2 Minute Medicine Rewind August 14, 2023

Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality

1. This post hoc analysis of two phase 3 randomized trials found that the use of Esketamine (ESK) nasal spray in conjunction with a standard-of-care oral antidepressant was significantly more effective in achieving remission from major depressive disorder (MDD) symptoms and active suicidality. 

2. The ESK plus standard-of-care group was also able to achieve this remission a significantly quicker rate than the placebo plus standard-of-care group. 

Evidence Rating Level: 1 (Excellent)

MDD remains a leading cause of worldwide disability and is also the psychiatric condition most closely associated with risk of suicide. Given that typical antidepressant pharmacotherapies act within 4 to 6 weeks, there remains a need for faster-acting interventions in crisis situations. Esketamine nasal spray (ESK; also known as SPRAVATO®), is an enantiomer of ketamine and an N-methyl-D-aspartate (NMDA) receptor antagonist. It was recently approved for use as an adjunct to an oral antidepressant in acutely suicidal adults with MDD. In two recent clinical trials, it demonstrated the ability to reduce depressive symptoms within 24 hours, up to as early as 4 hours after the first dose. The current post hoc analysis assessed data pooled from the ASPIRE I and ASPIRE II double-blind randomized clinical trials to determine the time to and consistency of remission for those using ESK nasal spray plus a standard of care (SOC) oral antidepressant versus a placebo nasal spray with the SOC. In the original trial, patients were screened and randomized in phase 1 for MDD symptoms and suicidality, and then a 4-week treatment phase was followed by a 9-week post-treatment follow-up phase. Depressive symptoms were measured by the MADRS (Montgomery-Åsberg Depression Rating Scale) score, and the degree of suicidality was measured by the CGI-SS-r (Clinical Global Impression-Severity of Suicidality-revised). A total of 451 MDD-diagnosed patients (226 in the ESK group, 225 in the placebo group) who were actively suicidal within 24 hours were included. Time to remission of MDD was significantly reduced in patients treated with ESK (15 vs 23 days, respectively; p = .005), as was time to consistent MDD remission (remission on ≥ 2 consecutive visits; 23 vs 50 days; p = .007). The probability of achieving remission within 25 days was also higher in the ESK group (65.2%) compared to the placebo group (55.5%). Combined MDD remission and scores of ‘not suicidal’ or ‘questionably suicidal’ on the CGI-SS-r were also achieved significantly more quickly in the ESK group (17 vs 25 days; p = .003). By day 25 (end of double-blind treatment phase), 63.4% of the ESK group and 51.3% of the placebo group had achieved combined remission. At 90 days (post-follow-up phase), the cumulative probability of combined remission was 84.4% and 83.4% for ESK and placebo-treated patients, respectively. Time to consistent combined remission (remission of both suicidality and MDD symptoms on ≥ 2 consecutive visits) was 25 days for the ESK group and 52 days for the placebo group (p = .020). Lastly, during the 9-week follow-up phase (where patients received only an oral antidepressant), ESK patients demonstrated a median of 63.5% of their days in remission, compared to 38.1% of days for patients who originally received the placebo (p = .049). The results of this study point towards a possibly more effective and timely treatment option for patients experiencing MDD and active suicidality. This study should be replicated in an ad hoc manner in order to better elucidate the effects of ESK in this vulnerable population.

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial

1. This phase 2, single-arm, multicenter trial found that in HER2-positive breast cancer patients demonstrating resistance to trastuzumab, the combination of pyrotinib and capecitabine improved progression-free survival and objective response rates while maintaining an adequate safety profile. 

2. Results also indicate that different underlying mechanisms of trastuzumab resistance may impact disease progression and the response to treatment.

Evidence Rating Level: 1 (Excellent)

Approximately one-fifth of patients diagnosed with breast cancer are HER2-positive. Trastuzumab, also known as Herceptin, is a passive immunotherapy which, in this type of cancer, can significantly alter the course of the disease. However, a large proportion of breast cancer patients develop either primary resistance to the drug, which increases the risk of relapse, or earlier progression. There is some evidence that pan-HER tyrosine kinase inhibitors (TKIs) may be a solution to primary resistance to trastuzumab. Pyrotinib is one such irreversible pan-HER TKI, and capecitabine, an antimetabolite, has been shown to work synergistically with pyrotinib in advanced metastatic HER2-positive breast cancers. Thus, the current phase 2 trial investigated the efficacy of this combination in patients with primary trastuzumab-resistant HER2-positive breast cancer. A total of 100 patients from 16 clinical sites in China were enrolled in this single-arm trial. They received pyrotinib 400 milligrams per oral once daily and capecitabine 1000 mg/m2 orally twice daily for fourteen days in each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The standard of care in China in 2019 for trastuzumab-pretreated patients was trastuzumab plus vinorelbine, and the historical control median PFS was 5.78 months. The primary outcome, median PFS, was 11.8 months for the study group (95% CI 8.4-15.1). At the data cutoff date, 66 patients had either experienced disease progression or had died. The overall 1-year survival rate was 86.6%, but 25 deaths occurred over the course of the study. In a subgroup analysis of these primary trastuzumab-resistant patients, those who either had: rapid progression during adjuvant trastuzumab treatment (median PFS 8.2 months) or advanced disease within 6 months of initiating first-line trastuzumab (median PFS 5.6 months), had significantly lower median PFS than those who had progression within 12 months of completing adjuvant trastuzumab (median PFS 17.8 months; Ps < .05). All seven patients who achieved complete response to the treatment were from this latter subgroup. There were no differences in PFS between hormone receptor-positive versus negative patients (P = .765). Another 63 patients achieved a partial response to treatment. There was a disease control rate of 87% among all patients. From a safety perspective, 12 of the 100 patients required dose reductions of pyrotinib due to treatment-emergent adverse events (TEAEs), as did 37 patients requiring dose reductions of capecitabine. The most common TEAEs included diarrhea, palmar-plantar erythrodysesthesia syndrome, decreased neutrophil counts, hypokalemia, and anorexia. However, the combination of pyrotinib and capecitabine did not signal any new safety concerns and was well-tolerated relative to similar immunotherapies. The different subgroup median PFS’ could indicate underlying mechanisms of drug resistance which should be elucidated in future studies. 

Gestational Age and Birth Outcomes in Term Singleton Pregnancies Conceived With Infertility Treatment

1. This population-based cohort study is the first to establish an evidence-based recommendation of delivery at 39 weeks for females with pregnancies conceived via infertility treatments and ART. 

Evidence Rating Level: 2 (Good)

The proportion of females between the ages of 15 to 49 receiving infertility therapies has risen over recent years. Assisted reproductive technology (ART) more specifically, although useful, is also associated with the risk for low birth weight, perinatal mortality, and stillbirth. The lack of current recommendations surrounding timing of delivery in infertility-conceived pregnancies is what the current study sought to explore. This population-based retrospective cohort study analyzed data from 178,448 singleton infertility-conceived pregnancies in the US from 2014 to 2018. The study defined ‘risk of delivery’ as the collective rate of neonatal morbidity (Apgar score of ≤ 3 at 5 minutes, ventilation of ≥ 6 hours, seizure, or NICU admission) and infant death (within 1 year of life) in a gestational week per 10,000 deliveries. This was compared with the risk of delivery in the subsequent week, which included infant death and neonatal morbidity, plus the rate of stillbirths per 10,000 pregnancies in that subsequent week. Overall mortality and morbidity risk increased with advanced gestation. The rate of stillbirths per 10,000 pregnancies was lowest at 37 weeks and highest at 42 weeks gestation, a pattern observed regardless of type of infertility treatment. The rate of infant death per 10,000 live births was lowest at 39 weeks for infertility (6.2; 95% CI, 4.2-9.1) and ART-specific (5.2; 95% CI, 3.2-8.1) pregnancies. For both infertility and ART pregnancies, the overall risk of delivery at 39 weeks was significantly lower than risk of delivering in the subsequent gestational week (Infertility: 479 vs 599 per 10 000 live births; ART: 510 vs 664 per 10 000 live births). At 39 weeks, the combined mortality and morbidity relative risk (RR; 95% CIs) of delivery in the subsequent week of gestation exceeded the risk of delivering in the 39th week for both infertility (RR, 1.25; [95% CI, 1.19-1.31]) and ART (RR, 1.30; [95% CI, 1.22-1.39]). Mortality risk in infertility pregnancies was higher starting at 38 weeks gestation and later (38 weeks: RR, 1.72 [95% CI, 1.04-2.86]), whereas for ART pregnancies, this was the case at 39 weeks and later (RR, 2.24; [95% CI, 1.23-4.10]). A total of 128 infant deaths (representing 0.7% of the study population) and 248 stillbirths (representing 0.14% of the study population) were recorded. This cohort study is the first to provide comprehensive evidence for the recommendation of delivery at 39 weeks’ gestation for pregnancies conceived through infertility treatments, and findings also suggested a potentially increased risk for adverse outcomes both early-term as well as late-term in this population.

Effects of 30% vs. 60% inspired oxygen fraction during mechanical ventilation on postoperative atelectasis: a randomised controlled trial

1. In postoperative patients randomized to receive either 30% FiO2 and 60% FiO2 via mechanical ventilation while under general anesthesia, there was no difference in the incidence of postoperive alectasis between the two groups. 

Evidence Rating Level: 1 (Excellent)

A sizeable proportion of patients undergoing surgery with mechanical ventilation under general anesthesia develop postoperative atelectasis, which itself lends to longer hospital stays and increased 90-day mortality. The literature investigating which amount of inspired oxygen fraction (FiO2) is optimal for patients under general anesthesia has been conflicting. The current randomized controlled study investigated the effects of 30% versus 60% FiO2 without positive end-expiratory pressure (PEEP) and other recruitment maneuvers since most of the literature has either only compared very high FiO2 (80 to 100%) with low FiO2 (30 to 40%), or has made use of PEEP and recruitment maneuvers which may have interfered with the ability to infer causation about FiO2 use alone. A total of 120 patients undergoing neurosurgery were randomized into either the 60% or 30% FiO2 groups. They were also stratified by age (either < 60, or ≥ 60 years old). Patients would receive the same percentage of FiO2 after extubation and in the post-anesthesia care unit (PACU), and within half an hour of extubation, chest CTs were performed in order to measure postoperative atelectasis volume (as a % of total lung volume). A total of 113 patients (n = 55 in the 30% FiO2 group and n = 58 in the 60% FiO2 group) had their data analyzed. The overall incidence of postoperative atelectasis (representing > 1% of lung volume) in this study was 83.2%, but this was similar between both the 30% and 60% FiO2 groups. In addition to this, the percentage of postoperative atelectasis volume between the 30% and 60% FiO2 groups did not differ significantly (P = .121). There were also no significant differences between the groups with respect to over-aeration (P = .629), normal-aeration (P = .389), or poor-aeration volumes (P = .966). Overall, the results of this study suggest that a moderate FiO2 of 50-60%, which is more commonly used in the clinical environment, does not increase the risk for postoperative atelectasis. Future studies should elaborate on these results but also incorporate PEEP and recruitment maneuvers in order to understand best the implications of low and moderate FiO2 in a more realistic clinical environment.

Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates: A Secondary Analysis of the PENUT Randomized Clinical Trial

1. A secondary analysis of a randomized clinical trial found that when correcting for fluid balance, AKI was more commonly diagnosed in extremely premature neonates. 

2. A diagnosis of fluid-corrected AKI resulted in a significantly higher risk of requiring mechanical ventilation, longer hospital stay, and bronchopulmonary dysplasia (BPD).

Evidence Rating Level: 1 (Excellent)

Acute kidney injury (AKI) is a common condition in premature neonates, particularly those of extremely low gestational age. The potential complications of AKI do not exist solely in the short term; AKI in neonates also increases the risk of future chronic kidney disease. The diagnosis of AKI can be complicated and delayed by levels of fluid balance due to its effects on serum creatinine levels, and fluid imbalance is quite common in extremely low gestational age neonates. The current analysis sought to determine whether correcting for serum creatinine based on fluid balance would refine the diagnosis of AKI in neonates and alter AKI’s association with short-term and long-term outcomes. This post hoc cohort analysis of 923 premature neonates (born at < 28 weeks gestational age) was conducted using date from the Preterm Erythropoietin Neuroprotection trial (PENUT), conducted between 2013 to 2016 at several centers and neonatal intensive care units (NICUs) in the United States. Fluid-corrected serum creatinine was calculated based on change in weight from birth. Of the total study population, 23.3% (n = 215) neonates received a diagnosis of AKI when not correcting for serum creatinine, whereas after correction for fluid balance, 33.9% of neonates (n = 313) met criteria for fluid-corrected AKI; 13 neonates were no longer classified as having AKI after fluid correction and 111 neonates not previously diagnosed with AKI were found to have fluid-corrected AKI. There was 87% concordance in AKI diagnosis and 95% concordance in severe AKI diagnosis between the two methods of diagnosis. The vast majority of patients who went from no AKI to a fluid-corrected AKI were classified as Stage 1. Those who were newly diagnosed with fluid-corrected AKI were more likely to require mechanical ventilation than their non-AKI counterparts (75% versus 44.3%), had longer hospital stays (102 days versus 90 days). They were also more likely to experience severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). There were no associations found between either type of AKI diagnosis with long-term kidney outcomes, and there were no differences in mortality between these groups. Overall, this study reflects the importance of precision in the diagnosis of AKI in premature neonates, particularly due to the fluctuating nature of fluid balance in the early days and weeks of life.

Image: PD

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