By Kevin Zhang, MD
Peer Reviewed
This last week saw yet another school shooting when a student in Texas opened fire on his classmates, killing 10, fueling the ongoing debate about our nation’s gun laws as well as skepticism that any meaningful action would be taken to prevent future tragedies[1]. Perhaps the most poignant comment in came from satirical news site The Onion who wrote, ‘No Way To Prevent This,’ Says Only Nation Where This Regularly Happens.
On the other side of the Atlantic, Meghan Markle and Prince Harry got married in a wedding that surprised many with its subtle feminism and influences from African-American culture. These gestures were interpreted by many as move toward a more inclusive and relevant monarchy[2].
At the same time, news broke that months before the 2016 election, the president’s son Donald Trump Jr. had met with an emissary for two wealthy Arab princes who offered to help his father’s campaign. This was the first indication that countries besides Russia may have assisted Trump’s campaign, and it has become a subject of interest in the investigation being led by Robert S. Mueller III[3].
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA
This was a large RCT of 4900 patients presenting with a minor stroke (NIHSS score of 3 or less) or high-risk TIA (ABCD2 score of 4 or more)[4]. They were predominantly older white Americans, many with hypertension, diabetes, and ischemic heart disease. They were exluded if imaging showed another explanation for their symptoms, if they were candidates for thrombolysis or invasive therapies, or if they were on DAPT for another reason. They were randomized to receive either aspirin with clopidogrel, or aspirin with placebo, for 90 days.
The primary outcome was a composite of ischemic stroke, MI, or death from ischemic vascular causes, and it was significant with a HR of 0.75 (95% CI 0.59-0.95). This outcome was driven by ischemic stroke which had a similar significant reduction to the primary outcome. The primary safety outcome was major hemorrhage, which was more common in the DAPT group, with a HR of 2.3 (95% CI 1.1-4.9). The number needed to treat to prevent one ischemic stroke was 6, while the number needed to harm for causing one hemorrhage was 20. The authors felt that most clinicians would consider this an acceptable tradeoff.
This study provided quality evidence that one should consider using clopidogrel with aspirin for short-term secondary prevention of stroke after a minor stroke or high risk TIA, though there would be a higher risk of hemorrhage. The study was limited by the low event rates and the exclusion of patients with more severe strokes or those who were candidates for thrombolysis.
MDMA-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers
This was a very small RCT that examined the safety and efficacy of MDMA in outpatient treatment of chronic, treatment-resistant PTSD[5]. The MDMA-induced state of positively-toned emotion and reduced fear is hypothesized to facilitate processing of traumatic material during therapy sessions, and the pro-social effects are thought to improve therapeutic alliance.
30 subjects were recruited and screened. They were included if they met DSM-IV criteria for treatment-resistant PTSD with a threshold CAPS score (a validated PTSD symptom scoring tool) and having already undergone treatment with psychotherapy and SSRI. They were excluded if they had most comorbid psychiatric disorders aside from anxiety, depression, and eating disorders, and if they had recent substance abuse. Ultimately 12 subjects were randomized to have therapy sessions with either full-dose MDMA or a low-dose “active placebo.” There was no true placebo because there was concern that blinding would otherwise be impossible as MDMA’s effects are obvious to both the user and observer.
The study showed no serious adverse events from the MDMA, and had a trend toward reduced CAPS scores in the treatment arm (24% reduction, narrowly missing significance at p = 0.07). This study had many limitations with its small size, lack of true placebo, poor blinding due to the effects of MDMA itself, and use of psychotherapy with uncertain standardization. Bottom line: MDMA is promising and likely safe in the treatment of PTSD, and further investigation (already underway) will hopefully answer questions about efficacy.
Intensified therapy with inhaled corticosteroids and long-acting beta-agonists at the onset of upper respiratory tract infection to prevent chronic obstructive pulmonary disease exacerbations
This RCT of patients with COPD looked at intensified ICS/LABA therapy at the onset of URI symptoms to see if it could prevent COPD exacerbations[6]. Older patients with significant smoking histories and a wide range of COPD severity were included. All participants were given an open-labeled low-dose ICS/LABA that was continued for the whole study. If they were already on a LAMA it was left unchanged. They were randomized to get a third inhaler, which contained either double-dose ICS/LABA, or placebo, and this inhaler was added to the existing regimen at the onset of URI (in other words, triple-dose vs. unchanged dose of ICS/LABA). They were then were followed for weeks after the URI, with COPD exacerbation as the primary endpoint and severity of exacerbation as a secondary endpoint.
The study did not find a significant difference in the overall number of COPD exacerbations between the treatment and placebo groups. However, there was an impressive reduction in severe exacerbations (i.e. hospital admissions) in the treatment group with HR of 0.28 (95% CI 0.11-0.74). There was also an impressive reduction in all COPD exacerbations in the subgroup of patients with more severe COPD (GOLD C or D), with a HR of 0.23 (95% CI 0.11-0.54).
This study provides solid evidence that instructing patients with severe COPD to their ICS/LABA inhalers at the onset of a URI can prevent COPD exacerbations and hospitalizations. This practice has appeal as a way for severe COPD patients to reduce their cumulative exposure to ICS (which is shown to increase pneumonia risk) by having lower baseline doses and escalating only when needed. The overall endpoint was not significant, but that was driven by the patients with less severe COPD who (under the new guidelines) should not be on an ICS/LABA inhaler anyway.
Risk of stroke and transient ischemic attack in patients with a diagnosis of resolved atrial fibrillation
This was a large retrospective case-control study investigating the stroke risk in patients with resolved atrial fibrillation[7]. It used data from UK-based primary care practices with coded data on patient characteristics and diagnoses. It compared a large group of patients with resolved AF, ongoing AF, and who never had AF. These conditions were defined purely by diagnostic codes entered in the patients’ charts. The patients were matched for baseline characteristics such as sex, age, wealth, comorbidities (which included prior CVA or TIA), and medication prescriptions (i.e. statins and anticoagulants).
The primary outcome was incidence of stroke or TIA; the secondary outcome was all-cause mortality. In a median follow-up of about 3 years, patients with resolved AF had strokes/TIA at an adjusted RR of 0.76 (95% CI 0.67 to 0.85) compared to those with ongoing AF. The more important finding was the comparison of resolved AF to the never AF group. Those with resolved AF still had an adjusted RR 1.63 (95% CI 1.46 to 1.84) of stroke/TIA compared to those who never had the condition.
This study provides moderate evidence that patients with resolved AF remain at substantially higher risk of stroke than patients who never had AF. This is important because current guidelines do not address the use of anticoagulation in these patients, and this study suggests that ongoing anticoagulation after resolution may have a role. This study did have significant limitations, namely its case-control design and reliance on clinical documentation codes for diagnoses.
MINICUTS
A meta-analysis of several RCTs that included 16,000 acutely ill patients who received either liberal or conservative supplemental oxygenation concluded that there was a significantly higher risk of death at 30 days in patients who received liberal oxygen[8].
Guidelines generally recommend delaying LP in patients on DAPT. This small retrospective study found that in 100 cases of patients who had LPs while on DAPT, they did not have adverse outcomes (including traumatic taps, or serious complications such as epidural hematoma) more commonly than patients not on DAPT, according to adverse outcome rates reported in prior literature[9].
This RCT compared aspirin and rivaroxaban for secondary prevention of embolic strokes when their origin was not known[10]. After nearly a year the rivaroxaban group had the same stroke rate but a higher bleeding rate, so the trial was stopped early.
A small RCT showed that for acute variceal bleeds, applying a hemostatic spray within the first two hours of presentation, plus usual therapy (including follow up elective endoscopy after 12-24 hours of pharmacotherapy) had less early and late rebleeding, and lower mortality at 30 days[11]. Hemostatic sprays were recently approved by the FDA for endoscopic use, though not for variceal bleeds; this study suggests that it should have an expanded role.
Dr. Kevin Zhang is aa PGY-3 Internal Medicine Resident at NYU Langone Health
Peer reviewed by Ian Henderson, MD, a Chief Resident in Internal Medicine at NYU Langone Health
Image courtesy of Wikimedia Commons
References
- Fernanez, Manny. “In Texas School Shooting, 10 Dead, 10 Hurt and Many Unsurprised”. NY Times 2018 May 18. https://nyti.ms/2Gus1cd.
- Barry, Ellen. “As Prince Harry and Meghan Markle Wed, a New Era Dawns”. NY Times 2018 May 19. https://nyti.ms/2IwdFd9.
- Mazzetti, Mark. “Trump Jr. and Other Aides Met With Gulf Emissary Offering Help to Win Election”. NY Times 2018 May 19. https://nyti.ms/2IV6EpU.
- Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018 May 16; [e-pub]. (https://doi.org/10.1056/NEJMoa1800410)
- Mithoefer MC et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: A randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry 2018 Apr 30; [e-pub]. (https://doi.org/10.1016/S2215-0366(18)30135-4)
- Stolz D et al. Intensified therapy with inhaled corticosteroids and long-acting β2-agonists at the onset of upper respiratory tract infection to prevent chronic obstructive pulmonary disease exacerbations. A multicenter, randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2018 May 1; 197:1136. (https://doi.org/10.1164/rccm.201709-1807OC)
- Adderley NJ et al. Risk of stroke and transient ischaemic attack in patients with a diagnosis of resolved atrial fibrillation: retrospective cohort studies. BMJ 2018 May 9; [e-pub]. (https://doi.org/10.1136/bmj.k1717)
- Chu DK et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): A systematic review and meta-analysis. Lancet 2018 Apr 28; 391:1693. (https://doi.org/10.1016/S0140-6736(18)30479-3)
- Carabenciov ID et al. Safety of lumbar puncture performed on dual antiplatelet therapy. Mayo Clin Proc 2018 May; 93:627. (https://doi.org/10.1016/j.mayocp.2018.02.005)
- Hart RG et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018 May 16; [e-pub]. (https://doi.org/10.1056/NEJMoa1802686)
- Ibrahim M et al. Early application of haemostatic powder added to standard management for oesophagogastric variceal bleeding: A randomised trial. Gut 2018 May 5; [e-pub]. (https://doi.org/10.1136/gutjnl-2017-314653)