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Issue 39

Appetizers (to whet your appetite) 
Palate Cleanser (aka the melon part of the meal) 
The Main Course
A Digestif or two 


Jennifer Desalvo MD; Alyssa Mancini MD; Hannah Smith MD 


Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels.
  • Severe CAP: Another space for steroids? This multicenter double-blind phase 3 trial in NEJM randomized 800 ICU patients with severe community acquired pneumonia (CAP) to receive intravenous hydrocortisone (200 mg daily for either 4 or 8 days, duration determined by clinical improvement, followed by a taper) or placebo, in addition to standard therapy including antibiotics and supportive care. Those treated with steroids had a significantly lower risk of death by 28 days than those who received placebo (death in 6.2% with hydrocortisone versus 11.9% with placebo), and also lower rates of death within 90 days, initiation of ventilation, and initiation of vasopressors. There were no differences in rates of  hospital-acquired infection or gastrointestinal bleeding, though those receiving steroids did have higher insulin requirements. (JD) 

  • Can’t stop the bleeding (cue Justin Timberlake) – In the PROCOAG multicenter randomized controlled clinical trial published in JAMA, over 300 trauma patients at high risk of requiring massive transfusion protocols were randomized to receive 4-factor prothrombin complex concentrate (4F-PCC) or placebo. There was no difference in total 24-hour blood product consumption among patients treated with 4F-PCC (12 U) versus placebo (11 U), with more thromboembolic events occurring in the 4F-PCC group. More studies are needed to further optimize the management of trauma patients with hemorrhage and trauma-induced coagulopathy. (JD)

  • The Coffee Trials Continue. In a prospective, randomized, case-crossover trial in NEJM, researchers assessed the effects of caffeinated coffee on cardiac arrhythmia, step count, and sleep in 100 adults via continuous electrocardiogram, blood glucose monitors, and Fitbits. For alternating 2-day periods over two weeks, participants were randomly assigned to receive text message instructions to consume caffeinated coffee or to avoid caffeine. Coffee consumption was associated with a higher daily premature ventricular contraction burden (154 versus 102), a higher step count (10,646 versus 9665), and fewer sleep minutes (397 versus 432) compared to no consumption--but there was no difference in the number of premature atrial contractions or serum glucose levels. (HS) 

  • For frail older adults with non-ST-segment elevation myocardial infarction (NSTEMI), less is more? In this Spanish multicenter randomized trial published in JAMA Internal Medicine, 167 older adults (mean age 86) with frailty and NSTEMI were randomized to a routine invasive (coronary angiography and revascularization if feasible) or conservative (medical treatment with coronary angiography for recurrent ischemia) strategy.  A routine invasive strategy did not significantly increase the number of days alive and out of the hospital over 1 year, when compared to a conservative strategy–with a numerical but not statistically significant increase for those treated conservatively. There were also no significant differences in ischemic cardiac events or all-cause mortality.  Of note, the study was prematurely stopped due to the COVID-19 pandemic after 95% of intended enrollment. (AM) 

  • Hydrocortisone with a side of fludrocortisone for septic shock.  JAMA Internal Medicine recently published a retrospective cohort study of claims data from >88,000 adults hospitalized with septic shock receiving norepinephrine and either hydrocortisone + fludrocortisone (started on the same calendar day) or hydrocortisone alone.  The composite outcome of hospital death or discharge to hospice occurred among 47.2% of patients treated with hydrocortisone + fludrocortisone, compared to 50.8% of patients treated with hydrocortisone alone. Though guidelines still recommend hydrocortisone alone, this study adds to the prior COIITSS trial data suggesting a benefit of adding fludrocortisone to hydrocortisone for patients with septic shock. (AM) 


Palate Cleanser 

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

Kate Grant MBChB, DipGUMed

The Main Course

Alexander Chaitoff MD MPH 


Treating Depression in Older Adults


Depression affects over 21 million adults in the United States each year.  Yet the American Psychiatric Association has not updated its guidelines for the treatment of Major Depressive Disorder since 2010, despite two updates to the definition of depression (in the DSM V and DSM V-TR) in that same period.  Equally troubling is the lack of specific guidance for treating depression in older adults, in whom both depression itself and the pharmacologic treatments for the disease are associated with poorer outcomes.  The complexity increases when first-line therapy fails and clinicians must weigh the risks of next steps – augment with additional agents but add to polypharmacy, or switch to a new medication?  While there are guidelines from Canada about approaching this challenge, those mostly extrapolate from studies conducted in younger adults.

Fortunately, in March 2023, the OPTIMUM trial was published, assessing the risks and benefits of augmenting versus switching antidepressants in older adults with treatment-resistant depression that did not respond to initial pharmacotherapy.  However, before diving into those results, it’s important to understand the foundation upon which OPTIMUM is built – STAR*D and VAST-D.

Breaking Down The Depression Trials 

STAR*D is the most cited evidence for depression treatment algorithms.  The trial included around 4000 patients with depression, treated with citalopram. Those with an inadequate response could choose to either switch to an SSRI/SNRI/bupropion or augment citalopram with bupropion on buspirone, and were randomized to an option within the category they chose.  If neither strategy worked, participants were again randomized to switch or augment their medications with other medications.  In STAR*D, a third of participants achieved remission with citalopram, and all medications in both the switch and augment groups led to additional gains in remission.  However, this trial had a glaring limitation – patients chose whether they would switch or augment therapy, thus limiting its ability to identify which strategy was best.

With this limitation in mind, the VAST-D trial evaluated 1522 patients with treatment resistant depression already on an SSRI, SNRI, or mirtazapine and randomized them to one of three-arms: 1) switch to bupropion, 2) augment with aripiprazole, or 3) augment with bupropion.  Participants who augmented with aripiprazole were slightly more likely to achieve remission compared with those who switched to bupropion (28.9% versus 22.3%, p=0.02), with no apparent difference between augmenting with aripiprazole versus bupropion.  Enrolling patients through the Veterans Health Administration, trial limitations included its mostly male (85%) and younger (mean age 54) population. 

Enter OPTIMUM, which randomized 619 adults over sixty with treatment-resistant depression to 1) augmentation of existing antidepressant medication with aripiprazole, 2) augmentation with bupropion, or 3) a switch to bupropion.  The results largely mirrored what was seen in VAST-D: those randomized to augmentation with aripiprazole had better well-being scores than those who switched to bupropion (difference in well-being score of 2.79 points, 95% CI 0.56 - 5.02, p 0.014), and a numerically higher incidence of remission.  Patients who did not experience benefit were then randomized again to augmentation with lithium or switch to nortriptyline, which were both equally effective.  While limited by some imbalance in baseline covariates (e.g. the augment-aripiprazole had higher PHQ9 scores) and an open-label design, the results still provide useful information specific to older adults.  And notably, falls, which are typically associated with antipsychotic use, were actually highest in the augment-with-bupropion group, not with aripiprazole. 

STAR*D, VAST-D, and OPTIMUM – what’s the takeaway? 

As we wait for updated guidelines, it appears that in treatment-resistant depression, augmenting baseline antidepressant therapy is safe and more effective than switching agents, even in older adults.  Aripiprazole may be a particularly attractive option, with a lower fall risk than other augmentation options–though we still need to be cognizant of polypharmacy and its contributions to morbidity in elderly patients.  At the end of the day, also remember that there is a new nation-wide suicide and crisis lifeline telephone number – 988 – that’s available for all!


Read the Paper Here




Before you go....
we’ve got a few nibbles!

Consolidate your learning with a Quiz

This week on Curbsiders: In our exquisitely high-yield Episode #388, we explore the best practices of managing HIV in the primary care setting–from health care maintenance to medication interactions to co-infections and CD4 counts–with Dr. JJ Nunez.

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest
Issue 39

Editor in Chief: Nora Taranto MD
Banner: Kate Grant  MBChB, DipGUMed


Hannah Smith, Alyssa Mancini, Jennifer Desalvo, and Nora Taranto report no disclosures. 

Alex Chaitoff reports consultancy for Alosa Health 

Kate Grant reports no disclosures 



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