2 Minute Medicine Rewind May 17, 2021

Cardiovascular safety of hydroxychloroquine in veterans with rheumatoid arthritis

1. Among a large, matched cohort of veterans with rheumatoid arthritis, initiation of hydroxychloroquine was not associated with a higher risk of adverse cardiovascular events or death.

Evidence Rating Level: 1 (Excellent)

In anecdotal case reports, hydroxychloroquine (HCQ) has been reported to prolong the QT interval, thus increasing the risk of arrhythmia and sudden cardiac death. This concern had been heightened in the recent past due to the brief, and now-revoked, authorization of HCQ for the treatment of COVID-19. Because HCQ is often used in the management of patients with rhematic diseases, this study sought to evaluate the safety of HCQ among veterans with rheumatoid arthritis (RA). A strategy that attempted to emulate the design of a randomized controlled trial was utilized, though ultimately the study was of a propensity score-matched cohort design. The primary outcomes were incident long QT syndrome (LQTS), arrhythmia-related hospitalization, and all-cause mortality. 4,426 veterans with RA treated with HCQ (mean [SD] age = 63.9 [12.0] years, 13.8% female) were matched with 4,426 veterans with RA treated with a disease-modifying antirheumatic drug (DMARD) other than HCQ (mean [SD] age = 63.9 [11.9] years, 14.2% female). There were found to be 3 LQTS events and 56 arrhythmia-related hospitalizations, of which 2 and 30, respectively, belonged to the HCQ cohort. Finally, all-cause mortality occurred in 144 and 136 veterans in the HCQ and non-HCQ cohorts, respectively (HR 1.16, 95% CI 0.68 to 1.95). In all, initiation of HCQ for the treatment of RA was found to be safe and not associated with increased all-cause mortality. Furthermore, this study demonstrates that the incidence of LQTS is extremely low, and not heightened by administration of HCQ, at least in this particular cohort.


A multi-center evaluation of probiotic use for the primary prevention of clostridioides difficile infection

1. The administration of probiotics to high-risk inpatients receiving antibiotics identified by computerized clinical decision support was not shown to decrease the incidence of Clostridioides difficile infection.

Evidence Level Rating: 2 (Good)

Clostridioides difficile infection (CDI) is prevalent in the U.S. and produces substantial morbidity and mortality. Meta-analyses have suggested that the ingestion of probiotics during antibiotic therapy helps reduce the risk of CDI. This study evaluated the efficacy of using computerized clinical decision support (CCDS) at a large health care facility to reduce the risk of CDI by identifying high-risk patients who might benefit from primary prevention with probiotics. Patients were analyzed during a 13-month baseline period and a subsequent 13-month intervention period. Hospital-onset CDI before and after the probiotic intervention was assessed, as was a patient-level analysis among patients in the post-intervention cohort, examining CDI risk between patients who received probiotics compared with those who did not. In the hospital-level analysis, there was shown to be a pre-intervention decrease in CDI with a significant immediate decrease, but followed by a gradual increase, post-intervention (change in slope 1.4 per 10,000 patient days, p = 0.001). In the patient-level analysis, 132 and 153 patients had CDI in the pre- and post-intervention cohorts, respectively, corresponding to a 1.4-fold increased risk of CDI (95% CI 1.13 to 1.84, p = 0.003) in the post-intervention cohort after controlling for confounders. Finally, patients in receipt of probiotics were not shown to have lower rates of CDI compared with those who did not receive probiotics (OR 1.46, 95% CI 0.87 to 2.45). In all, CCDS-facilitated probiotic use for the primary prevention of CDI was not found to be effective in this cohort, with higher rates of CDI seen in the post-intervention period as well as a higher, though not significant, risk of CDI among patients receiving probiotics.


Fortification of breast milk with preterm formula powder vs human milk fortifier in preterm neonates: a randomized noninferiority trial

1. Fortification of expressed breast milk with preterm formula was found to be non-inferior to human milk fortifier with regards to short-term weight gain among preterm neonates.

Evidence Level Rating: 1 (Excellent)

Because expressed breast milk (EBM) is not sufficient to meet the high nutrient requirements of preterm neonates, many countries, especially low- and low-middle income countries, fortify it with human milk fortifiers (HMF). However, the prohibitively high cost and adverse effects of HMF limit its utility in resource-poor settings; as such, this study tested the hypothesis that fortification of EBM with preterm formula (PTF) is safer, more economical, and potentially a viable alternative. The study was conducted in Delhi, India, and neonates born at or before 34 weeks of gestation with a birth weight less than 1500 g were eligible. The primary outcome was the rate of in-hospital weight gain measured as gram per kilogram per day from the date of randomization to the day of discharge or 40 weeks postmenstrual age, whichever was earlier. 59 neonates were randomized to receive PTF fortification and 63 to receive HMF. The mean weight gain from the time of fortification until hospital discharge was 15.7±3.9 and 16.3±4.0 g/kg/d in the PTF and HMF cohorts, respectively (mean difference -0.5 g/kg/d, 95% CI -1.9 to 0.7). The lower bound of the 95% CI did not cross the prespecified noninferiority margin of 2 g/kg/d; thus, noninferiority of PTF was established. The gain in length and head circumference between the two cohorts was comparable. Additionally, the incidence of feeding intolerance among neonates in the PTF cohort was significantly lower (1.4 vs. 6.8 per 1,000 patient days, IRR 0.19, 95% CI 0.04 to 0.95). There was no difference in the rate of adverse outcomes like incident mortality or sepsis between the two cohorts. Overall, this study demonstrates that PTF is noninferior to commercial HMF with regards to short-term weight gain and growth and may be a more economical alternative.


Primary trabeculectomy for advanced glaucoma: pragmatic multicentre randomised controlled trial (TAGS)

1. At 24 months, visual quality of life for patients with advanced open angle glaucoma was similar if treated initially with trabeculectomy or with medical management.

Evidence Level Rating: 1 (Excellent)

Glaucoma is one of the leading causes of blindness in the U.S., and the incidence is increasing due to an aging population. Open angle glaucoma in particular is difficult to manage, with some practitioners opting for trabeculectomy as a primary intervention, though there are a paucity of robust data to support this, especially among patients presenting with advanced disease. This multicenter, randomized controlled trial compared primary medical management with primary trabeculectomy for patients presenting with untreated open angle glaucoma. The primary outcome was quality of life as measured by the Visual Function Questionnaire-25 (VFQ-25) at 24 months. 227 patients were randomized to undergo trabeculectomy (mean [SD] age = 67 [12.2] years, 69% male) and 226 to receive medical management (mean [SD] age = 68 [12.4] years, 65% male). It was found that, at 24 months, there was no significant difference in mean VFQ-25 scores between the trabeculectomy and medical management cohorts (85.4±13.8 vs. 84.5±16.3, mean difference 1.06, 95% CI -1.32 to 3.34, p = 0.38). The mean intraocular pressure, however, was significantly lower in the trabeculectomy cohort. Adverse events were similar between the two cohorts. In all, no difference between trabeculectomy and medical management for the treatment of advanced open angle glaucoma was seen. Surgery was safe and effective at reducing intraocular pressure. Such findings will help guide decision making for patients presenting with advanced disease.


Maternal weight gain and pregnancy outcomes in twin gestations

1. In a large cohort of women with twin gestations, gestational weight gain very often falls outside of established recommendations, contributing to adverse outcomes like preterm birth.

Evidence Level Rating: 2 (Good)

Pre-pregnancy BMI and gestational weight gain (GWG) are important determinants of pregnancy outcomes, with adverse effects seen in both insufficient and excessive weight gain. With regards to twin gestations, there are limited data as to the optimal range of GWG; as such, the Institute of Medicine (IOM) provides only provisional guidelines concerning GWG. This retrospective cohort study spanning 17 years sought to both clarify the recommendations from the IOM and delineate optimal GWG in twin gestations. 1,274 women met study inclusion criteria, with 247 included in the low-risk cohort (i.e. those with no risk factors and normal outcomes) and 1,027 in the high-risk cohort. Of those included for analysis, 43 were underweight, 777 were of normal weight, 278 were overweight, and 176 were obese. The primary outcome was preterm birth. It was found that almost half of the women in this cohort gained weight above or below current IOM recommendations. Low GWG was found to be associated with an increased risk of preterm birth and birthweight < 10th percentile, especially among women in the normal weight and obese cohorts. However, there was a reduction in the incidence of hypertensive disorders among these women. For those experiencing high GWG, there was an increased risk of hypertensive disorders but a reduction in the risk of birthweight < 10th percentile. Finally, for the obese cohort, the estimation of optimal GWG at 37 weeks of 9.3 to 16.3 kg appears to be more predictive of adverse outcomes than the IOM recommendation of 11.3 to 19.1 kg. These findings highlight GWG as a modifiable risk factor for adverse outcomes in twin gestations. Further, prospective studies are needed to optimize current recommendations to further enhance future outcomes.

Image: PD

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