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.
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The management of myocardial infarction includes complementary pharmacotherapy for pain relief and cardioprotection. |
The safety and efficacy of some commonly used treatments have been questioned by recent evidences. |
Considering the interaction between opioids and oral P2Y12 inhibitors, morphine administration should be reserved for those patients having persistent severe chest pain despite alternative analgesics which avoid opioids. |
Considering the results of therapies for cardioprotection, many drugs should not be part of routine standard care, but they should be wisely and selectively administered. |
Future research efforts need to focus on novel therapeutic approaches for improving clinical outcomes. |
In the current era of ST elevation myocardial infarction (STEMI) treatment, the “as soon as possible” therapies (“ASAP”) remain Aspirin, Second antiplatelet agent, Anticoagulant and of course Primary percutaneous coronary intervention. |
1 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.
2 Early Pharmacological Treatment
2.1 Relief of Pain: Opioids
In STEMI patients, intravenous (IV) opioids such as morphine are largely used to relieve pain and anxiety. Opioids are also often used in patients with pulmonary congestion, as it is believed that they can also ameliorate dyspnea and favorably affect ventricular loading conditions through vasodilation. However, the evidence for these mechanisms is relatively poorly demonstrated [3]. The main concerns about morphine use is the interaction between opioids and oral P2Y12 inhibitors; indeed, opioids may delay the absorption of oral P2Y12 inhibitors by delaying gastric emptying, and therefore decreasing P2Y12 inhibitor plasma levels [4].
2.1.1 Interaction Between Opioids and P2Y12 Inhibitors
The pharmacokinetic and pharmacodynamic interaction between opioids and P2Y12 inhibitors has been shown for all the P2Y12 inhibitors in randomized settings (Table 1) [5,6,7,8,9] and in a cross-over study [10]; moreover, morphine use has been associated with delayed onset of action of both prasugrel and ticagrelor, without a difference between the two drugs [11].
The PERSEUS trial evaluated a head-to-head randomized comparison between fentanyl and morphine in STEMI patients requiring analgesia. The trial showed that patients who received fentanyl did not have higher platelet inhibition at 2 h after the ticagrelor loading dose [8]. However, fentanyl might have the potential to reduce the delay of absorption of ticagrelor, resulting in a higher platelet inhibition at 4 h, in comparison to morphine. Nevertheless, the results of this trial are hypothesis generating, considering the loss of statistical power attributable to premature study termination [8].
Further studies evaluated whether the effects of morphine on P2Y12 inhibitors may lead to a significant clinical effect. In the ATLANTIC trial, STEMI patients received a ticagrelor loading dose and in half of the cases (49.5%, n = 921) opioids (morphine in 97.6%). Morphine-treated patients had more frequently an absence of pre-PCI thrombolysis in myocardial infarction (TIMI) flow 3 compared to patients with no morphine administration (85.8% vs 79.7%; p = 0.001). In addition, morphine treatment was associated with increased glycoprotein IIb/IIIa inhibitor (GPI) use [12]. On the other hand, the French FAST-MI Registry showed that pre-hospital administration of morphine (n = 453, 19%) was not associated with a higher rate of in-hospital adverse complications or worse long-term survival. However, the rate of non-fatal recurrent myocardial infarction (MI) was higher in patients pretreated with morphine (1.8 vs 0.7%, p = 0.03) [13]. Similarly, in the CIRCUS trial, administration of IV morphine before angiography in half of STEMI patients (57.1%, n = 554) was not associated with a significant increase of major adverse cardiovascular events (MACE) at 1 year, but a non-significant trend towards an increase in the incidence of recurrent MI in the morphine group (3.8% vs 1.7%, p = 0.08) was demonstrated [14]. Interestingly, the use of morphine has been associated with the occurrence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in anterior STEMI [15].
2.1.2 Alternative Analgesics that Avoid Opioids
Various studies searched for effective management of pain in STEMI patients with simultaneously fast and optimal platelet inhibition by investigating alternative analgesics that avoid opioids. The ON-TIME 3 trial compared IV acetaminophen with IV fentanyl in STEMI patients with ongoing chest pain, who all received crushed ticagrelor in a pre-hospital setting [9]. IV acetaminophen did not result in significantly lower platelet reactivity, but was associated with higher plasma concentrations of crushed ticagrelor at several time points and resulted in effective pain relief [9].
Opioid use is recommended by both the European and American STEMI guidelines [1, 2]. However, in the current European guideline, the class of the recommendation has been reduced from class I to IIa (level of evidence C), as a result of the increasing knowledge about the potential adverse effects of opioids. Recently, the US Food and Drug Administration (FDA) posted an official warning on the use of opioids in STEMI patients and recommended consideration of the use of a parenteral anti-platelet agent in acute coronary syndrome (ACS) patients requiring co-administration of morphine or other opioid agonists.
Pain relief remains a priority of any medical care; however, considering current data, morphine administration should be restricted as much as possible in the setting of acute MI. Alternative agents like acetaminophen may be considered, and morphine may be reserved for those having persistent severe chest pain despite the administration of acetaminophen.
2.2 Oxygen
Oxygen (O2) therapy has commonly been used in the initial treatment of patients with STEMI. Indeed, it seems plausible that enhancing O2 supply to an ischemic myocardium would lead to a beneficial effect attenuating ischemic tissue injury. However, evidence questioned the routine administration of supplemental O2 in the absence of hypoxemia. Although the mechanisms of the potential harm of supplemental O2 are not clearly elucidated, hyperoxia may decrease the activity of endothelium-derived vasodilators and may cause a reduction in coronary blood flow due to an increase in coronary vascular resistance [16].
In 2012, a small randomized trial found no difference in MI size in STEMI patients (n = 136) treated with high-concentration (6 L/min) or titrated O2 for 6 h after presentation [17]. The AVOID trial [18] demonstrated in 441 STEMI patients without hypoxia that the use of supplemental O2 (8 L/min) increased early myocardial injury (assessed with cardiac enzymes sampling), which led to a greater infarct size (assessed with cardiac magnetic resonance [CMR] at 6 months) and in more frequent recurrent MI and cardiac arrhythmia, compared to patients without supplemental O2. The subsequent SOCCER trial evaluated 95 STEMI patients and found no effect of high-flow O2 (10 L/min) on myocardial salvage index, myocardium at risk or infarct size at CMR performed 2–6 days after the inclusion, in comparison to patients with only room air [19]. The large DETO2X–AMI trial and its pre-specified subanalysis of STEMI patients (n = 2807) provided solid evidence for a lack of benefit of routine supplemental O2 therapy in normoxemic patients. In these patients, the administration of O2 (6 L/min for 6–12 h) resulted in no significant difference in 1-year clinical outcomes [20]. Moreover, in a subanalysis of DETO2X–AMI trial, O2 therapy compared with ambient air was not associated with improved outcomes regardless of baseline oxygen saturation [21].
In a meta-analysis including eight randomized controlled trials, supplemental O2 therapy was not associated with important clinical benefit in normoxemic patients with suspected or confirmed acute MI [22].
Finally, a recent pragmatic, cluster-randomized, crossover trial neither confirmed nor excluded difference in 30-day mortality from supplementary O2 in a subgroup of patients presenting with STEMI (odds ratio 0.81, 95% confidence interval 0.66–1.00) [23].
Based on the current evidence, supplemental O2 provides no clear benefit and there is no need to administer supplemental O2 in non-hypoxic (O2 saturation of ≥ 90% on pulse oximetry) STEMI patients undergoing primary PCI.
2.3 Nitrates
Most of the data available in literature about the use of nitrates in the setting of acute MI derive from the era before primary PCI had become the standard revascularization strategy.
In 1995, the large ISIS-4 trial demonstrated no significant benefit of nitrates on mortality [24]. The GISSI-3 trial confirmed the lack of beneficial effects of glyceryl trinitrate in acute MI patients, most of whom were treated with fibrinolysis [25].
In everyday clinical practice, nitrates can be useful in hypertensive and/or decompensated STEMI patients. During primary PCI, intracoronary (IC) administration of nitrates can be useful to counteract the component of vasoconstriction which is often present in STEMI patients. However, IV nitrates should be avoided in right ventricular (RV) infarction, in which nitrates may negatively impact the preload in patients who are particularly dependent upon preload for RV filling and for maintaining cardiac output. Furthermore, nitrates should be avoided in patients who have used phosphodiesterase type 5 (PDE5) inhibitors in the previous 48 h, as both drugs share a common mechanism of action in facilitating the release of nitric oxide (NO) and the synergistic lowering of blood pressure may put the patients at a high risk of developing severe hypotension.
Therefore, nitrates should be selectively administered and should not be part of a routine standard therapy in STEMI patients undergoing primary PCI.
3 Cardioprotective Pharmacotherapy
3.1 Beta-Blockers
Acute MI represents a state of reduced O2 supply to the affected portion of the myocardium. Early administration of IV beta-blocker, slowing the heart rate, reducing myocardial contractility, and lowering systemic blood pressure by the blockade of β1 receptors may be beneficial during MI as it results in reduced myocardial workload and O2 demand [26]. The cardioprotective effect associated with beta blockade seems to occur especially when the drug is given before coronary reperfusion [27], suggesting that beta-blockers might also have a role in reducing reperfusion injury, by targeting neutrophils and inhibiting neutrophil–platelet interactions in MI patients [28].
The effect of beta-blockers in STEMI patients undergoing primary PCI has been investigated in four randomized trials [29,30,31,32] (Table 2), which included patients in Killip class I or II and excluded patients with a low systolic blood pressure, a heart rate < 60 beats/min, or atrioventricular (AV) block type II or III. In the METOCARD-CNIC trial, 15 mg of IV metoprolol administered during transfer to PCI or at the emergency department in patients with anterior STEMI and Killip class I or II was associated with a reduced infarct size when compared to placebo [31]. Interestingly, a subanalysis [33] showed that beta-blockers have a greater cardioprotective effect (smaller infarct size) the sooner they are injected in the course of STEMI. Because myocardial necrosis is a time‐dependent ischemic process, the cardioprotective agent can be effective if administered when cellular ischemic death is not already complete. The time of administration of beta-blockers seems, therefore, fundamental; indeed, beta-blockers, when administered early, may slow the rate of myocardial death during ischemia by reducing myocardial O2 consumption.
However, the results of the METOCARD-CNIC trial were not confirmed by the EARLY-BAMI trial, in which STEMI patients were pre-treated twice with 5 mg of IV metoprolol (first bolus in ambulance and second bolus immediately before PCI) and showed no differences in terms of infarct size at CMR compared to placebo [32]. However, patients who received metoprolol had a lower incidence of malignant arrhythmias (3.6% in the metoprolol group vs 6.9% in the placebo group, p = 0.050) [32].
A patient-pooled meta-analysis of these trials showed that early administration of IV beta-blocker is safe, but no difference in the main outcome of 1-year death or MI was shown [34].
Considering the existing evidence, it seems reasonable and safe to administer beta-blockers early to hemodynamically stable and not bradycardic STEMI patients undergoing primary PCI. Whether higher doses of beta-blocker administered early may be beneficial should be explored in a further large trial.
3.2 Adenosine and Other Coronary Vasodilators
Adenosine is a potent direct vasodilator of coronary microcirculation. Data from animal models with MI suggested that adenosine and adenosine agonists could be myocardial protectants, although the molecular basis for acute adenosinergic cardioprotection remains incompletely understood [35]. The effect of periprocedural adenosine administration on myocardial perfusion and ventricular function in STEMI patients remains in controversy [36,37,38,39,40,41,42,43] (Table 3).
In the large AMISTAD-2 trial, adenosine showed a positive signal for reduction of infarct size [44], but improvement in clinical outcomes was confined to patients with early onset of MI [45]. Similarly, infarct size was significantly reduced by adenosine in those receiving early PCI (ischemia duration < 200 min) [46]. In the REOPEN-AMI trial [47], STEMI patients with TIMI flow grade 0–1 were randomly allocated 1:1:1 to receive adenosine, nitroprusside, or saline, and IC adenosine was shown to improve ST resolution (STR). The improvement in clinical outcomes did not reach statistical significance at 1 month, but adenosine reduced MACE rate at 1 year and was associated with less left ventricular (LV) negative remodeling [48]. Conversely, in the most recent REFLO-STEMI trial [49], IC adenosine (2–3 mg total) immediately following thrombectomy and stenting showed no significant difference in infarct size compared to nitroprusside or control. Moreover, a per-protocol analysis, suggested a potential harm of IC adenosine in terms of mid-term clinical outcomes.
In summary, adenosine has shown the potential to improve no-reflow in STEMI patients [50]; however, whether it can also limit infarct size and improve clinical outcomes is still not clearly proven. Interestingly, a recent meta-analysis of clinical studies undertaken in the primary PCI era suggests a beneficial effect of IC adenosine in terms of less heart failure (HF) following STEMI [51].
Importantly, while early reperfusion of the infarct-related artery may salvage a substantial amount of jeopardized myocardium, flow restoration also results in “reperfusion damage” due to production of oxygen free radicals, neutrophil activation, and endothelial damage. Therefore, ischemia and reperfusion both contribute to myocardial damage. Marzilli et al. [36] used a strategy for selective treatment of the ischemic territory right before the onset of reperfusion, injecting adenosine through the central lumen of an over-the-wire balloon catheter downstream of the obstruction. Adenosine, given distally to the coronary obstruction and before the onset of reperfusion, was associated with beneficial effects on coronary flow and ventricular function, potentially counteracting some of the mechanisms of reperfusion damage [36]. This may suggest that a protective agent should be administered downstream of the occlusion and prior to vessel reopening to be effective. It is also to be noted that the full therapeutic potential of adenosine may be limited by its ultra-short half-life and by possible dilution of the administered dose when delivered via a guiding or balloon catheter. Distal coronary administration of adenosine using a microinfusion catheter may be preferred, and a drug-releasing guidewire platform has been recently developed to allow continuous release of adenosine directly into the microvasculature during a PCI procedure [52].
Other vasodilators such as calcium channel blockers (verapamil, diltiazem, or nicardipine) during primary PCI have been evaluated in a limited number of studies. However, diltiazem or verapamil reverses no-reflow more effectively than nitroglycerin [53, 54]. Also, IC nitroprusside seems to reduce the incidence of angiographic no-reflow during primary PCI [55].
Nowadays, adenosine and other coronary vasodilators are not used routinely during primary PCI; however, they may be used in the attempt to reverse the no-reflow phenomenon on the basis of the potential benefit of the vasodilatation of microcirculation.
3.3 Agents Targeting Mitochondrial Permeability
Mitochondrial permeability transition is a key event in cell death and one of the mechanisms leading to reperfusion injury [56]; various adjunctive agents targeting mitochondria have been administered during the acute phase of MI as a potential cardioprotective strategy. In preclinical studies, many of these therapies were promising; however, most did not show clinical benefit in the clinical trials.
Cyclosporin-A, a mitochondrial permeability transition pore (mPTP) inhibitor, failed to protect the myocardium against reperfusion injury in STEMI patients and failed to improve hard clinical outcomes [57,58,59]. Also, the administration of TRO40303, another small-molecule mitochondria pore modulator that inhibits mPTP opening, did not show a reduction of the infarct size compared to placebo [59]. Moreover, elamipretide (MTP-131 or Bendavia), a cell-permeable peptide that preserves the integrity of cardiolipin, a phospholipid on the inner mitochondrial membrane, did not decrease myocardial infarct size in a sizable multicenter trial including STEMI due to a proximal or mid left anterior descending (LAD) lesion [60].
In conclusion, all the presented data show that complementary pharmacotherapies targeting mitochondria in STEMI patients treated with early primary PCI do not provide cardioprotection during the acute phase and are not able to improve clinical outcomes.
4 Ischemic Conditioning
Deep review of reperfusion injury is beyond the scope of this review; however, reperfusion injury could be mitigated through a process known as “conditioning,” which increases the tolerance of the myocardium to sustained ischemia by interrupting reperfusion with short inflation and deflation of the angioplasty balloon immediately after establishing perfusion, i.e., “ischemic post-conditioning.” Early studies suggested that post-conditioning may protect the human heart during acute MI [61], and subsequent small studies of STEMI patients have reported mixed results [62,63,64,65,66]. The largest study powered to detect a reduction in clinical endpoints, the DANAMI-3–iPOST trial [67], showed that ischemic post-conditioning was not superior to conventional primary PCI in terms of all-cause death and hospitalization for HF, in STEMI patients. “Remote ischemic conditioning,” which may also be established with cycles of reversible ischemia and reperfusion applied to a tissue far from the heart, had been a promising potential cardioprotective strategy [68,69,70,71]. Unfortunately, the recent and large CONDI-2/ERIC-PPCI trial [72], including 5401 STEMI patients, provided definitive evidence that remote ischemic conditioning offers no benefits regarding either myocardial infarct size or clinical outcomes.
5 Other Complementary Therapies at the Time of Reperfusion
N-acetylcysteine (NAC) is an antioxidant with reactive O2 species scavenging properties. In the LIPSIA-N-ACC trial [70], IV NAC did not reduce myocardial salvage index assessed with CMR. Conversely, the NACIAM trial [73] showed that NAC given at the moment of primary PCI with a background low dose of nitroglycerin reduced myocardial infarct size and increased myocardial salvage compared to placebo [73]. In another small randomized trial, NAC improved myocardial reperfusion markers (peak high sensitivity troponin T [hs-TnT]) and coronary blood flow (TIMI flow 3) [74]. However, these positive results need to be confirmed in larger studies with relevant clinical endpoints.
Exenatide, a glucagon-like-peptide-1 analog, administered at the time of reperfusion has been shown to increase myocardial salvage, but without improvement in clinical events at 30 days [75]. However, in the recent COMBAT-MI trial [76], exenatide alone or the combination of exenatide and remote ischemic conditioning were not able to reduce the infarct size.
6 Conclusions
Timely and complete reperfusion is the most effective way to improve cardiovascular outcomes in STEMI patients. Primary PCI together with early antithrombotic/antiplatelet therapy remains the cornerstone for achieving this goal. The implementation of additional strategies during the acute phase of STEMI for the improvement of clinical outcomes remains disappointing; however, some treatments may be used in selected patients (Figure 1). Beta-blockers may be administered in non-bradycardic and hemodynamically stable patients. Therapy with nitrates should be selectively administered in hypertensive or decompensated patients with LV MI and avoided in RV infarction. For pain relief, acetaminophen may be considered and morphine reserved for those patients having persistent severe chest pain despite acetaminophen. O2 should be given only in hypoxic patients, and adenosine (or other vasodilators such as calcium channel blockers or nitroprusside) should be given in an attempt to reverse the no-reflow phenomenon. Unfortunately, to date, other pharmacological approaches are not recommended because of a lack of efficacy. Future research efforts need to focus on novel therapeutic approaches to provide cardioprotection during the acute phase of STEMI.
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Dr. E. Kedhi reports personal fees from Abbott and personal fees from Medtronic, outside this submitted work; Dr. A. van't Hof reports grants from Medtronic, Abbott, Boehringer Ingelheim, and AstraZeneca, all outside this submitted work; Dr. E. Fabris, A. Selvarajah, A. Tavenier, R. Hermanides, and G. Sinagra have declared no potential conflicts of interest that might be relevant to this work.
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Fabris, E., Selvarajah, A., Tavenier, A. et al. Complementary Pharmacotherapy for STEMI Undergoing Primary PCI: An Evidence-Based Clinical Approach. Am J Cardiovasc Drugs 22, 463–474 (2022). https://doi.org/10.1007/s40256-022-00531-y
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DOI: https://doi.org/10.1007/s40256-022-00531-y