trials. However, the safety and efficacy of further shortened DAPT regimens remain unclear. The ACS sub-group analysis of the GLOBAL LEADERS (Long-Term Ticagrelor Monotherapy versus Standard Dual Anti-platelet Therapy Followed by Aspirin Monotherapy in Patients Undergoing Biolimus-Eluting Stent Implantation) study involving 1-month DAPT followed by ticagrelor monotherapy resulted in a similar risk of death or MI (1.5% vs. 2.0%, P = 0.07) and a lower risk of BARC 3/5 bleeding (0.8% vs. 1.5%, P = 0.004) at 1 year than standard treatment.^[30] On the contrary, the ongoing STOPDAPT-2 ACS (Short and Optimal Duration of Dual Anti-platelet Therapy-2 Study for the Patients with ACS, NCT03462498) trial demonstrated in its newly revealed 1-year outcomes that a 1-month regimen of DAPT followed by P2Y12 monotherapy was not non-inferior to standard DAPT for the combined primary outcome of ischemia and bleeding (3.20% vs. 2.83%, P_{non-inferiority} = 0.06), but showed a trend toward an increased risk of cardiovascular death, MI, stent thrombosis, and stroke (2.76% vs. 1.86%; HR, 1.50; 95% CI, 0.99–2.26). Care should be taken to further reduce DAPT duration, as MI patients possess intrinsically higher risk profiles than those with stable CHD.^[31] Furthermore, re-endothelialization of the stents could be inadequate during such a short duration, which could further increase the risk of late stent thrombosis.^[32] Therefore, a DAPT duration of <3 months after the MI is currently lacking evidence and could be detrimental owing to the increased risk of ischemic events.

Extended DAPT and use of oral anti-coagulants

Although extended DAPT could further reduce long-term ischemic events, the inevitable increase in bleeding risk undermines its clinical benefit. The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial compared extended ticagrelor-based DAPT beyond 1 year to standard treatment in high-risk MI patients.^[18] Despite the significant decrease in cardiovascular death, MI, or stroke in the extended DAPT group (7.81% vs. 9.04%, P = 0.001), the increase in TIMI major bleeding (the primary safety endpoint) nearly offset the reduction in ischemic events (2.6% vs. 2.3% vs. 1.1%, P_{90 mg vs. placebo} < 0.001, P_{60 mg vs. placebo} < 0.001). Therefore, the net clinical benefit of extended DAPT was limited.

Similarly, a recent study showed that a dual pathway anti-thrombotic therapy approach did not ensure favorable outcomes compared to standard DAPT. The GEMINI-ACS-1 (A Study to Compare the Safety of Rivaroxaban versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants with Acute Coronary Syndrome) trial is a phase Ⅱ double-blind randomized study that evaluated the efficacy of low-dose rivaroxaban and aspirin in addition to P2Y12 inhibitors (ie, clopidogrel and ticagrelor).^[19] The results were generally neutral for bleeding outcomes (TIMI non-coronary bypass grafting (CABG) significant bleeding: 4.9% vs. 5.3%; P = 0.584) and ischemic events (cardiovascular death, MI, stroke, or definite stent thrombosis: 4.7% vs. 5.0%; P = 0.732). Unlike previous trials (eg, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial) that demonstrated the potential of oral anti-coagulants for reducing ischemic events,^[33,34] the GEMINI-ACS-1 trial did not show the advantages of low-dose rivaroxaban for such prevention,^[19] which could be due to the more frequent use of ticagrelor and greater number of participants receiving PCI treatment. Likewise, rivaroxaban was able to reduce mortality in the COMPASS trial, in which aspirin monotherapy was used as a control.^[34] In the context of the more prevalent use of potent P2Y12 inhibitors and adequate revascularization, low-dose rivaroxaban might not be appropriate for routine clinical practice, but its clinical implications still warrant further evaluation for MI patients with risk factors driving up the probability of ischemia (eg, diabetes, multivessel disease, peripheral artery disease, history of stroke) or those with recurrent ischemic events.

Platelet function testing and genotype-guided DAPT strategy

Compared to an ambitious shortened DAPT regimen, a modified DAPT approach for patients with responsiveness toward certain P2Y12 inhibitor types serves as a more conservative approach to reduce the bleeding risk while maintaining dual platelet inhibition. Two RCTs evaluated the potential of the platelet function test (PFT) for early escalation and de-escalation of prasugrel and clopidogrel.^[20,21] Although the ANTARCTIC (Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged > 75 Years to Reduce the Composite of Bleeding, Stent Thrombosis and Ischemic Complications) trial failed to show the superiority of PFT-guided DAPT strategy based on the VerifyNow assay,^[20] the TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Anti-platelet Treatment for Acute Coronary Syndromes) trial demonstrated that de-escalation from prasugrel to clopidogrel guided by the adenosine diphosphate aggregation test is non-inferior to conventional DAPT in terms of ischemic events (cardiovascular death, MI, or stroke: 3% vs. 3%; P_{non-inferiority} = 0.0115), although the BARC 2 bleeding rate was not significantly reduced (5% vs. 6%, P = 0.23).^[21]

Individualizing the DAPT strategy has also been proven feasible by the identification of non-responders to clopidogrel (ie, CYP2C19*2 or CYP2C19*3 loss-of-function (LOF) allele carriers) through early genetic testing.^[22] The POPular Genetics trial demonstrated that genotype-guided DAPT not only reduces bleeding events (9.8% vs. 12.5%, P = 0.04) but also adequately prevents ischemic events (2.7% vs. 3.3%; absolute difference, −0.3%; 95% CI, −1.4% to 0.8%). In the TAILOR-PCI (Tailored Anti-platelet Initiation to Lesson Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention) trial of LOF carriers undergoing PCI due to ACS or stable CHD, the escalation from clopidogrel to ticagrelor resulted in a trend toward a decrease in ischemic events (cardiovascular death, MI, stroke, stent thrombosis, and severe recurrent ischemia: 4.0% vs. 5.9%; P = 0.06), with a similar risk of bleeding (1.9% vs. 1.6%, P = 0.58).^[23] Although the actual clinical benefit was based on marginal differences in outcomes, the results of the 2 trials laid a foundation for genotype-guided escalation and de-escalation of DAPT among patients with different risk levels of ischemia and bleeding. For example, clopidogrel in addition to aspirin could be an alternative for non-carriers of LOF at high bleeding risk despite the first-line recommendations of prasugrel and ticagrelor according to current guidelines. For LOF carriers at high thrombotic risk, switching to potent P2Y12 inhibitors is appropriate and potentially beneficial for reducing long-term ischemic event rates, which might be more suitable for those with a lower bleeding risk.

Clinical implications and future directions

To date, advances in anti-thrombotic medications have provided abundant choices for physicians to treat patients with various risk profiles, and standard 12-month DAPT is no longer the only long-term anti-thrombotic treatment choice for patients with MI. Varying results from numerous trials suggest that no perfect anti-thrombotic treatment is universally applicable to all patients with MI. Tailored regimes of anti-thrombotic medications should be formulated for each individual, including but not limited to considering the combinations of anti-platelet agents or anti-coagulants, treatment duration, and dynamic reassessment of lesion progression. The choice of treatment strategy should be based on a comprehensive assessment of the risks of ischemia and bleeding, including but not limited to clinical conditions, lesion complexity, PFT, and genotyping [Figure 1]. A shortened DAPT could be considered for patients at low ischemic risk; however, the use of potent P2Y12 inhibitors seems a safer choice after discontinuation of DAPT. Routine use of extended DAPT and dual pathway inhibition has limited clinical benefit but could be considered for those at an extremely high risk of ischemia. Genetic testing and PFT are feasible for triaging patients to more potent or conventional P2Y12 inhibitors and could help with further lower the bleeding risk in a very early stage after MI. Regarding clinical scores for risk assessment, their modest accuracy for event predictions does not support their routine use in clinical practice,^[35] suggesting the need for further refinements of the prediction models and validations.

Figure 1:: Anti-thrombotic strategies options stratified by bleeding and ischemic risk. PFT: Platelet function test.

Despite progress with anti-thrombotic treatment, several key issues remain undetermined. First, head-to-head trials comparing long-term monotherapy with aspirin and P2Y12 inhibitors are lacking,^[36] although the latest guidelines still recommend aspirin as a first-line choice for long-term secondary prevention.^[5] This issue is extremely important with the ongoing trend of shortening DAPT, as the TICO trial demonstrated superior outcomes with ticagrelor, while trials with aspirin monotherapy show non-inferiority and, specifically, a trend toward increased MI as suggested by the SMART-DATE trial. Second, the optimal anti-thrombotic strategy remains unclear for patients with high ischemic and bleeding risks. PFT-guided de-escalation from potent P2Y12 inhibitors to clopidogrel seems appropriate, because it could partially reduce the bleeding risk while maintaining dual anti-platelet inhibition [Figure 1].^[21] Long-term P2Y12 inhibitor monotherapy could be considered, as it demonstrates superiority for bleeding events and marginal improvement of ischemic outcomes compared to standard DAPT.^[4] A recent observational study also showed that ticagrelor along with a reduced dosage of aspirin could lower the incidence of bleeding while still preventing ischemic events,^[25] which seems feasible as a treatment option but requires further validation. With the call for precision medicine, future trials are warranted to identify the most suitable strategies for patients at various ischemic and bleeding risk levels.

Long-term management of lipids

Reducing lipid levels is undoubtedly a central issue for the long-term management of patients with MI. Most secondary prevention guidelines suggest a target low-density lipoprotein cholesterol (LDL-C) level of 1.8 mmol/L (70 mg/dL) or a reduction of 50% in LDL-C level from baseline.^[15,16,37] Meanwhile, accumulating evidence shows that reaching extremely low LDL-C levels, of which the level could be lowered to 30 mg/dL with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, is prognostically beneficial and safe.^[38–42] Therefore, it is possible to use more intensive lipid-lowering treatments to achieve lower LDL-C goals [Table 2].^{[37,38,41,42]} In contrast, a considerable number of patients fail to reach the pre-specified targets despite the use of current optimal medications, while others still suffer from adverse events due to residual risk of cholesterol and other lipid contents (eg, lipoprotein (a), triglycerides).^[43,44] Concerns have also arisen regarding the safety of reaching extremely low LDL-C levels^{[39,40,45,46]} and the need for routine combinations of statin and non-statin agents to achieve new targets.^[7,45] Therefore, physicians are expected to strike a balance between attaining lipid levels that are as low as possible and maintaining reasonable cost-effectiveness.

Table 2 - Randomized clinical trials focusing on lipid-lowering treatments in patients with MI or ACS.

Study (year)	Key inclusion/ exclusion criteria	Clinical presentations	Lipid-lowering medications	On trial LDL-C	Clinical endpoints
PROVE-IT TIMI 22 (2004)[37]	Patients with ACS within 10 days	STEMI: 34.6% NSTEMI: 36.1% UA: 29.3%	Atorvastatin 80 mg vs. pravastatin 40 mg: 2099 vs. 2063	Median (beyond 30 days): 1.60 mmol/L (62 mg/dL) vs. 2.46 mmol/L (95 mg/dL)	Primary endpoint (24 months): All-cause death, MI, re-hospitalization for UA, revascularization, and stroke: 22.4% vs. 26.3% (P = 0.005) Secondary endpoints (24 months): CHD death, MI, revascularization: 19.7% vs. 22.3% (P = 0.029) All-cause death: 2.2% vs. 3.2% (P = 0.07) CHD death: 1.1% vs. 1.4% (P > 0.05) MI: 6.6% vs. 7.4% (P > 0.05) Revascularization: 16.3% vs. 18.8% (P = 0.04) Recurrent UA: 3.8% vs. 5.1% (P = 0.02) Stroke: 1.0% vs. 1.0% (P = NA)
IMPROVE-IT (2015)[38]	Patients with ACS within 10 days	STEMI: 28.6% NSTEMI: 47.2% UA: 24.2%	Simvastatin 40 mg + ezetimibe 10 mg vs. simvastatin 40 mg: 9067 vs. 9077	Average (1 year): 1.4 mmol/L (53.7 mg/dL) vs. 1.8 mmol/L (69.5 mg/dL)	Primary endpoint (6 years): Cardiovascular death, non-fatal MI, re-hospitalization for UA, coronary revascularization, and non-fatal stroke: 32.7% vs. 34.7% (P = 0.016) Secondary endpoints (6 years): CHD death, non-fatal MI, and urgent revascularization: 17.5% vs. 18.9% (P = 0.02) Cardiovascular death, non-fatal MI, re-hospitalization for UA, any revascularization, and non-fatal stroke: 34.5% vs. 36.2% (P = 0.04) All-cause death: 15.4% vs. 15.3% (P = 0.78) Cardiovascular death: 6.9% vs. 6.8% (P = 1.00) CHD death: 5.7% vs. 5.8% (P = 0.50) Non-fatal MI: 12.8% vs. 14.4% (P = 0.002) Ischemic stroke: 3.4% vs. 4.1% (P = 0.008) Urgent coronary revascularization: 7.0% vs. 8.6% (P = 0.001) Re-hospitalization for UA: 2.1% vs. 1.9% (P = 0.62)
FOURIER (2017)[41]	Patients with clinically evident atherosclerotic cardiovascular disease (eg, history of MI, non-hemorrhagic stroke, or symptomatic peripheral artery disease)	MI: 81.1%*	Evolocumab + statin vs. statin: 13,784 vs. 13,780 High-intensity statin: 69.3%	Median (48 weeks): 0.78 mmol/L (30 mg/dL) vs. 1.90 mmol (73 mg/dL)	Primary endpoint (2.2 years): Cardiovascular death, MI, stroke, hospitalization for UA, or coronary revascularization: 9.8% vs. 11.3% (P < 0.001) Secondary endpoints (2.2 years): Cardiovascular death, MI, or stroke: 5.9% vs. 7.4% (P < 0.001) Cardiovascular death: 1.8% vs. 1.7% (P = 0.62) All-cause death: 3.2% vs. 3.1% (P = 0.54) MI: 3.4% vs. 4.6% (P < 0.001) Stroke: 1.5% vs. 1.9% (P = 0.01) Hospitalization for UA: 1.7% vs. 1.7% (P = 0.89) Coronary revascularization: 5.5% vs. 7.0% (P < 0.001)
ODYSSEY OUTCOMES (2018)[42]	Patients with ACS in the last 1–12 months	STEMI: 34.4% NSTEMI: 48.5% UA: 16.8% (Missing data: 0.3%)	Alirocumab + statin vs. statin: 9462 vs. 9462 High-intensity statin: 88.8%	Median (12 months): 1.2 mmol/L (48 mg/dL) vs. 2.5 mmol/L (96 mg/dL)	Primary endpoint (2.8 years): CHD death, non-fatal MI, ischemic stroke, or hospitalization for UA: 9.5% vs. 11.1% (P < 0.001) Secondary endpoints (2.8 years): CHD death, non-fatal MI, hospitalization for UA, and ischemia-driven revascularization: 12.7% vs. 14.3% (P = 0.001) All-cause death, non-fatal MI, non-fatal stroke: 10.3% vs. 11.9% (P < 0.001) CHD death: 2.2% vs. 2.3% (P = 0.38) Non-fatal MI: 6.6% vs. 7.6% (P = NA) Ischemic stroke: 1.2% vs. 1.6% (P = NA) Hospitalization for UA: 0.4% vs. 0.6% (P = NA)

^*In the FOURIER trial, the types of atherosclerosis for the remaining 18.9% of patients were non-hemorrhagic stroke and peripheral artery disease. ACS: Acute coronary syndrome; MI: Myocardial infarction; STEMI: ST-segment–elevation myocardial infarction; NA: not available; NSTEMI: Non-ST-elevation myocardial infarction; UA: Unstable angina.

Statins: a basis for lipid-lowering treatment

Currently, the 1.8-mmol/L target of LDL-C for MI patients adopted by most guidelines worldwide was derived from the PROVE-IT TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22) trial,^[37,47] which aimed to compare the efficacy of high-intensity statin therapy (80 mg of atorvastatin daily) for lowering LDL-C to approximately 70 mg/dL (1.8 mmol/L) and moderate statin therapy (40 mg of pravastatin daily) for lowering LDL-C to 100 mg/dL (2.6 mmol/L) in ACS patients. The trial successfully demonstrated that compared with moderate statin therapy, high-intensity statin therapy attained lower LDL-C levels (62 mg/dL vs. 95 mg/dL) while reducing the relative risk of ischemic events by 16% (26.3% vs. 22.4%; absolute risk reduction: 3.9%; P = 0.005), which was mainly driven by a lower incidence of revascularization (16.3% vs. 18.8%, P = 0.04) and recurrent unstable angina (3.8% vs. 5.1%, P = 0.02). Computational tomography studies recently demonstrated the inhibitory effect of statins on coronary plaque progression by reducing fibro-fatty components and promoting calcification,^[48,49] mechanistically affirming the beneficial effects of statins for preventing ischemic events. However, it should be noted that liver function abnormalities (defined by alanine aminotransferase levels that are 3 times higher than the upper limit of normal) occurred more frequently in the high-intensity group than moderate group (3.3% vs. 1.1%, P < 0.001), although muscle-related adverse events did not increase in frequency.^[37]

Considering that real-world patients have more co-existing conditions than those in trials, the use of high-dose statins could be limited in daily clinical practice, while many MI patients actually use moderate-intensity statins. Moreover, >40% of patients fail to reach the 1.8-mmol/L LDL-C target with 80 mg of atorvastatin or 20 mg of rosuvastatin daily,^[50] placing numerous patients at residual cholesterol risk. In summary, statin monotherapy is insufficient for the long-term management of cholesterol in MI patients, as varying responses of individuals do not ensure an adequate reduction in LDL-C or the subsequent risk of ischemia.

Non-statin lipid-lowering agents: new options to tackle the cholesterol risk

With the concept of “the lower the better,” the necessity for further lowering LDL-C in patients with MI has been intensively studied in recent years. Combined evidence from RCTs of statins and non-statins shows close relationships between greater LDL-C reduction, lower achieved LDL-C levels, and fewer cardiovascular events in both primary and secondary prevention cohorts.^[39,46,51] The recently updated European Society of Cardiology guidelines have further lowered the target LDL-C levels to 1.4 mmol/L (55 mg/dL) for MI patients and 1.0 mmol/L (40 mg/dL) for those who experience a second vascular event within 2 years.^[17] Such modifications are based on the results of recent clinical trials.^[38,41,42]

Following the PROVE-IT trial,^[37] the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trial offered another option to reach a low LDL-C level with the combination of statin and ezetimibe in ACS patients, who attained an average LDL-C level of 1.4 mmol/L (53.7 mg/dL) compared to that of 1.8 mmol/L (69.5 mg/dL) with simvastatin monotherapy.^[38] The overall ischemic risk was reduced by 6.4% with the addition of ezetimibe, mainly driven by a lower incidence of MI, ischemic stroke, and urgent revascularization. A post-hoc analysis of the PROVE-IT and IMPROVE-IT trials showed that patients achieving extremely low LDL-C levels (<30–40 mg/dL) experienced the largest risk reduction without an increase in side effects.^[46,52] Results of PCSK9 inhibitor trials have directly led to the formulation of the new 1.4-mmol/L (55-mg/dL) goal in the updated guidelines. The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial evaluated the efficacy of evolocumab in addition to statins in patients with clinically evident atherosclerotic cardiovascular disease,^[41] among whom over 80% had experienced MI. Compared to statin monotherapy, the addition of evolocumab led to lower LDL-C levels (0.78 vs. 1.90 mmol/L) at 48 weeks and a significantly lower risk of ischemic events (9.8% vs. 11.3%, P < 0.001). Notably, the incidence rates of recurrent MI (3.4% vs. 4.6%, P < 0.001) and stroke (1.5% vs. 1.9%, P = 0.01) were substantially lower in the treatment group than the control group.

Subsequently, the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome during Treatment with Alirocumab) trial evaluated the addition of 75 mg of alirocumab every 2 weeks to a statin medication regimen in patients with ACS 1 to 12 months before randomization.^[42] The results demonstrated that the addition of alirocumab led to lower LDL-C levels (1.2 vs. 2.5 mmol/L) and effectively reduced composite endpoint events of CHD death, non-fatal MI, ischemic stroke, and hospitalization for angina (9.5% vs. 11.1%, P < 0.001) compared to high-intensity statin treatment. The clinical benefit of PCSK9 inhibitors could be mediated by the stabilization and regression of coronary plaques, as PCSK9 inhibitors further reduce the atheroma volume beyond the effects of moderate- or high-intensity statins according to intravascular imaging studies.^[53,54] Meanwhile, neither trial showed an increase in adverse events due to extremely low LDL-C levels or PCSK9 inhibitor use, except for the increased incidence of injection-site reactions (eg, itching, redness, and swelling).

Clinical implications and future directions

With mounting evidence that the ischemic risk reduction is closely associated with lowering LDL-C, patients are expected to attain LDL-C levels as low as possible, which is technically safe and feasible, as the normal population with extremely low LDL-C levels due to genetic variants (eg, PCSK9 LOF) do not show increased adverse effects.^[7] However, despite the increased efficacy of lipid-lowering agents, it is already challenging for many patients to reach the old target (<1.8 mmol/L) set by guidelines with conventional lipid-lowering medications.^[50] Thus, it should be carefully decided in a case-by-case manner whether a patient should receive high-dose statins or a combination of medications with ezetimibe or PCSK9 inhibitors and to what extent their LDL-C level should be reduced.^[7,45]

The need to achieve a lower LDL-C level should be assessed according to the baseline, reduction, and on-treatment LDL-C levels; the risk of recurrent ischemia; and the clinical benefit that a patient could expectedly gain from treatment. Overall, each 1-mmol/L (40 mg/dL) decrease in LDL-C level could lower the risk of MACEs by 20%, and the risk reduction is more significant in younger populations.^[40,51,55] In addition, more intensive lipid-lowering treatments generally lose their benefit of reducing overall and cardiovascular mortality rates if the baseline LDL-C level is <2.6 mmol/L (100 mg/dL).^[56] Although the risk reduction of MACEs is consistent despite the baseline LDL-C level, a greater clinical benefit has been observed for patients with higher baseline LDL-C levels (eg, >3.0 mmol/L).^[57] For patients who already have low LDL-C levels (eg, <1.8 mmol/L), further lowering carries a 20% risk reduction,^[40] but the prescription of more potent agents should consider the patient’s baseline risk and cost-effectiveness.

Taken together, statin treatment remains the mainstream agent for all MI patients, while those with higher baseline LDL-C levels should consider the high-intensity regime [Figure 2]. Ezetimibe and PSCK9 inhibitors are conditionally recommended for patients within the highest risk categories (eg, MI with poorly controlled risk factors, peripheral or cerebrovascular diseases) or those who fail to achieve the target LDL-C level with the maximum tolerated statin dose.^[15–17] Although updated guidelines have proposed lower LDL-C targets, physicians should evaluate the need to achieve these goals. Key factors to consider include the lipid profile, life expectancy, risk for future ischemia, and response to previous treatments. It remains to be determined how much lower LDL-C levels could be reduced, as the target LDL-C levels might be further decreased in the foreseeable future. Theoretically, a plasma LDL-C level as low as 0.32 mmol/L (12.5 mg/dL) is adequate to sustain the cellular uptake of LDL-C, but long-term outcome data showing the potential risk caused by low LDL-C levels are scarce and remain to be gathered during ongoing follow-up of large-scale randomized trials.^[58]

Figure 2:: Long-term management of LDL-C. LDL-C: Low-density lipoprotein cholesterol.

In addition to controlling LDL-C levels, recent studies demonstrate that other lipid contents also have a significant impact on the outcomes of patients with MI. Due to the nature of examination techniques, a major component of “LDL-C” in optimally controlled patients could actually be lipoprotein(a),^[59] which is associated with an increased risk of MACEs, especially in those cases complicated by systemic inflammation.^[43] Moreover, for patients on statin treatment, the association between LDL-C and outcomes is attenuated, while non-high-density lipoprotein (HDL) and triglyceride levels contribute to the residual risk of ischemia.^[60] In these scenarios, reference to secondary goals (eg, non-HDL <2.2 mmol/L, triglyceride <1.7 mmol/L) could be helpful for deciding prescriptions for extra lipid-lowering medications. Future studies are warranted to validate the benefits of controlling lipid content in addition to LDL-C levels.

Long-term management of residual inflammation

In addition to activated thrombosis and dyslipidemia, continuous inflammation has recently been identified as an important cause of atherosclerosis progression and recurrent ischemic events in patients with MI.^[61] The elevation of high-sensitivity C-reactive protein (hsCRP), which is commonly used to detect inflammation due to infectious or autoimmune diseases, is associated with an increased risk of MACEs in patients with MI or CHD.^[62,63] Although hsCRP elevations are very common and could be indispensable for acute-phase healing of the myocardium,^[64] over 40% of patients still suffer from chronic inflammation after intensive lipid-lowering treatment^[61] as indicated by a continuous level of hsCRP ≥2 mg/L, which is associated with a 2-fold increased risk of death and a 72% increased risk of MACEs.^[63,65] The high prevalence of residual inflammation and its detrimental effects have led to the need for more effective anti-inflammatory medications.

Despite their major pharmacological lipid-lowering effects, statins are still the most frequently used anti-inflammatory agents. As early as the PROVE-IT trial, patients randomized to high-dose statins showed lower hsCRP levels by 1 month (1.6 vs. 2.3 mg/L, P < 0.001), while those achieving the LDL-C (<70 mg/dL) and hsCRP (<2 mg/L) targets acquired a lower risk of recurrent MI or death than those who achieved neither (2.4 vs. 4.6 per 100 person-years, P < 0.001).^[66] A more intensive anti-inflammatory effect was also observed for the combination of moderate statins and ezetimibe compared to statin monotherapy in the IMPROVE-IT trial.^[67] Intravascular imaging studies suggested that the clinical benefit of lowering hsCRP could be mediated by the recession of inflammatory content within coronary plaques, such as reductions in necrotic core size and increases in fibrous tissue.^[68] However, both trials showed a modest but significant correlation between achieved hsCRP and LDL-C levels, making it difficult to rule out the possibility that lower chronic inflammation levels are secondary to the lipid reduction.^[66,67]

The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial evaluated the efficacy of a monoclonal antibody targeting interlukin-1β (IL-1β) to reduce cardiovascular inflammation, which further demonstrated that the suppression of chronic inflammation alone could reduce the future cardiovascular risk of MI patients without affecting their lipid profiles.^[9] This randomized double-blind trial recruited 10,061 patients with previous MI complicated by elevated hsCRP levels (≥2 mg/L) despite intensive secondary treatment, among whom the injection of canakinumab effectively reduced hsCRP levels in 3 months (1.8 vs. 3.5 mg/L). Compared to placebo, the risk of MI, stroke, and cardiovascular death was significantly reduced by 150-mg (HR, 0.85; 95% CI, 0.74–0.98; P = 0.021) and 300-mg (HR, 0.86; 95% CI, 0.75–0.99; P = 0.031) canakinumab injections given every 3 months. Interestingly, the risk reduction was only significant for the 150-mg dosage group after adjustment for multiplicity, while the risk reduction afforded by canakinumab was significant only for those attaining a lower hsCRP level (<2 mg/L) by the end of the first 3-month round of treatment (HR, 0.75; 95% CI, 0.66–0.85; P < 0.0001) but not for those who failed to attain the target (HR, 0.90; 95% CI, 0.79–1.02; P = 0.11).^[9,69] Such disparities were also observed when stratifying patients by the median downstream IL-6 level (1.65 mg/L) attained by 3 months.^[70] A post-hoc analysis showed that 45% of patients on canakinumab failed to achieve the hsCRP < 2 mg/L goal, while the on-treatment hsCRP level was associated with its baseline level. Moreover, the risk of fatal infection was substantially increased with canakinumab treatment, which probably limits its application in frail and high-risk patients. Therefore, although the targeted suppression of the NOD-like receptor protein 3/IL-1β/IL-6 pathway indeed reduces the long-term risk of MI patients, a considerable proportion of patients are less responsive to canakinumab, and residual inflammation caused by other triggers remains to be addressed. Canakinumab could be considered for MI patients if their hsCRP level remains high after intensive lipid-lowering treatment and should be based on the dynamic assessment of inflammatory biomarkers (ie, hsCRP, IL-6) to identify patients who benefit most from the treatment and maximize their risk reduction.

More recently, non-specific anti-inflammatory agents have been investigated for the suppression of chronic inflammation in MI patients.^[10,71] Colchicine has been widely used as an anti-inflammatory agent because of its inhibitory effect on tubulin polymerization, microtubule generation, and possibly inflammasome suppression.^[72] In the randomized double-blind COLCOT (Colchicine Cardiovascular Outcomes Trial) study, for which 4745 patients with recent MI were recruited, low-dose colchicine (0.5 mg daily) substantially reduced the primary endpoint events (HR, 0.77; 95% CI, 0.61–0.96; P = 0.02), including a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or revascularization due to angina during a median follow-up of 22.6 months.^[10] However, in the randomized double-blind COPS (Colchicine in Patients with Acute Coronary Syndrome) trial with a smaller sample size, the use of colchicine was associated with a greater risk of all-cause death (2.0% vs. 0.3%) compared to placebo, although it showed a trend of reducing the total ischemic risk (death, ACS, urgent revascularization, and ischemic stroke: 6.1% vs. 9.5%; P = 0.09).^[73] The sacrificed cases were mainly attributed to death from non-cardiovascular causes (eg, pneumonia, acute leukemia, metastatic cancer), while the number of patients lost to follow up was similar to the number of deaths being analyzed, suggesting a finding by chance. A pooled analysis also showed that colchicine further reduced hsCRP levels and cardiovascular risk in CHD patients, a trend which is mainly driven by fewer MI, stroke, and re-hospitalization episodes, while the mortality rate remained similar despite treatment.^[74] As an easily accessed and orally administered medication, colchicine is a promising agent for tackling chronic cardiovascular inflammation and reducing ischemic events, but concerns regarding prevalent gastroenteric adverse effects and increased chances of infections could impair patient adherence. Ongoing trials and real-world studies should evaluate its efficacy and safety and prompt its usage in a broader population.

In addition to anti-inflammatory therapies, an unhealthy lifestyle contributes to chronic inflammation. A recent observational study showed that the hsCRP level correlates with the number of modifiable lifestyle risk factors in CHD patients.^[75] Patients who were simultaneously overweight (body mass index ≥ 25 kg/m²), smokers, lacked physical activity (<1.5 h/week), and had a poor diet acquired an hsCRP level of 2.8 mg/L, which was substantially higher than that of those with none of these risk factors (1.1 mg/L, P < 0.001). These findings show that worse outcomes associated with modifiable risk factors could be mediated by continuous inflammation, which again highlights the need for long-term lifestyle interventions.

In summary, the risk of residual inflammation has become an increasingly important risk factor for patients with MI. Lipid-lowering agents are the first-line anti-inflammatory medications, whereas canakinumab and colchicine could be considered if chronic inflammation persists despite the use of high-dose statins or ezetimibe.

Long-term use of other medications to improve MI patient outcomes

In addition to managing lipid, thrombotic, and inflammatory risks, conventional secondary prevention of MI includes a wide range of medications dedicated to controlling established risk factors and relieving ischemia, including renin-angiotensin-aldosterone system (RAS) inhibitors, β-blockers, calcium channel blockers, and nitrates.^[5,15,16] Although these agents can effectively control blood pressure or suppress anginal symptoms, only RAS blockade and β-blocker usage improve the long-term outcomes of MI patients. The established role of these drugs is highlighted in the latest MI and chronic coronary syndrome guidelines, as they are recommended to all patients for long-term treatment.^[5,15,16] However, with the more prevalent use of revascularization techniques, intensive lipid-lowering treatments, and DAPT, accumulating evidence has cast doubt upon the need for routine use of these agents in patients with MI, especially those with preserved cardiac function. Gaps in evidence regarding the use of the aforementioned medications for the management of patients with MI remain to be filled [Figure 3].

Figure 3:: Gaps in evidence for long-term use of renin-angiotensin blockade and β-blockers. √: Beneficial/recommended; ?: Controversial; ×: Harmful/not recommended; -: Not illustrated; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin Ⅱ receptor blocker; ARNI: Angiotensin receptor-neprilysin inhibitor; EF: Ejection fraction; MRA: Mineralocorticoid receptor antagonist.

RAS system inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin Ⅱ receptor blockers (ARBs) are the major RAS inhibitors recommended to all MI patients unless contraindicated by mainstream guidelines, especially patients with an ejection fraction (EF) <40%, diabetes, or anterior infarcts, as early trials show these agents could reduce mortality and recurrent ischemic events.^[15,16] However, emerging evidence has shown that ACEI/ARB medications have limited clinical benefits in patients with normal left ventricular (LV) function and active secondary prevention. A meta-analysis of 24 randomized trials with 198,275 patient-years of follow-up showed that the risk reduction in death and recurrent ischemia was not significant when RAS inhibitors were used in addition to active controls for stable CHD patients without heart failure (HF),^[76] while the clinical benefit of RAS inhibitors is closely associated with the control group event rate. More recent real-world studies also showed conflicting findings regarding the use of ACEIs/ARBs, as the risk reduction brought on by the medication varies according to LV systolic function (EF <40% vs. ≥40%), clinical presentation (STEMI vs. non-STEMI), and renal function, etc.^[14,77,78] Therefore, it is necessary to reassess the prognostic impacts of ACEIs/ARBs for low-risk MI patients, among whom these medications might not be routinely indicated but could be prescribed as anti-hypertensive agents to achieve blood pressure targets.

Similarly, several small- to medium-sized randomized trials of mineralocorticoid receptor antagonists (MRAs) generally failed to show improvements in hard endpoints in MI patients without HF.^[79,80] However, a recent meta-analysis of 11,861 patients from 15 trials showed that MRAs reduced the risk of all-cause mortality by 16% in MI patients; interestingly, the risk reduction was even more significant in those without LV systolic dysfunction.^[81] Although MRAs are only recommended for MI patients with severe LV dysfunction in addition to conventional ACEIs and β-blockers,^[82] their potential for improving outcomes in a broader MI population remains to be investigated in larger trials.

In addition to traditional RAS inhibitors, newly developed angiotensin receptor-neprilysin inhibitors (ARNIs) (ie, sacubitril/valsartan) are not able to reduce cardiovascular deaths and re-hospitalizations among high-risk MI patients versus ramipril as shown in the PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction) trial.^[83] However, patients recruited in this trial were older and more often had LV systolic dysfunction (EF <40%) compared to participants of other studies showing the clinical benefits of ANRI.^[84,85] In a meta-analysis of 1358 patients from 13 trials, ARNI substantially reduced the risk of re-hospitalization due to HF while improving LV function parameters (eg, EF, N-terminal pro-B-type natriuretic peptide, and LV end-diastolic diameter). Therefore, ANRI could be considered if conventional medication fails to relieve HF symptoms but might not be appropriate as a routine prescription after MI.

Taken together, the benefit of routine ACEI/ARB medication seems to be attenuated with progress in more intensive secondary prevention and requires reassessment in future trials, whereas other types of RAS inhibitors should be limited to MI patients with treatment-resistant HF.

β-blockers

In most of the latest guidelines, the continuous use of β-blockers has been recommended for MI patients since it can effectively lower the risks of death and recurrent ischemia, especially among those patients with HF or reduced LV function.^[15,16] However, the clinical benefits of β-blockers for patients in the reperfusion era are lacking, especially for those without HF.^[86] A recent meta-analysis of 22,423 MI patients from 25 trials showed that β-blocker use in the non-acute phase after MI probably reduces the risk of all-cause mortality and MI in patients aged <75 years,^[13] but most of the included studies were conducted 2 decades ago and suffer from a high risk of bias, leading to a moderate to low certainty of evidence. To date, the CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) study is the only trial to focus on non-HF STEMI patients successfully treated with PCI,^[87] and carvedilol did not reduce the risk of all-cause death, MI, or hospitalization for HF. However, the study was underpowered due to the small sample size, while the carvedilol dosages in this study were comparatively lower than those usually prescribed. On the other hand, post-hoc analyses based on large cohorts and observational studies show conflicting results,^[86,88–90] as β-blockers exhibit varying degrees of efficacy by clinical presentation. Younger patients and those with more severe myocardial damage, higher heart rates, and better medication adherence seem to benefit more from β-blocker treatment.^{[13,86,91,92]} Taken together, the routine use of β-blockers after MI should be re-considered, as its efficacy remains unclear and requires proper assessment in newer clinical trials.

Long-term management of non-culprit coronary lesions

With an evidence class of Ⅱa or Ⅱb, complete revascularization (CR) after MI has been recommended by mainstream guidelines if achievable.^[15,16] The recently published COMPLETE (Complete vs. Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI) trial further demonstrated the safety and efficacy of treating non-culprit lesions during the index hospitalization or after discharge [Table 3],^[12,93–98] affirming the feasibility of staged revascularization strategy for stable MI patients.^[12] A recent pooled analysis of randomized trials showed that CR leads to substantial risk reductions of 38% for cardiovascular death, 32% for recurrent MI, and 71% for repeated revascularization, respectively.^[99] Although it is attempting to routinely treat all non-culprit vessels, approximately 70% of these lesions involve intermediate coronary stenosis (50%–70% stenosis in diameter),^[100,101] for which PCI treatments might not ensure a lower ischemic risk or future benefit. Therefore, it is important to carefully assess and identify clinically significant lesions that require treatment in order to maximize the risk reduction afforded by CR while reducing unnecessary invasive procedures and medical costs.

Table 3 - Randomized clinical trials evaluating various strategies of complete revascularizations in patients with MI.

Study (year)	Key inclusion/exclusion criteria for non-culprit lesion	Revascularization strategy	Location of culprit lesion	Location of non-culprit lesion	Clinical endpoints
Politi et al[93] (2010)	Lesions with stenosis >70% assessed by CAG	CR vs. staged revascularization vs. culprit-only revascularization: 65 vs. 65 vs. 84	Anterior: 43.9% Others: 56.1%	NA	Primary endpoint (2.5 years): All-cause death, re-infarction, re-hospitalization for acute coronary syndrome, and repeat revascularization: 23.1% vs. 20.0% vs. 50.0% (P < 0.001) Secondary endpoints (2.5 years): All-cause death: 9.2% vs. 6.2% vs. 15.5% (P = 0.170) Cardiac death: 6.3% vs. 3.1% vs. 11.9% (P = 0.120) Re-infarction: 3.1% vs. 6.2% vs. 8.3% (P = 0.412) Repeat revascularization: 9.2% vs. 12.3% vs. 33.3% (P < 0.001)
PRAMI[94] (2013)	Lesions with stenosis ≥50% assessed by CAG	Preventive PCI vs. no preventive PCI: 234 vs. 231	Anterior: 33.5% Posterior: 60.6% Inferior: 5.2% LBBB: 0.6%	NA	Primary endpoint (23 months): Death from cardiac causes, non-fatal MI, or refractory angina: 9.0% vs. 22.9% (P < 0.001) Secondary endpoints (23 months): Death from cardiac causes or non-fatal MI: 4.7% vs. 11.7% (P = 0.004) Death from cardiac causes: 1.7% vs. 4.3% (P = 0.07) Non-fatal MI: 3.0% vs. 8.7% (P = 0.009) Refractory angina: 5.1% vs. 13.0% (P = 0.002) Repeat revascularization: 6.8% vs. 19.9% (P < 0.001)
DANAMI-3–PRIMULTI[95] (2015)	Lesions with stenosis >50% in diameter assessed by CAG	FFR-guided (<0.8) CR vs. infarct-related artery-only revascularization: 314 vs. 313	Infarct area: Anterior: 34.6% Posterior: 59.6% Inferior: 4.8% LBBB: 1.0%	NA	Primary endpoint (27 months): All-cause mortality, non-fatal re-infarction, and ischemia-driven revascularization of lesions in non–infarct-related arteries: 13% vs. 22% (P = 0.004) Secondary endpoints (27 months); All-cause mortality: 5% vs. 4% (P = 0.43) Non-fatal re-infarction: 5% vs. 5% (P = 0.87) Ischemia-driven revascularization: 5% vs. 17% (P < 0.0001) Cardiac death: 2% vs. 3% (P = 0.29) Cardiac death and MI: 6% vs. 8% (P = 0.47) Urgent PCI: 2% vs. 6% (P = 0.03) Non-urgent PCI: 3% vs. 9% (P = 0.002)
CvLPRIT[96] (2015)	Lesions in an epicardial artery or branch ≥2.0 mm, with significant stenosis on CAG (>70% in single view or >50% in 2 views)	CR vs. infarct-related artery-only revascularization: 150 vs. 146	pRCA: 19.9% mRCA: 15.9% LM: 0 pLAD: 20.3% mLAD: 12.8% pLCX: 7.4% Others: 23.6%	pRCA: 15.2% mRCA: 15.9% LM: 1.0% pLAD: 16.2% mLAD: 31.4% pLCX: 13.5% Others: 6.8%	Primary endpoint (12 months): All-cause death, recurrent MI, heart failure, and ischemia-driven revascularization: 15.0% vs. 21.2% (P = 0.009) Secondary endpoints (12 months): All-cause death: 1.3% vs. 4.1% (P = 0.14) Recurrent MI: 1.3% vs. 2.7% (P = 0.39) Heart failure: 2.7% vs. 6.2% (P = 0.14) Ischemia-driven revascularization: 4.7% vs. 8.2% (P = 0.20) Cardiovascular mortality: 1.3% vs. 4.8% (P = 0.11) Stroke: 1.3% vs. 1.4% (P = 0.96)
Compare-Acute[97] (2017)	Lesions in an epicardial artery ≥2.0 mm with stenosis >50% in diameter identified by quantitative CAG or visual assessment	FFR-guided (≤0.8) CR vs. infarct-related artery-only revascularization: 295 vs. 590	Infarct area: Anterior: 35.1% Posterior: 16.8% Inferior: 51.5% Lateral: 14.4% Unknown: 0.8%	RCA: 24.8% pRCA: 7.1% mRCA: 10.3% LAD: 4.2% pLAD: 11.9% mLAD: 20.4% LCX: 33.6% pLCX: 8.5% LM: 0	Primary endpoint (12 months): All-cause death, non-fatal MI, revascularization, and cerebrovascular events: 7.8% vs. 20.5% (P < 0.001) Secondary endpoints (12 months): Cardiac death, MI, any revascularization, stroke, and major bleeding: 8.5% vs. 29.5% (P < 0.001) All-cause death: 1.4% vs. 1.7% (P = 0.70) MI: 2.4% vs. 4.7% (P = 0.10) Revascularization: 6.1% vs. 17.5% (P < 0.001) Cerebrovascular event: 0% vs. 0.7% (P = NA) Major bleeding: 1.0% vs. 1.4% (P = 0.67)
COMPLETE[12] (2019)	Lesions in an epicardial artery ≥2.5 mm with either: • Stenosis ≥70% in diameter visually assessed by CAG; and • Stenosis of 50%–60% accompanied by FFR ≤0.8.	CR vs. culprit lesion-only revascularization: 2016 vs. 2025	LM: 0.2% LAD: 34.1% LCX: 16.9% RCA: 48.8%	LM: 0.2% LAD: 39.5% pLAD: 10.1% mLAD: 22.7% LCX: 36.0% pLCX: 26.9% dLCX: 11.1% RCA: 24.3%	Primary endpoints (3 years): Cardiovascular death and MI: 7.8% vs. 10.5% (P < 0.004) Cardiovascular death, MI, or ischemia-driven revascularization: 8.9% vs. 16.7% (P < 0.001) Secondary endpoints (3 years): Cardiovascular death, MI, ischemia-driven revascularization, unstable angina, or NYHA class IV heart failure: 13.5% vs. 21.0% (HR, 0.62; 95% CI, 0.53–0.72) MI: 5.4% vs. 7.9% (HR, 0.68; 95% CI, 0.53–0.86) Ischemia-driven revascularization: 1.4% vs. 7.9% (HR, 0.18; 95% CI, 0.12–0.26) Unstable angina: 3.5% vs. 6.4% (HR, 0.53; 95% CI, 0.40–0.71) Cardiovascular death: 2.9% vs. 3.2% (HR, 0.93; 95% CI, 0.65–1.32) All-cause death: 4.8% vs. 5.2% (HR, 0.91; 95% CI, 0.69–1.20) NYHA class IV heart failure: 2.9% vs. 2.8% (HR, 1.04; 95% CI, 0.72–1.50)
FLOWER-MI (2021)[98]	Major epicardial coronary artery or major side branch measuring ≥2.0 mm in diameter with stenosis ≥50% in diameter assessed by CAG	FFR vs. CAG-guided CR: 586 vs. 577	Infarct area: Anterior: 32.2% Posterior: 2.3% Inferior: 59.0% Posterolateral: 5.8% LBBB: 0.8%	LM: 1.4% LAD: 57.4% LCX: 39.6% RCA: 30.2%	Primary endpoint (1 year): All-cause death, non-fatal MI, or urgent revascularization: 5.5% vs. 4.2% (P = 0.32) Secondary endpoints (1 year): All-cause death: 5.5% vs. 4.2% (HR, 0.89; 95% CI, 0.36–2.20) Non-fatal MI: 3.1% vs. 1.7% (HR, 1.77; 95% CI, 0.82–3.84) Urgent revascularization: 2.6% vs. 1.9% (HR, 1.34; 95% CI, 0.62–2.92) Any revascularization: 6.5% vs. 4.5% (HR, 1.45; 95% CI, 0.88–2.38) Stent thrombosis: 0.7% vs. 1.0% (HR, 0.65; 95% CI, 0.19–2.32)

CAG: Coronary angiography CI: Confidence interval; CR: Complete revascularization; d: Distal; FFR: Fractional flow research; HR: Hazard ratio; LAD: Left anterior descending artery; LBBB: Left bundle branch block; LCX: Left circumflex; LM: Left main; m: Middle; MI: Myocardial infarction; NA: Not available; NYHA: New York Heart Association; p: Proximal; PCI: Percutaneous coronary intervention; RCA: Right coronary artery.

Although it is basic and conventional, CR guided by coronary angiography improves the outcomes of patients with MI.^[94,96] The PRAMI (Preventive Angioplasty in Acute Myocardial Infarction) trial showed that completely revascularized STEMI patients had a lower rate of adverse events than patients treated only for an infarct-related artery (9.0% vs. 22.9%, P < 0.001). Notably, cardiac death and non-fatal MI rates were substantially reduced (4.7% vs. 11.7%, P = 0.004), suggesting a firm benefit of CR. Such improvement in hard endpoints was not observed for the later CvLPRIT (Complete versus Lesion-Only Primary PCI Trial) study, although the overall incidence of ischemic events was lower, which could have been due to the smaller sample size, lower event rate, and shorter follow-up, leading to a reduction in the power to detect a risk reduction caused by CR. These favorable outcomes have laid the foundation for recommendations of routine CR for patients with MI.

However, with the development of functional testing for ischemia (eg, fractional flow reserve (FFR) and quantitative flow ratio (QFR)), a considerable number of lesions with intermediate stenosis are now deemed unnecessary for revascularization in patients with stable CHD.^[100,101] Therefore, it is tempting to use these techniques to achieve precise revascularization in MI patients with multivessel disease, which is expected to avoid repeated invasive procedures and unnecessary stenting.^[102] However, the results from trials testing FFR-guided CR strategies have cast doubt on the suitability of these techniques in the acute phase of MI. In the DANAMI-3-PRIMULTI (The Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: Primary PCI in Multivessel Disease) trial, non-culprit lesions with ≥50% stenosis were further evaluated using FFR to decide on whether to pursue stenting or not. The incidence of hard endpoints was similar between the 2 groups, including MI (5% vs. 5%, P = 0.87) and all-cause death (5% vs. 4%, P = 0.43).^[95] Overall, the FFR-guided CR group acquired a lower rate of ischemic events (13% vs. 22%, P = 0.004), which was mainly driven by a reduction in revascularization driven by ischemia (5% vs. 17%, P < 0.001). Similar findings were observed in the later Compare-Acute (Comparison Between FFR-guided Revascularization vs. Conventional Strategy in Acute STEMI Patients with Multivessel Disease) trial, which also demonstrated that the outcome improvements by FFR-guided CR were mainly attributed to the reduction of repeated revascularization.^[97] It is therefore difficult to interpret the clinical benefits of FFR assessment, as CR solely following functional testing fails to prevent acute ischemic events and only seems to advance the timing of revascularization for stable lesions causing ischemia. The newly published FLOWER-MI (Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction) trial showed that FFR-guided CR was not superior to an angiography-guided strategy regarding the primary outcome of death, MI, and urgent revascularization (5.5% vs. 4.2%, P = 0.31), further questioning the necessity of routine functional testing for non-culprit lesions. Technical issues arise during functional testing in the early phase after MI.^[101] During FFR assessment, impairment of microvascular dilation could have resulted in suboptimal hyperemia, leading to an apparently higher FFR value and an underestimated severity of stenosis, which could be an interpretation of the non-reduced rate of ischemia after MI. Other functional tests that do not require hyperemia could be alternatives,^[100,101] but the instantaneous wave-free ratio tends to overestimate stenosis severity, while QFR accuracy also suffers from the impact of acute microvascular dysfunction. The optimal timing for functional testing is controversial, as the results could be substantially different for the acute versus stable phases. On the other hand, the COMPLETE trial adopted a mixed strategy to identifying lesions requiring treatment, either by significant stenosis (>70%) or functional ischemia (FFR <0.8).^[12] Surprisingly, the CR group showed a substantially lower incidence of cardiovascular death and MI (7.8% vs. 10.5%, P = 0.004). Considering the neutral results of the FLOWER-MI trial, the improved outcomes of CR could be mainly mediated by interventions for vessels with significant stenosis but not the identification of lesions with significant functional ischemia. FFR assessment might not be indispensable in building up a CR strategy, but it remains valuable for clinical decision-making regarding the treatment of moderate stenosis. Based on current evidence,^{[12,100,101,103]} the CR strategy should be primarily based on anatomical assessments of non-culprit lesions through coronary angiography, while functional tests could serve as an additional reference for lesions with moderate stenosis. Considering the dynamics of coronary vascular function and feasibility of staged PCI, it seems more reasonable to perform functional tests and CR during the sub-acute or stable phase after MI.

Another issue of note is the high prevalence of unstable plaques among patients with MI that are frequently detected by intravascular imaging techniques. Pan-coronary scanning with optical coherence tomography (OCT) shows that nearly 40% of STEMI patients present with thin-cap fibroatheroma (TCFA) in non-culprit lesions,^[104] while 70% have non-culprit plaques with high-risk features (eg, severe stenosis, microphage accumulation, great lipid arc), which are more prevalent in those with plaque rupture at the culprit vessels. Decreased plaque stability is associated with rapid progression and an elevated future risk of ischemia. In a mixed population (of stable CHD and ACS patients), approximately 10% of non-culprit plaques showed rapid progression during a mean of 7.1 months, for which the incidence should be more frequent in a pure MI population.^[105] Notably, lipid-rich plaques, TCFA, and layered plaques are independent predictors of lesion progression and long-term cardiovascular events.^[106] In the CLIMA (Relationship Between Coronary Plaque Morphology of Left Anterior Descending Artery and Long-term Clinical Outcome) study, CHD patients with coronary plaques fulfilling all 4 high-risk features (ie, minimal lumen area <3.5 mm², fibrous cap thickness <75 μm, lipid arc >180°, and macrophage infiltration) were at a 6.5-fold increased risk of cardiac death and target-segment MI (19.4% vs. 3.1%).^[106] Interestingly, an OCT sub-study of the COMPLETE trial showed that obstructive non-culprit lesions with significant stenosis (>70%) are more often complicated by TCFA (35.4% vs. 25.3%, P = 0.022) than non-obstructive lesions,^[107] which could be the reason for risk reduction in hard endpoints of MI and death observed in the COMPLETE trial, as these obstructive lesions amenable to PCI were all treated according to the trial design.

Taken together, CR for non-culprit lesions is generally beneficial; however, approaches to precisely identifying lesions in need of treatment remain to be validated. Considering the pros and cons of different techniques,^[100,101] a comprehensive assessment of non-culprit plaques using a combination of visual assessment, functional testing, and intracoronary imaging seems secure and feasible for planning CR, as functional testing can evaluate the extent of physiological ischemia caused by stenosis, while angiographic assessment and intravascular imaging are able to predict the risk of acute coronary events due to plaque instability [Figure 4].

Figure 4:: Assessment of non-culprit lesions for complete revascularization. FFR: Fractional flow reserve; IVUS: Intravascular ultrasound; Mφ: Microphage infiltration; OCT: Optical coherence tomography; PCI: Percutaneous coronary intervention; TCFA: Thin-cap fibroatheroma.

Long-term cardiac rehabilitation after MI

Apart from medications and coronary revascularization, cardiac rehabilitation programs (RPs) are currently gaining interest and emphasis for improving long-term outcomes and quality of life for patients with a history of MI. With abundant clinical evidence, RPs are generally indicated for all patients with MI with high-level recommendations.^{[5,15,16,108,109]} The concept of RP is also expanding, as it is no longer limited to the prescription of physical exercise but also includes lifestyle changes, risk factor management, psychosocial care, and dynamic evaluations. However, RPs have been widely underutilized worldwide despite their proven benefit in reducing mortality and recurrent ischemia rates.^[109–113] Imperatively, it is necessary to update physician knowledge of RP advances in current clinical settings.

The clinical benefits of RPs have been intensively studied in numerous randomized trials. According to a recently updated Cochrane systematic review of 85 randomized trials, exercise-based RPs result in a 42% lower risk of cardiovascular death and 33% lower risk of MI during long-term follow-up (>36 months) of patients with CHD.^[108] Moreover, RPs containing elements of physical exercise could offer broader cardiovascular protection than those without exercise.^[114] The underlying mechanisms by which an RP improves the outcomes of MI patients could be multiple, primarily attributed to improved exercise capacity, preserved cardiac function, attenuated LV remodeling, and better control of modifiable atherosclerotic risk factors.^[109,112] In a recent meta-analysis of 1683 patients with MI, RPs substantially improved peak oxygen uptake (VO₂) (standardized mean difference (SMD), 1.00; P < 0.001) and EF (SMD, 0.21; P = 0.03) while reducing the resting heart rate (SMD, −0.59; P < 0.05) and LV end-diastolic volume (SMD, −0.31; P < 0.05).^[115] Other beneficial effects of exercise-based RPs include improvements in endothelial function (coronary and peripheral), plaque stability, ventilation, chronic inflammation, and autonomic nervous system function.^[109,112] In summary, RPs benefit patients with a history of MI due to its positive prognostic and physical impacts and should be a routine treatment for the long-term management of MI.

However, several issues have arisen regarding the implementation of RPs in clinical settings. On the one hand, universal standards are lacking for the prescription of RPs, especially for the dosage of physical exercise. Although the latest pooled analysis suggested that the risk reduction was consistent across various doses of exercise (dose = number of sessions × average duration of each session (min)), more sessions of RP appear to offer a greater clinical benefit.^{[108,116,117]} In a meta-analysis of 33 trials, Santiago et al^[117] reported that a medium (12–35 sessions) to high (≥36 sessions) dose of RP is more effective at reducing overall mortality, while only a high dose of RP reduced the need for PCI in a mixed population with various cardiovascular diseases. Apart from that, the addition of low- to moderate-intensity resistance training further improves physical function compared to traditional aerobic exercise alone, as indicated by greater peak oxygen uptake, work capacity, and muscle strength.^[118]

Despite the varying details of exercise intensity, the general rules of exercise components in RPs are quite similar across cardiac rehabilitation guidelines from different nations [Table 4].^{[112,119–122]} The ideal exercise prescription for RP is mainly based on moderate- to high-intensity aerobic training, whereas additional resistance training at a low-to-moderate intensity could bring extra benefits for improving physical performance, such as increased muscle strength and greater exercise capacity.^{[112,119,121–123]} However, owing to safety concerns, the prescription of physical exercise varies greatly and is highly individualized in real clinical settings. Several key factors require consideration, including symptoms, comorbidities, family history, lifestyle, cardiac function, the electrocardiogram at rest, and exercise stress test results, to determine the exercise type, intensity, and duration to be employed for the planned RP sessions.^[112,122]

Table 4 - Recommendations for cardiac rehabilitation after myocardial infarction in major guidelines.

Guideline (year)	Recommendations*
ESC (2021)[119]	Overall dose: >1000 units and >36 RP sessions Aerobic training: 150–300 min/week at moderate intensity; or 75–150 min/week at vigorous intensity Resistance training: ≥2 days/week in addition to aerobic training; 1–3 sets × 8–12 repetitions at 60%–80% of 1RM × ≥2 days/week
AHA/ACCF (2011)[120]	Aerobic training: 30–60 min × 5–7 days/week; Supplemented by an increase in daily lifestyle activities (eg, walking breaks at work, gardening, household work) Resistance training: ≥2 days/week in addition to aerobic training
Korea (2019)[121]	Aerobic training: Should be included in RP; High-intensity interval training may yield better results than aerobic exercise Resistance training: Resistance (strengthening) exercises should be included in RP.
Japan (2012)[112]	Aerobic training: 15–60 min × 3–7 days/week Exercise at anaerobic threshold level: 40%–60% of the peak VO2; 40%–60% of maximum heart rate; or Achieve RPE of 12–13 Resistance training: Resistance exercises should be included in RP; 2–3 sets × 12–15 repetitions at 40%–60% of 1RM × 2–3 days/week Avoid strenuous upper-extremity exercise within 3 months after open-heart surgery
China (2020)[122]	Overall dose: 36 RP sessions (at least 25 sessions) within 12 months after discharge Aerobic training: 30–45 min × 5 days/week at moderate intensity; or 15 min × 3 days/week at high intensity Resistance training: Resistance exercises could be included in RP Upper limbs exercise: 4 sets × 20 repetitions at 30%–40% of 1RM × 3 days/week (RPE 11–13) Lower limbs/waist/back exercise: 4 sets × 20 repetitions at 50%–60% of 1RM × 3 days/week (RPE 11–13) Initiate resistance training ≥5 weeks after myocardial infarction Avoid strenuous upper-extremity exercise within 3 months after or coronary bypass grafting

^*1 unit = week × sessions per week × duration of each session (min). ACCF: American College of Cardiology Foundation; AHA: American Heart Association; ESC: European Society of Cardiology; RM: Repetition maximum; RP: Rehabilitation program; RPE: Ratings of perceived exertion (Borg scale); VO₂: Oxygen uptake.

Although carrying an abundant clinical benefit, the delivery of RPs is unsatisfactory in the current health care system, as shown by the under-expected participation in RPs.^[109,113] This could be due to the low availability of hospitals that offer these programs.^[111] For example, only 24% of Chinese hospitals offer RPs according to a survey of 454 large medical centers, although most already perform a high volume of cardiology procedures (eg, PCI, CABG). On the other hand, a low referral rate or failure to maintain patient adherence to rehabilitation sessions are the main reasons for the low participation in RPs in more developed countries.^{[110,112,124,125]} Interestingly, patients undergoing CABG are more frequently referred to RPs than those treated by PCI (91% vs. 48%), for whom an RP is usually prescribed to foster recovery from surgeries rather than the treatment of underlying cardiovascular disorders.^[109,110] Imbalances in RP referral and completion are also present between the genders and among operators, hospitals, regions, and socioeconomic statuses.^{[110,113,124,126]} In addition, maintaining patient adherence to the RP is also increasingly challenging, as home-based RPs have been proven safe for and adopted by many low-risk patients, for whom more interventions are needed through the primary care system to promote program completion.^{[112,125,127]} Continuous medical education is warranted to improve physician awareness and introduce RPs as a routine treatment for MI, while relevant issues of facilities and resources for RPs in primary care deserve more attention from health care policy-makers.

Conclusions

Advances in medications and therapeutics have substantially improved the outcomes of patients with MI, as there are more options and strategies for the long-term management of lipid level, thrombotic, and inflammatory risks. A shortened DAPT has been proven feasible for the prevention of ischemic events, while the use of more potent P2Y12 inhibitors and oral anti-coagulants offers more combinations for treating patients at different thrombotic risk levels. The suppression of coronary plaques and ischemic risk is no longer limited to intensive lipid-lowering treatment; it can also resolve chronic inflammation. CR should be achieved for most stable MI patients; however, the identification of suitable lesions requiring treatment remains a challenge. On the other hand, several conventional medications (ie, RAS inhibitors, β-blockers) to improve long-term outcomes should be reassessed due to a lack of evidence in the era of revascularization and intensive secondary prevention, while cardiac rehabilitation is generally underutilized and requires further promotion. At the call of precision medicine, future studies should focus on refining risk-stratifications of MI patients to assign certain treatments to suitable patients that might benefit maximally from these therapies.

Funding

This study was supported by the National Natural Science Foundation of China (81970308), the Fund of the “Sanming” Project of Medicine in Shenzhen (SZSM201911017), the Shenzhen Key Medical Discipline Construction Fund (SZXK001), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-009).

Author contributions

Conceptualization: Runzhen Chen, Hanjun Zhao, and Hongbing Yan;

Literature search: Runzhen Chen and Hanjun Zhao;

Funding acquisition: Hongbing Yan;

Writing—original draft: Runzhen Chen;

Writing—review & editing: Runzhen Chen, Hanjun Zhao, and Hongbing Yan.

All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

None.