Complementary Pharmacotherapy for STEMI Undergoing Primary PCI

An Evidence-Based Clinical Approach

Enrico Fabris; Abi Selvarajah; Annerieke Tavenier; Rik Hermanides; Elvin Kedhi; Gianfranco Sinagra; Arnoud van't Hof

Am J Cardiovasc Drugs. 2022;22(5):463-474.

Abstract and Introduction

Abstract

Antithrombotic therapy is the cornerstone of pharmacological treatment in patients undergoing primary percutaneous coronary intervention (PCI). However, the acute management of ST elevation myocardial infarction (STEMI) patients includes therapy for pain relief and potential additional strategies for cardioprotection. The safety and efficacy of some commonly used treatments have been questioned by recent evidence. Indeed a concern about morphine use is the interaction between opioids and oral P2Y₁₂ inhibitors; early beta-blocker treatment has shown conflicting results for the improvement of clinical outcomes; and supplemental oxygen therapy lacks benefit in patients without hypoxia and may be of potential harm. Other additional strategies remain disappointing; however, some treatments may be selectively used. Therefore, we intend to present a critical updated review of complementary pharmacotherapy for a modern treatment approach for STEMI patients undergoing primary PCI.

Introduction

Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment in patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).^[1,2] However, the optimal treatment for pain relief and additional strategies for cardioprotection during the acute phase are debatable. Indeed, the safety and efficacy of some commonly used treatments have been questioned by recent evidence.

We intend to present a critical updated review of complementary pharmacotherapy for a modern treatment approach for STEMI patients undergoing primary PCI.

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Next Section

Abstract and Introduction
Early Pharmacological Treatment
Cardioprotective Pharmacotherapy
Ischemic Conditioning
Other Complementary Therapies at the Time of Reperfusion
Conclusions
References
Sidebar

Table 1. Principal randomized trials testing the effect of drugs for pain relief on platelet inhibition
Trial	Year	N of patients	Randomization	Drug administration	Endpoints	Results of endpoints
Hobl et al. [5]	2014	24	Morphine vs placebo	Morphine 5 mg	AUC of clopidogrel active metabolite	Morphine reduced the AUC of clopidogrel active metabolite 34%, p = 0.001
IMPRESSION trial [6]	2016	70	Morphine vs placebo	Morphine 5 mg	AUC_(0–12) for ticagrelor during the first 12 h after the administration of the LD	Ticagrelor 6307 ± 4359 vs. 9791 ± 5136 ng h/mL in morphine vs placebo; a difference of 36%, p = 0.003
PACIFY trial [7]	2017	70	Fentanyl vs routine care	IV fentanyl (dose at the discretion of treating providers)	Ticagrelor concentration during the 24 h after loading as assessed by the AUC_(0–24)	2107 vs 3301 ng·h⁻¹ mL in fentanyl vs no fentanyl, p = 0.05
PERSEUS trial [8]	2020	38	Fentanyl vs morphine	IV fentanyl (50–100 μg) or IV morphine (4–8 mg)	Platelet reactivity at 2 h after ticagrelor LD	At 2 h, mean P2Y₁₂ reaction units were 173.3 ± 89.7 and 210.3 ± 76.4 in patients treated with fentanyl and morphine, p = 0.463
ON-TIME 3 trial [9]	2020	195	Acetaminophen vs fentanyl	Paracetamol (1000 mg) or fentanyl titrated based on the weight of the patient	Level of PRU measured immediately after primary PCI in patients treated with ticagrelor	Median PRU 104 (IQR 37–215) for acetaminophen vs. 175 (63–228) for fentanyl, p = 0.18

AUC area under the curve, h hour, IQR interquartile range, IV intravenous, LD loading dose, PCI percutaneous coronary intervention, PRU platelet reactivity units

Table 2. Randomized studies of beta-blocker administration in patients treated with primary PCI
Trial	Year	N of patients	Randomization	Drug administration	Endpoints	Results of endpoints
Hanada et al. [29]	2012	96	Non-blinded, open-label, no placebo (routine care)	Landiolol 3 μg/kg/min infusion for 24 h after PCI	LV function assessed by left ventriculography during the acute phase and during a 6-month follow-up	LVEF increased from 49.1 ± 1.5% to 52.0 ± 1.5% in the chronic phase (p = 0.01) in the landiolol group, no significant difference was found in the control group (from 50.2 ± 1.4% to 50.2 ± 1.2%)	+
METOCARD-CNIC trial [31]	2013	270 (220 with CMR)	Single-blind, no placebo (routine care)	IV metoprolol 15 mg during transfer to PCI or at the emergency department	Infarct size by CMR (extent of myocardial necrosis quantified by delayed gadolinium enhancement) performed 5 to 7 days after STEMI	Adjusted difference, −6.52 in metoprolol group (95% CI −11.39 to −1.78; p = 0.012)	+
BEAT-AMI trial [30]	2016	101	Single-blind, placebo-controlled	Esmolol infusion after PCI	Maximum change in troponin T from baseline to 48 h	Median troponin T concentration increased from 0.2 to 1.3 ng/mL in the esmolol group and from 0.3 to 3.2 ng/mL in the placebo group (p = 0.01)	+
EARLY-BAMI trial [32]	2016	683 (342 with CMR)	Double-blind, placebo-controlled	Metoprolol IV doses of 5 mg. First bolus in ambulance. Second bolus immediately before PCI	Myocardial infarct size as measured by CMR at 30 days	Infarct size (percent of LV) 15.3 ± 11.0% in metoprolol group and 14.9 ± 11.5% in placebo group (p = 0.616)	−

+ denotes positive results, − denotes negative results, CI confidence interval, CMR cardiac magnetic resonance, IC intracoronary, IV intravenous, LVEF left ventricular ejection fraction, LV left ventricular, PCI percutaneous coronary intervention, STEMI ST elevation myocardial infarction

Table 3. Randomized studies of adenosine administration in patients treated with primary PCI
Authors	Year	N of patients	Randomization	Administration	Endpoints	Results of endpoints
Marzilli et al. [36]	2000	54	Adenosine:placebo	IC distal to occlusion during balloon inflation	Feasibility and safety of IC adenosine administration	+
Petronio et al. [37]	2005	30	Adenosine:placebo	IC distal to occlusion during balloon inflation	Left ventricular remodeling at 6 months	−
Ross et al. [44] (AMISTAD-II trial)*	2005	2118	Adenosine:placebo	IV within 15 min either of the start of fibrinolysis or before coronary intervention	New CHF, first re-hospitalization for CHF, or death from any cause within 6 months	−
Ross et al. [44] (AMISTAD-II trial)*	2005	2118	Adenosine:placebo		Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography	+
Stoel et al. [38]	2008	51	Adenosine:placebo	IC after last balloon inflation	STR and TIMI frame count, MBG, coronary blood flow, coronary, vascular resistance	+
Fokkema et al. [43]	2009	448	Adenosine:placebo	IC after thrombus aspiration and after stenting	The incidence of residual ST-segment deviation (< 0.2 mV) after PCI	−
Desmet et al. [40]	2011	112	Adenosine:placebo	IC	Myocardial salvage on CMR 2–3 days post perfusion	−
Grygier et al. [39]	2011	70	Adenosine:placebo	IC after crossing the lesion and then after first balloon inflation	ST-segment elevation resolution after PCI; MBG, TIMI flow grade and TIMI frame count at the end of procedure	+
Zhang et al. [42]	2012	90	1:1:1 To receive adenosine low-dose:high-dose:placebo	IV after the guide wire crossed the lesion	Left ventricular function, and infarct size	+
Wang et al. [41]	2012	69	Adenosine:placebo	IV prior to stent implantation	Myocardial perfusion and segmental contractile function	+
Niccoli et al. [47] (REOPEN-AMI trial)	2013	240	1:1:1 To receive adenosine: nitroprusside:saline	IC following thrombus aspiration	ST-segment resolution (> 70%) after PCI	+
Garcia-Dorado et al. [46]	2014	201	Adenosine:placebo	IC before thrombectomy and direct stenting	Infarct size by late enhancement on CMR imaging performed between 2 and 7 days post-reperfusion	−
Nazir et al. [49] (REFLO-STEMI trial)	2016	247	1:1:1 To receive adenosine:nitroprusside:control (standard primary PCI alone)	IC after thrombectomy and Immediately following stent deployment	Infarct size by CMR performed at 24–96 h	−

*About 40% treated with primary PCI
+ denotes positive results, − denotes negative results, CHF congestive heart failure, CMR cardiac magnetic resonance, IC intra coronary, IV intravenous, MBG myocardial blush grade, N number, PCI percutaneous coronary intervention, STR ST resolution, TIMI thrombolysis in myocardial infarction