2 Minute Medicine Rewind September 7, 2020

Timing of Oral P2Y12 Inhibitor Administration in Non-ST Elevation Acute Coronary Syndrome

1. There does not appear to be any difference in outcome between pre- and post-treatment administration of P2Y12 inhibitors among patients experiencing a non-ST elevation acute coronary syndrome with planned invasive intervention.

2. Prasugrel and ticagrelor showed similar outcomes when administered post-treatment.

Evidence Rating Level: 1 (Excellent)

Though it is well established that dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor – often prasugrel or ticagrelor – is standard of care in patients experiencing acute coronary syndrome (ACS), the optimal timing of administration is highly contested, especially among patients with non-ST elevation ACS (NSTE-ACS). The administration of prasugrel prior to performing coronary angiography and defining coronary anatomy (i.e. upstream / pre-treatment) may have advantages in theoretically preventing periprocedural thrombotic events, providing more ischemic protection and providing more time for the P2Y12 inhibitor to achieve full anti-platelet effects. However, this is currently not recommended due to an increased risk of bleeding; data for ticagrelor, however, are lacking. This multi-center, randomized trial assessed the efficacy and safety of upstream administration of ticagrelor compared with no pre-treatment and with administration of ticagrelor or prasugrel after defining coronary anatomy (i.e. downstream) among NSTE-ACS patients with planned invasive intervention. 711 patients (median [IQR] age = 64 [57-72] years, 25.3% female) were assigned to an upstream strategy of P2Y12 administration, while 721 patients (median [IQR] age = 65 [56-73] years, 23.6% female) were assigned to a downstream strategy. Among those assigned to the downstream strategy, patients were randomized 1:1 to receive either prasugrel or ticagrelor. The primary endpoint – death at 30 days due to vascular causes, non-fatal myocardial infarction, stroke, and significant bleeding – did not differ between the upstream and downstream groups (3.3% vs. 2.9%, ARR -0.46, 95% CI -2.87 to 1.89). Indeed, the trial was terminated early at the interim analysis in light of a probable futility scenario. Furthermore, when considering the downstream group, the primary endpoint did not differ significantly between patients treated with prasugrel and patients treated with ticagrelor (4.1% vs. 3.1%, ARR 0.9, 95% CI -3 to 5). In all, these findings suggest that both pre-treatment administration of ticagrelor and post-treatment administration of either ticagrelor or prasugrel show similar rates of major ischemic and bleeding events among NSTE-ACS patients with planned invasive intervention. Thus, there is, at this time, little evidence to favor one strategy over the other.


Angiotensin II Infusion for Shock: A Multicenter Study of Post-Marketing Use

1. The administration of angiotensin II among patients with refractory shock was associated with improved hemodynamic stability and decreased total vasopressor requirement at three hours.

Evidence Level Rating: 2 (Good)

Vasodilatory shock that is refractory to catecholamine- and arginine-based vasopressors is common in critical illness and associated with significant mortality, often exceeding 90%. The U.S. Food and Drug Administration and the European Medicines Agency recently approved the use of angiotensin II, a synthetic analogue of the endogenous human peptide that results in potent vasoconstriction and increased blood pressure. Though promising, there is a scarcity of data to provide insight into the drug’s applicability. This multicenter, retrospective observational study included 270 patients (mean [SD] age = 60 [15] years, 66% male) who received an angiotensin II infusion as part of their treatment. The primary outcome was hemodynamic responsiveness three hours following angiotensin II administration, defined by a mean arterial pressure (MAP) ≥ 65 mmHg with a stable or reduced total vasopressor dose. The study population was severely ill; mean APACHE II and SOFA scores among patients were 30±9 and 12±4, respectively, while baseline lactate concentration was 7.5±6.0 mmol/L. 67% of patients were classified as responders to angiotensin II, and exhibited a significantly greater increase in MAP (+10.3 vs. +1.6 mmHg, p < 0.001) and reduction in vasopressor requirement as measured in norepinephrine equivalents (-0.20 vs. +0.04 mcg/kg/min, p < 0.001) at three hours. Lower lactate concentration and active infusion of vasopressin at the time of angiotensin II administration were associated with significantly higher odds of responsiveness to angiotensin II. Furthermore, hemodynamic responsiveness was found to be associated with increased 30-day survival (41% vs. 25%, p = 0.001). The most common adverse effects noted among patients were transaminitis and thrombocytopenia. In all, this study showed that angiotensin II was associated with increased hemodynamic stability and decreased total vasopressor requirement among patients with refractory shock. More work is needed, however, to delineate optimal dosages and timing of administration in order to maximize patient outcomes.


Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents

1. Selective serotonin reuptake inhibitor use among children and adolescents with public health insurance was found to be associated with a mildly increased risk for the developed of type 2 diabetes mellitus.

2. The magnitude of this risk, overall, was substantially lower than that of other risk factors for the developed of type 2 diabetes mellitus.

Evidence Level Rating: 2 (Good)

Selective serotonin reuptake inhibitor (SSRI) use among children aged 10 to 14 and adolescents aged 15 to 19 is widespread, with estimates at 3.5% and 6.2%, respectively. An association between SSRI use and type 2 diabetes mellitus (T2DM) has been reported in several studies conducted among adults; there is, however, a paucity of data as it relates to children and adolescents. This retrospective cohort study involved 1,582,914 children and adolescents (mean [SD] age = 15.1 [2.3] years, 58.3% female) between the age of 10 and 19 with an indication for an SSRI, identified from two national databases: the Medicaid Analytic eXtract database, consisting of patients enrolled in Medicaid and Children’s Health Insurance Programs; and the IBM Market-Scan database, consisting of patients enrolled in private health insurance plans. Patients were followed until the first diagnosis of T2DM. Among patients with public health insurance, it was found that the initiation of SSRIs was associated with a mildly increased risk of developing T2DM after adjustment (aHR 1.13, 95% CI 1.04 to 1.22). If treatment was continuous, the magnitude of association increased mildly (aHR 1.33, 95% CI 1.21 to 1.47), corresponding to a number needed to harm of 1,515 if treated continuously for at least two years and 352 if treated continuously for at least five years. Among patients with private health insurance, there was no significant association between SSRI use and T2DM, even when used continuously. Within-class risk did not differ significantly by individual SSRI medication. Furthermore, bupropion use was not associated with an increased risk of T2DM. Overall, these data suggest that SSRI use among children and adolescents with public health insurance is associated with a mildly increased risk for the development of T2DM. This magnitude of this risk is low, much lower than other risk factors for T2DM, but should be kept in mind when weighing the pros and cons of initiating SSRIs among children and adolescents.


The survival benefit of low molecular weight heparin over unfractionated heparin in pediatric trauma patients

1. Among trauma patients aged 10 to 17, the use of low molecular weight heparin as compared with unfractionated heparin was associated with fewer episodes of venous thromboembolism as well as a reduction in mortality.

Evidence Level Rating: 2 (Good)

Low molecular weight heparin (LMWH) and unfractionated heparin (UFH) are the two most common prophylactic agents used to prevent venous thromboembolism (VTE) among trauma patients. Such prophylaxis is standard of care among adults, though its effectiveness and impact on survival is less well-studied among pediatric trauma patients. This retrospective cohort study included 3,934 pediatric trauma patients from the Pediatric American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) database who received either LMWH or UFH as pharmacological VTE prophylaxis. The primary outcomes were VTE events, including pulmonary embolism (PE) and deep vein thrombosis (DVT), and mortality. Among patients aged 0 to 9 (n = 477) there was found to be no significant difference in the incidence of DVT (p = 0.47) and PE (p = 0.31) or in the rate of mortality (p = 0.65). However, among patients aged 10 to 14 (n = 730), the incidence of DVT was significantly lower among patients receiving LMWH compared with UFH (1.6% vs. 5.2%, p = 0.02); the rate of mortality was also lower (1.6% vs. 4.8%, p = 0.04). Similar findings were observed among patients aged 15 to 17 (n = 2,599), with the incidence of DVT (1.2% vs. 3.1%, p = 0.03) and rate of mortality (1.2% vs. 2.9%, p = 0.04) lower among those treated with LMWH compared with UFH. Furthermore, among this age group, the incidence of PE was significantly lower (0% vs. 0.6%, p = 0.04). Finally, average hospital length of stay was found to be significantly lower among patients aged 10 to 17 treated with LMWH. These findings suggest that LMWH is a more favorable choice for VTE prophylaxis among pediatric trauma patients aged 10 to 17. Additional, prospective studies should be done to further elucidate this possible benefit.


Conditional risk of diverticulitis after non-operative management

1. Among patients managed without surgery, the conditional recurrence-free survival of diverticulitis increased with each year survived recurrence-free.

2. Lower age and higher comorbidity burden were both associated with an increased risk of recurrence.

Evidence Level Rating: 2 (Good)

Sigmoid diverticulitis is a very common gastrointestinal condition, and although the rate of occurrence is increasing in the U.S., the rate of emergent surgery as a means of treatment is decreasing. Recurrence of diverticulitis is one of the most important determinants of surgery; as such, a robust understanding of future risk is important for navigating surgical decision making. This retrospective cohort study involving 991 (median [IQR] age = 62 [50-73] years, 45.7% male) patients evaluated the conditional recurrence-free survival (RFS) after an initial episode of diverticulitis managed without surgery. Conditional RFS accounts for the dynamic nature of risk and does not assume that risk is static throughout the follow-up period. Among patients experiencing recurrence of diverticulitis, 76.7% occurred within the first two years of follow-up, and 53.1% occurred within the first year. It was found that one-year conditional RFS increased with each additional year survived recurrence-free, exceeding 95% for all subsequent years after surviving the first four years recurrence-free. Furthermore, at two years after the initial episode, lower age (HR 0.98, 95% CI 0.96 to 0.99) and Charlson Comorbidity Index (CCI) score of ≥ 2 (HR 2.41, 95% CI 1.30 to 4.46) were found to be associated with recurrence. While initially associated with recurrence at the time of the initial episode, immunosuppression was no longer associated with recurrence after two years (HR 1.02, 95% CI 0.50 to 2.09). In all, this study showed that conditional RFS of diverticulitis improved with each year survived recurrence free and identified specific risk factors associated with recurrence. These data have practical implications for clinical decision making; it can inform patients of their own risk of recurrence and aid in the process of shared decision making with regards to elective surgery for recurrent diverticulitis.


Image: PD

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