Age as a predictor of clinical outcomes and determinant of therapeutic measures for emergency medical services treated cardiogenic shock.

BACKGROUND: The impact of age on outcomes in cardiogenic shock (CS) is poorly described in the pre-hospital setting. We assessed the impact of age on outcomes of patients treated by emergency medical services (EMS). METHODS: This population-based cohort study included consecutive adult patients with CS transported to hospital by EMS. Successfully linked patients were stratified into tertiles by age (18-63, 64-77, and > 77 years). Predictors of 30-day mortality were assessed through regression analyses. The primary outcome was 30-day all-cause mortality. RESULTS: A total of 3523 patients with CS were successfully linked to state health records. The average age was 68 ± 16 years and 1398 (40%) were female. Older patients were more likely to have comorbidities including pre-existing coronary artery disease, hypertension, dyslipidemia, diabetes mellitus, and cerebrovascular disease. The incidence of CS was significantly greater with increasing age (incidence rate per 100,000 person years 6.47 [95% CI: 6.1-6.8] in age 18-63 years, 34.34 [32.4-36.4] in age 64-77 years, 74.87 [70.6-79.3] in age > 77 years, P < 0.001). There was a step-wise increase in the rate of 30-day mortality with increasing age tertile. After adjustment, compared to the lowest age tertile, patients aged > 77 years had increased risk of 30-day mortality (adjusted hazard ratio = 2.26 [95% CI: 1.96-2.60]). Older patients were less likely to receive inpatient coronary angiography. CONCLUSION: Older patients with EMS-treated CS have significantly higher rates of short-term mortality. The reduced rates of invasive interventions in older patients underscore the need for further development of systems of care to improve outcomes for this patient group.

Impact of prehospital opioid dose on angiographic and clinical outcomes in acute coronary syndromes.

BACKGROUND: An adverse interaction whereby opioids impair and delay the gastrointestinal absorption of oral P2Y12 inhibitors has been established, however the clinical significance of this in acute coronary syndrome (ACS) is uncertain. We sought to characterise the relationship between prehospital opioid dose and clinical outcomes in patients with ACS. METHODS: Patients given opioid treatment by emergency medical services (EMS) with ACS who underwent percutaneous coronary intervention (PCI) between 1 January 2014 and 31 December 2018 were included in this retrospective cohort analysis using data linkage between the Ambulance Victoria, Victorian Cardiac Outcomes Registry and Melbourne Interventional Group databases. Patients with cardiogenic shock, out-of-hospital cardiac arrest and fibrinolysis were excluded. The primary end point was the risk-adjusted odds of 30-day major adverse cardiac events (MACE) between patients who received opioids and those that did not. RESULTS: 10 531 patients were included in the primary analysis. There was no significant difference in 30-day MACE between patients receiving opioids and those who did not after adjusting for key patient and clinical factors. Among patients with ST-elevation myocardial infarction (STEMI), there were significantly more patients with thrombolysis in myocardial infarction (TIMI) 0 or 1 flow pre-PCI in a subset of patients with high opioid dose versus no opioids (56% vs 25%, p<0.001). This remained significant after adjusting for known confounders with a higher predicted probability of TIMI 0/1 flow in the high versus no opioid groups (33% vs 11%, p<0.001). CONCLUSIONS: Opioid use was not associated with 30-day MACE. There were higher rates of TIMI 0/1 flow pre-PCI in patients with STEMI prescribed opioids. Future prospective research is required to verify these findings and investigate alternative analgesia for ischaemic chest pain.

LidocAine Versus Opioids In MyocarDial infarction: the AVOID-2 randomized controlled trial.

AIMS: Opioid analgesia has been shown to interfere with the bioavailability of oral P2Y12 inhibitors prompting the search for safe and effective non-opioid analgesics to treat ischaemic chest pain. METHODS AND RESULTS: The lidocAine Versus Opioids In MyocarDial infarction trial was a prospective, Phase II, prehospital, open-label, non-inferiority, randomized controlled trial enrolling patients with suspected STEACS with moderate to severe pain [numerical rating scale (NRS) at least 5/10]. Intravenous lidocaine (maximum dose 300 mg) or intravenous fentanyl (up to 50 µg every 5 min) were administered as prehospital analgesia. The co-primary end points were prehospital pain reduction and adverse events requiring intervention. Secondary end points included peak cardiac troponin I, cardiac MRI (cMRI) assessed myocardial infarct size and clinical outcomes to 30 days. A total of 308 patients were enrolled. The median reduction in pain score (NRS) was 4 vs. 3 in the fentanyl and lidocaine arms, respectively, for the primary efficacy end point [estimated median difference -1 (95% confidence interval -1.58, -0.42, P = 0.5 for non-inferiority, P = 0.001 for inferiority of lidocaine)]. Adverse events requiring intervention occurred in 49% vs. 36% of the fentanyl and lidocaine arms which met non-inferiority and superiority favouring lidocaine (P = 0.016 for superiority). No significant differences in myocardial infarct size and clinical outcomes at 30 days were seen. CONCLUSION: IV Lidocaine did not meet the criteria for non-inferiority with lower prehospital pain reduction than fentanyl but was safe and better tolerated as analgesia in ST-elevation myocardial infarction (STEMI). Future trials testing non-opioid analgesics in STEMI and whether opioid avoidance improves clinical outcomes are needed. TRIAL REGISTRATION: CTRN12619001521112p.

HOSPITAL CHARACTERISTICS ARE ASSOCIATED WITH CLINICAL OUTCOMES IN PATIENTS WITH CARDIOGENIC SHOCK.

ABSTRACT: Background: Regionalized systems of care for the management of cardiogenic shock (CS) are increasingly being utilized. This study aims to assess whether receiving hospital characteristics such as the availability of 24-hour coronary angiography, on-site cardiac surgery, and annual treated CS volume influence outcomes in patients transferred by emergency medical services (EMS) to hospital with CS. Methods: This population-based cohort study included consecutive adult patients with CS who were transferred to hospital by EMS between January 1, 2015 and June 30, 2019 in Victoria, Australia. Data were obtained from individually linked ambulance, hospital, and state death index data sets. The primary outcome assessed was 30-day mortality stratified by the availability of 24-hour coronary angiography (cardiac center) at the receiving hospital. Results: A total of 3,217 patients were transferred to hospital with CS. The population had an average age of 67.9 +/- 16.1 years, and 1,289 (40.1%) were female. EMS transfer to a cardiac center was associated with significantly reduced rates of 30-day mortality (adjusted odds ratio [aOR], 0.78; 95% confidence interval [CI], 0.64-0.95), compared with noncardiac centers. Compared with the lowest annual CS volume quartile (<18 cases per year), hospitals in the highest volume quartile (>55 cases per year) had reduced risk of 30-day mortality (aOR, 0.71; 95% CI, 0.56-0.91). A stepwise reduction in the adjusted probability of 30-day mortality was observed in patients transferred by EMS to trauma level 1 centers (34.6%), compared with cardiothoracic surgical centers (39.0%), noncardiac surgical metropolitan (44.9%), and rural (51.3%) cardiac centers, all P < 0.05. Conclusion: Receiving hospital characteristics are associated with survival outcomes in patients with CS. These finding have important implications for establishing regionalized systems of care for patients with CS who are transferred to hospital by EMS.

P2Y12 Antagonists in Cardiovascular Disease-Finding the Best Balance Between Preventing Ischemic Events and Causing Bleeding.

Dual antiplatelet therapy comprising of aspirin and oral P2Y12 receptor antagonists are an established cornerstone of therapy in acute coronary syndromes and percutaneous coronary intervention. As a result, the platelet P2Y12 receptor remains a key therapeutic target in cardiovascular medicine since pharmacological antagonists were first developed in the 1990's. With a greater understanding of platelet biology and the role played by the P2Y12 receptor in the amplification of platelet activation and thrombus formation, there has been progressive refinement in the development of P2Y12 receptor antagonists with greater potency and consistency of antiplatelet effect. However, challenges remain in the utilization of these agents particularly in balancing the need for greater protection from ischemic events whilst minimizing the bleeding risk and present a real opportunity for the institution of individualized medicine. Future drug developments will provide clinicians with greater avenues to achieve this.

Gender Disparities in Cardiogenic Shock Treatment and Outcomes.

Cardiogenic shock is associated with a high risk for morbidity and mortality. The impact of gender on treatment and outcomes is poorly defined. This study aimed to evaluate whether gender influences the clinical management and outcomes of patients with prehospital cardiogenic shock. Consecutive adult patients with cardiogenic shock who were transferred to hospital by emergency medical services (EMS) between January 1, 2015 and June 30, 2019 in Victoria, Australia were included. Data were obtained from individually linked ambulance, hospital, and state death index datasets. The primary outcome assessed was 30-day mortality, stratified by patient gender. Propensity score matching was performed for risk adjustment. Over the study period a total of 3,465 patients were identified and 1,389 patients (40.1%) were women. Propensity score matching yielded 1,330 matched pairs with no differences observed in baseline characteristics, including age, initial vital signs, pre-existing co-morbidities, etiology of shock, and prehospital interventions. In the matched cohort, women had higher rates of 30-day mortality (44.7% vs 39.2%, p = 0.009), underwent less coronary angiography (18.3% vs 27.2%, p <0.001), and revascularization with percutaneous coronary intervention (8.9% vs 14.2%, p <0.001), compared with men. In conclusion, in this large population-based study, women with cardiogenic shock who were transferred by EMS to hospital had significantly worse survival outcomes and reduced rates of invasive cardiac interventions compared to men. These data underscore the urgent need for targeted public health measures to redress gender differences in outcomes and variation with clinical care for patients with cardiogenic shock.

Sex differences in prehospital analgesia in patients presenting with acute coronary syndromes and their association with clinical outcomes.

OBJECTIVES: This study examined if sex differences in prehospital pain scores, opioid administration, and clinical outcomes exist in acute coronary syndrome (ACS) patients. BACKGROUND: Sex differences persist in ACS presentation, management, and outcomes. The impact of sex differences on prehospital pain management of ACS with opioids is unknown. METHODS: Patients presenting with ACS via ambulance (2014-2018) that underwent percutaneous coronary intervention (PCI) were prospectively collected via the Victorian Cardiac Outcomes Registry and Melbourne Interventional Group, linked to the Ambulance Victoria database. The primary outcome was 30-day major adverse cardiac events (MACE). Secondary outcomes were descriptive analyses of prehospital pain score, intravenous morphine equivalent analgesic dosing, plus predictors of MACE and thrombolysis in myocardial infarction (TIMI) 0-1 flow pre-PCI. RESULTS: A total of 10,547 patients were included (female: 2775 [26%]). Opioids were administered to 1585 (57%) females, 5068 (65%) males (p < 0.001). Adjusted 30-day MACE was similar between opioid groups in both sexes (female: odds ratio [OR]: 1.21, confidence interval [CI] 0.82-1.79, p = 0.34; male: OR: 0.89, CI: 0.68-1.16, p = 0.40). Median pain score at presentation was 6 (interquartile range [IQR]: 4, 8) for both sexes. Median opioid dose was 2.5 mg (IQR: 0, 10) in females and 5 mg (IQR: 0, 10) in males (p < 0.001), with similar pain relief achieved. Adjusted rates of TIMI 0-1 pre-PCI were higher in patients administered opioids (female: OR 2.9, CI: 2.07-4.07, p < 0.001; male: OR: 2.67, CI: 2.19-3.25, p < 0.001). CONCLUSIONS: Female patients undergoing PCI received less opioid analgesia, but no sex differences in prehospital pain scores were seen. Opioid administration was associated with impaired antegrade flow in the culprit artery in both sexes, but not short-term MACE. Trials evaluating nonopioid analgesics in ACS are needed.

Incidence and Outcomes of Nontraumatic Shock in Adults Using Emergency Medical Services in Victoria, Australia.

Importance: Nontraumatic shock is a challenging clinical condition, presenting urgent and unique demands in the prehospital setting. There is a paucity of data assessing its incidence, etiology, and clinical outcomes. Objective: To assess the incidence, etiology, and clinical outcomes of patients treated by emergency medical services (EMS) with nontraumatic shock using a large population-based sample. Design, Setting, and Participants: This population-based cohort study included consecutive adult patients with shock not related to trauma who received care by EMS between January 1, 2015, and June 30, 2019, in Victoria, Australia. Data were obtained from individually linked ambulance, hospital, and state death index data sets. During the study period there were 2 485 311 cases attended by EMS, of which 16 827 met the study's inclusion criteria for shock. Main Outcomes and Measures: The primary outcome was 30-day mortality. Secondary outcomes included length of hospital stay, emergency department discharge disposition, rates of coronary angiography and revascularization procedures, and the use of mechanical circulatory support. Results: A total of 12 695 patients were successfully linked, with a mean (SD) age of 65.7 (19.1) years; 6411 (50.5%) were men. The overall population-wide incidence of EMS-treated prehospital shock was 76 (95% CI, 75-77) per 100 000 person-years. An increased incidence was observed in men (79 [77-81] per 100 000 person-years), older patients (eg, aged 70-79 years: 177 [171-183] per 100 000 person-years), regional locations (outer regional or remote: 100 [94-107] per 100 000 person-years), and in areas with increased socioeconomic disadvantage (lowest socioeconomic status quintile: 92 [89-95] per 100 000 person-years). Patients with hospital outcome data were stratified into shock etiologies; 3615 (28.5%) had cardiogenic shock: 3998 (31.5%), septic shock; 1457 (11.5%), hypovolemic shock; and 3625 (28.6%), other causes of shock. Nearly one-third of patients (4158 [32.8%]) were deceased at 30 days. In multivariable analyses, increased age (all etiologies: hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), female sex (cardiogenic shock: HR, 1.26; 95% CI, 1.12-1.42), increased initial heart rate (all etiologies: 1.01; 95% CI, 1.00-1.01), prehospital intubation (all etiologies: HR, 3.93; 95% CI, 3.48-4.44), and preexisting comorbidities (eg, chronic kidney disease, all etiologies: HR, 1.25; 95% CI, 1.10-1.42) were independently associated with 30-day mortality, while higher socioeconomic status (all etiologies: HR, 0.96; 95% CI, 0.94-0.98) and increased initial systolic blood pressure (all etiologies: HR, 0.99; 95% CI, 0.99-0.99) were associated with lower risk. Conclusions and Relevance: This population-level cohort study found that EMS-treated nontraumatic shock was a common condition, with a high risk of morbidity and mortality regardless of etiology. It disproportionately affected men, older patients, patients in regional areas, and those with social disadvantage. Further studies are required to assess how current systems of care can be optimized to improve outcomes.

Association between pre-hospital chest pain severity and myocardial injury in ST elevation myocardial infarction: A post-hoc analysis of the AVOID study.

BACKGROUND: We sought to determine if an association exists between prehospital chest pain severity and markers of myocardial injury. METHODS AND RESULTS: Patients with confirmed ST elevation myocardial infarction (STEMI) treated by emergency medical services were included in this retrospective cohort analysis of the AVOID study. The primary endpoint was the association of pre-hospital initial chest pain severity, cardiac biomarkers and infarct size based on cardiac magnetic resonance imaging. Groups were categorized based on moderate to severe chest pain (numerical rating scale pain ≥ 5/10) or less than moderate severity to compare procedural and clinical outcomes. 414 patients were included in the analysis. There was a weak correlation between initial pre-hospital chest pain severity and peak creatine kinase (r = 0.16, p = 0.001) and peak cardiac troponin I (r = 0.14, p = 0.005). Both were no longer significant after adjusting for known confounders. There was no association between moderate to severe chest pain on arrival and major adverse cardiac events at 6 months (20% vs. 14%, p=0.12). There was a weak correlation between history of ischemic heart disease (r = 0.16, p = 0.001), percutaneous coronary intervention (r = 0.16, p = 0.001), left anterior descending artery (r = 0.12, p = 0.012) as the culprit vessel and a weak negative correlation between age (r = -0.14, p = 0.039) and chest pain. CONCLUSION: Only a weak association between pre-hospital chest pain severity and markers of myocardial injury was identified, supporting more judicious use of opioid analgesia with a focus on patient comfort.

Totally Occluded Culprit Coronary Artery in Patients with Non-ST-Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

The short- and long-term implications of identifying totally occluded culprit coronary arteries (TOCCA) in patients presenting with non-ST-elevation myocardial infarction (NSTEMI) have not been well studied. This study compares clinical characteristics, short- and long-term outcomes of patients with NSTEMI identified with TOCCA to that of patients with non-TOCCA undergoing percutaneous coronary intervention (PCI). We analyzed data from patients with NSTEMI undergoing single-vessel PCI within the Melbourne Interventional Group multi-center registry between 2005 and 2017. Those with TOCCA were compared to those with non-TOCCA. The primary endpoint was 30-day major adverse cardiac events (MACE). Secondary endpoints included 12-month MACE and long-term mortality. A total of 6,829 patients with NSTEMI had single-vessel PCI of which 954 (14%) had TOCCA. Most TOCCA were non-left anterior descending (right coronary artery 39% versus circumflex 33% versus left anterior descending 26%; p <0.001). Cardiogenic shock and left ventricular dysfunction were higher in the TOCCA group, but non-TOCCA patients had more baseline comorbidities. Thirty-day MACE was higher in the TOCCA group (6.7% versus 3.8%; p <0.001). Long-term mortality with an average follow-up of 4.9 years was higher in the non-TOCCA group (12% versus 18%, p <0.01). Multivariable Cox-proportional hazards regression identified TOCCA as an independent predictor of 30-day MACE (HR = 1.93; 95%CI: 1.4-2.6), but not long-term mortality, which was predicted by baseline comorbidities. In conclusion, while patients with NSTEMI with TOCCA undergoing PCI represent a more unstable subgroup early on, long-term outcomes appear more dependent on baseline comorbidities.

Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial.

AIMS: We assessed the impact of intravenous fentanyl and lignocaine on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina and non-ST-elevation myocardial infarction and their procedural analgesic efficacy and safety. METHODS AND RESULTS: Seventy patients undergoing coronary angiography with ticagrelor loading were included in the pharmacokinetic and pharmacodynamic analyses of this randomized trial. Plasma ticagrelor levels 2 h post-loading dose were significantly lower in the fentanyl arm than in the lignocaine treatment arm (598 vs. 1008 ng/mL, P = 0.014). The area under the plasma-time curves for ticagrelor (1228 vs. 2753 ng h/mL, P < 0.001) and its active metabolite (201 vs. 447 ng h/mL, P = 0.001) were both significantly lower in the fentanyl arm. Expression of activated platelet glycoprotein IIb/IIIa receptor (2829 vs. 1426 mean fluorescence intensity, P = 0.006) and P-selectin (439 vs. 211 mean fluorescence intensity, P = 0.001) was significantly higher at 60 min in the fentanyl arm. A higher proportion of patients had high on-treatment platelet reactivity in the fentanyl arm at 60 min using the Multiplate Analyzer (41% vs. 9%, P = 0.002) and 120 min using the VerifyNow (30% vs. 3%, P = 0.003) and VASP (37% vs. 6%, P = 0.002) assays. Both drugs were well tolerated with a high level of patient satisfaction. CONCLUSIONS: Unlike fentanyl, lignocaine does not impair the bioavailability or delay the antiplatelet effect of ticagrelor. Both drugs were well tolerated and effective with a high level of patient satisfaction for procedural analgesia. Routine procedural analgesia during percutaneous coronary intervention should be reconsidered and if performed, lignocaine is a beneficial alternative to fentanyl.

Pre-hospital heparin use for ST-elevation myocardial infarction is safe and improves angiographic outcomes.

AIMS: This study aims to evaluate if pre-hospital heparin administration by paramedics is safe and improves clinical outcomes. METHODS AND RESULTS: Using the multicentre Victorian Cardiac Outcomes Registry, linked with state-wide ambulance records, we identified consecutive patients undergoing primary percutaneous coronary intervention for STEMI between January 2014 and December 2018. Information on thrombolysis in myocardial infarction (TIMI) flow at angiography was available in a subset of cases. Patients receiving pre-hospital heparin were compared to those who did not receive heparin. Findings at coronary angiography and 30-day clinical outcomes were compared between groups. Propensity-score matching was performed for risk adjustment. We identified a total of 4720 patients. Of these, 1967 patients had TIMI flow data available. Propensity-score matching in the entire cohort yielded 1373 matched pairs. In the matched cohort, there was no observed difference in 30-day mortality (no-heparin 3.5% vs. heparin 3.0%, P = 0.25), MACCE (no-heparin 7% vs. heparin 6.2%, P = 0.44), and major bleeding (no-heparin 1.9% vs. heparin 1.4%, P = 0.64) between groups. Propensity-score analysis amongst those with TIMI data produced 552 matched pairs. The proportion of cases with TIMI 0 or 1 flow in the infarct-related artery (IRA) was lower among those receiving pre-hospital heparin (66% vs. 76%, P < 0.001) compared to those who did not. CONCLUSION: In this multicentre, propensity-score matched study, the use of pre-hospital heparin by paramedics was safe and is associated with fewer occluded IRAs in patients presenting with STEMI.

An open-label, non-inferiority randomized controlled trial of lidocAine Versus Opioids In MyocarDial Infarction study (AVOID-2 study) methods paper.

Background There is increasing evidence that opioids interfere with the oral bioavailability of P2Y12 inhibitors leading to delayed onset of antiplatelet effects. Several strategies have been proposed to mitigate this interaction including utilizing alternative analgesic agents in the management of ischemic chest pain. Methods The lidocAine Versus Opioids In MyocarDial Infarction (AVOID-2) study is a phase II, pre-hospital, open-label, non-inferiority, randomized controlled trial conducted by Ambulance Victoria and Monash University in metropolitan Melbourne, Victoria, Australia. The purpose of the study is to compare the analgesic effect (reduction in pain by arrival to hospital) and safety (e.g. adverse drug reactions) (co-primary endpoints) of intravenous lidocaine versus intravenous fentanyl in 300 adult patients attended by ambulance with suspected ST-elevation myocardial infarction (STEMI). Secondary endpoints and a cardiac magnetic resonance imaging (MRI) sub-study will also compare infarct size between these two groups. Conclusions The evaluation of alternative analgesic agents in the management of acute coronary syndromes is urgently needed to manage the opioid-P2Y12 inhibitor interaction. The results of this trial will have significant implications on the emergency management of acute coronary syndromes internationally.

Rescue PCI in the management of STEMI: Contemporary results from the Melbourne Interventional Group registry.

BACKGROUND: Fibrinolysis is an important reperfusion strategy in the management of ST-elevation myocardial infarction (STEMI) when timely access to primary percutaneous coronary intervention (PPCI) is unavailable. Rescue PCI is generally thought to have worse outcomes than PPCI in STEMI. We aimed to determine short- and long-term outcomes of patients with rescue PCI versus PPCI for treatment of STEMI. METHODS AND RESULTS: Patients admitted with STEMI (excluding out-of-hospital cardiac arrest) within the Melbourne Interventional Group (MIG) registry between 2005 and 2018 treated with either rescue PCI or PPCI were included in this retrospective cohort analysis. Comparison of 30-day major adverse cardiac events (MACE) and long-term mortality between the two groups was performed. There were 558 patients (7.1%) with rescue PCI and 7271 with PPCI. 30-day all-cause mortality (rescue PCI 6% vs. PPCI 5%, p = 0.47) and MACE (rescue PCI 10.3% vs. PPCI 8.9%, p = 0.26) rates were similar between the two groups. Rates of in-hospital major bleeding (rescue PCI 6% vs. PPCI 3.4%, p = 0.002) and 30-day stroke (rescue PCI 2.2% vs. PPCI 0.8%, p < 0.001) were higher following rescue PCI. The odds ratio for haemorrhagic stroke in the rescue PCI group was 10.3. Long-term mortality was not significantly different between the groups (rescue PCI 20% vs. PPCI 19%, p = 0.33). CONCLUSIONS: With contemporary interventional techniques and medical therapy, rescue PCI remains a valuable strategy for treating patients with failed fibrinolysis where PPCI is unavailable and it has been suggested in extenuating circumstances where alternative revascularisation strategies are considered.

The opioid-P2Y12 inhibitor interaction: Potential strategies to mitigate the interaction and consideration of alternative analgesic agents in myocardial infarction.

Despite advances in medical and interventional management of acute myocardial infarction, treatment of the associated chest pain has remained relatively unchanged since opioids were first utilized in the 1930's. This dominance can be partially attributed to initial studies suggesting hemodynamic benefits with opioid treatment. However, delayed gastrointestinal absorption of P2Y12 inhibitors due to opioids and the consequent impairment in antiplatelet activity of this established therapy is cause for concern. Coupled with the lack of randomized clinical trial evidence to support widespread opioid use, there is now an opportunity to re-evaluate our approach to analgesia in myocardial infarction. This review characterizes the mechanism of the opioid-P2Y12 inhibitor interaction, strategies aimed at mitigating the interaction and appraises promising alternative agents to opioid therapy in patients with myocardial infarction.

Antithrombotic Therapy in Myocardial Infarction: Historic Perils and Current Challenges-A 70-Year Journey.

There have been numerous and intriguing advancements in antithrombotic therapy for myocardial infarction since it was described in the earliest issues of Thrombosis and Haemostasis. In this article, we revisit historical breakthroughs and describe the four most challenging contemporary themes relating to antithrombotic therapy in myocardial infarction. In all four, the challenge is to find the best balance of reducing specific levels of ischaemic risks without increasing bleeding risk. The first is the question of the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). This includes discussion of monotherapy after a period of DAPT. The second relates to the role of genotype and phenotype-guided individualisation of antiplatelet therapy. There is emerging evidence for a role of pheno/genotyping in identifying individuals at high risk for recurrent ischaemic events or in guiding the timing of cardiac surgery for patients on DAPT. The third addresses the increasing evidence for dual pathway inhibition, for example, with rivaroxaban in addition to aspirin in patients where high ischaemic and low bleeding risk is demonstrated. Finally the fourth highlights the challenge of the most appropriate combination of antiplatelet and anticoagulation therapy for patients with known atrial fibrillation after PCI. In most individuals, oral P2Y12 inhibitor therapy combined with a direct acting oral anticoagulant appears to be the best strategy based on the available evidence. Overall, the progress in antithrombotic therapy achieved over the last seven decades is remarkable, however, there are important issues to address and progress still to be made.

Prehospital opioid dose and myocardial injury in patients with ST elevation myocardial infarction.

OBJECTIVE: To characterise the relationship between opioid dose and myocardial infarct size in patients with ST elevation myocardial infarction (STEMI). METHODS: Patients given opioid treatment by emergency medical services with confirmed STEMI were included in this secondary, retrospective cohort analysis of the Air versus Oxygen in Myocardial Infarction (AVOID) study. Patients with cardiogenic shock were excluded. The primary endpoint was comparison of cardiac biomarkers as a measure of infarct size based on opioid dose (low ≤8.75 mg, intermediate 8.76-15 mg and high >15 mg of intravenous morphine equivalent dose). RESULTS: 422 patients were included in the analysis. There was a significantly higher proportion of patients with Thrombolysis in Myocardial Infarction (TIMI) 0 or 1 flow pre-percutaneous coronary intervention (PCI) (94% vs 81%, p=0.005) and greater use of thrombus aspiration catheters (59% vs 30%, p<0.001) in the high compared with low-dose opioid group. After adjustment for potential confounders, every 1 mg of intravenous morphine equivalent dose was associated with a 1.4% (95% CI 0.2%, 2.7%, p=0.028) increase in peak creatine kinase; however, this was no longer significant after adjustment for TIMI flow pre-PCI. CONCLUSIONS: Our study suggests no benefit of higher opioid dose and a dose-dependent signal between opioid dose and increased myocardial infarct size. Prospective randomised controlled trials are required to establish causality given that this may also be explained by patients with a greater ischaemic burden requiring higher opioid doses due to more severe pain. Future research also needs to focus on strategies to mitigate the opioid-P2Y12 inhibitor interaction and non-opioid analgesia to treat ischaemic chest pain.

Opioids and ST Elevation Myocardial Infarction: A Systematic Review.

BACKGROUND: Traditionally, opioids have been the analgesia of choice for patients with ST-Elevation Myocardial Infarction (STEMI). Recent studies, however, have raised the possibility of harmful effects of opioid administration through delayed onset of antiplatelet agents. OBJECTIVE: To perform a systematic review of the effects of parenteral opioids in patients presenting with STEMI. METHODS: Medical databases were systematically searched to 28 February 2018. Randomised control trials (RCTs) and observational studies were included if they interrogated the effects of parenteral opioids as compared to no opioid administration in STEMI patients. Outcomes included in-hospital, 30-day, one-year major adverse cardiac events (MACE) and platelet reactivity measures. The studies were evaluated using GRADE (Grade of Recommendation, Assessment, Development and Evaluation). RESULTS: One (1) RCT and 17 non-randomised, non-controlled observational studies were identified. The only RCT was of high quality, but only evaluated the pharmacokinetics of STEMI patients and had a small sample size. The remaining studies were of low-moderate quality, mainly due to eligibility criteria and confounding. Most studies report higher platelet reactivity with opioids, but clinical outcomes (MACE) were equivocal. CONCLUSION: This systematic review highlights the paucity of quality research evaluating the effect of opioids on its clinical and pharmacological effect on STEMI patients. Current literature indicates that opioids are associated with prolonged platelet reactivity. Whether this affects clinical outcomes remains to be established. Given the widespread use of opioids in STEMI, there is an urgent need for adequately powered trials investigating their safety.

Cardioversion of atrial fibrillation in obese patients: Results from the Cardioversion-BMI randomized controlled trial.

AIMS: Obesity is associated with higher electrical cardioversion (ECV) failure in persistent atrial fibrillation (PeAF). For ease-of-use, many centers prefer patches over paddles. We assessed the optimum modality and shock vector, as well as the safety and efficacy of the Manual Pressure Augmentation (MPA) technique. METHODS: Patients with obesity (BMI ≥ 30) and PeAF undergoing ECV using a biphasic defibrillator were randomized into one of four arms by modality (adhesive patches or handheld paddles) and shock vector (anteroposterior [AP] or anteroapical [AA]). If the first two shocks (100 and 200 J) failed, then patients received a 200-J shock using the alternative modality (patch or paddle). Shock vector remained unchanged. In an observational substudy, 20 patients with BMI of 35 or more, and who failed ECV at 200 J using both patches/paddles underwent a trial of MPA. RESULTS: In total, 125 patients were randomized between July 2016 and March 2018. First or second shock success was 43 of 63 (68.2%) for patches and 56 of 62 (90.3%) for paddles (P = 0.002). There were 20 crossovers from patches to paddles (12 of 20 third shock success with paddles) and six crossovers from paddles to patches (three of six third shock success with patches). Paddles successfully cardioverted 68 of 82 patients compared with 46 of 69 using patches (82.9% vs 66.7%; P = 0.02). Shock vector did not influence first or second shock success rates (82.0% AP vs 76.6% AA; P = 0.46). MPA was successful in 16 of 20 (80%) who failed in both (patches/paddles), with 360 J required in six of seven cases. CONCLUSION: Routine use of adhesive patches at 200 J is inadequate in obesity. Strategies that improve success include the use of paddles, MPA, and escalation to 360 J.