By Jonathan Whitehouse, MD
Peer Reviewed
In New York last week, Mayor de Blasio announced a plan to tax wealthy New Yorkers in order to raise funds for our enfeebled subway system. It was seen by many as a direct political clash with Governor Cuomo over funding for the Metropolitan Transportation Authority, at a time when the subways are plagued by delays and cancellations, and when both politicians are preparing for elections (1). Other well-documented problems include an “antiquated signal system, severe overcrowding, and trains that are breaking down at a much higher rate than in the past” (2). Local politicians recently participated in the two-day Riders Respond tour of the subways, interviewing and welcoming input from New York’s subway commuters. The consistent theme from riders was dismay over the political posturing between the governor and mayor, as well as a plea to attenuate the intolerable summer heat of the subway platforms (3).
MTA’s sweltering platforms are unlikely to cool off anytime soon, at least without major policy changes by the federal government. That’s the implication of a sweeping federal climate change report drafted by scientists from 13 federal agencies that reported that the average temperature in the United States has risen rapidly and drastically since 1980, concluding that that human activities, particularly greenhouse gas emissions, are primarily responsible for observed climate change. The authors are awaiting permission from the Trump administration for official release of the report, although those involved would not be shocked if the report is changed or suppressed (4).
Speaking of shock, kicking off this edition of Primecuts we’ll be looking at a trial evaluating the use of angiotensin II in the treatment of vasodilatory shock, followed by studies on the effect of methylprednisolone in the treatment of IgA nephropathy, the effect of exenatide in the treatment of Parkinson’s disease, and the predictive role of bio-active adrenomedullin in sepsis.
Angiotensin II for the Treatment of Vasodilatory Shock
The most common type of shock is vasodilatory shock, which is characterized by peripheral vasodilatation leading to reduced blood pressure in the setting of preserved cardiac output. First line therapy to restore blood pressure is intravenous fluid resuscitation, followed by two classes of vasopressors: catecholamines and vasopressin. While effective, these medications have narrow therapeutic windows, as they can be toxic at higher doses. Our bodies, however, also employ the renin-angiotensin-aldosterone system to increase blood pressure in vasodilatory shock. In this week’s NEJM, investigators sought to determine whether the addition of angiotensin II would improve blood pressure in patients with vasodilatory shock refractory to standard therapies (5).
In this multi-national, double-blind, randomized, controlled trial, a total of 344 patients with vasodilatory shock already receiving conventional vasopressor support were assigned to either receive intravenous angiotensin II or placebo. The primary endpoint was an increase in mean arterial pressure at 3 hours (either 10 mm Hg above baseline, or with an increase to at least 75 mm Hg); background vasopressors were not changed.
More patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) reached the primary endpoint; the odds ratio was 7.95 (95% CI, 4.76 to 13.3, p < 0.001). There was no statistically significant difference in the rate of adverse events between groups.
The study demonstrated that angiotensin II effectively raised blood pressure in patients with vasodilatory shock. Limitations include a relatively small sample size, opening the possibly that clinically important side effects attributable to angiotensin may not have been detected. Additionally, follow-up was limited to 28 days, prohibiting analysis of potential long-term effects of angiotensin II. Finally, the study was not powered to demonstrate a difference in mortality.
The introduction of a new class of vasopressors is certainly exciting, especially one designed to mimic a natural physiological response to hypotension. Will the addition of angiotensin II lead to better outcomes in vasodilatory shock? The current evidence is at least promising, and further investigations and direct comparisons are certainly on the horizon.
Effect of Oral Methylprednisolone on Clinical Outcomes in Patients with IgA Nephropathy
The most prevalent primary glomerular disease is IgA nephropathy. Patients with the disorder have an elevated risk of developing end stage renal disease (ESRD) and are typically treated with blockade of the renin-angiotensin-aldosterone system (RAAS) to prevent or slow disease progression. Current guidelines also recommend a 6-month course of corticosteroids for patients with persistent proteinuria and reduced GFR, although this recommendation is based on low-quality evidence, and the benefit of corticosteroid therapy has been considered uncertain. In the most recent edition of JAMA, investigators sought to evaluate the efficacy and safety of full-dose corticosteroid therapy (6).
The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multi-center, double-blind, randomized clinical trial that recruited 750 patients with IgA nephropathy. Those included had proteinuria greater than 1 g/d and an estimated glomerular filtration rate (eGFR) of 20-120 after at least 3 months of blood pressure control with RASS blockade. Patients were randomized to either oral methylprednisolone (0.6 to 0.8 mg/kg/d) or to placebo for two months followed by a 4-6 month weaning period. The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR.
Recruitment was discontinued after a median follow-up of 2.1 years, after observation of an increased rate of serious adverse events in the intervention group. Serious events occurred in 20 participants in the methylprednisolone group (14.7%) vs 4 in the placebo group (3.2%; p <0.001). Most occurred in the first three months of treatment and were due to serious infections.
Over this time, the primary composite renal outcome occurred in 8 patients in the methylprednisolone group (5.9%) and 20 patients in the placebo group (15.9%; hazard ratio 0.37; p = 0.02).
While proteinuria and eGFR improved in participants randomized to receive methylprednisolone, the high rates infections suggests a need for reconsideration of current guidelines. However, as IgA nephropathy is an immune-complex mediated disease, immune suppression with corticosteroids still holds promise as a valuable therapeutic option. As these authors suggest, future research into the use of corticosteroids combined with prophylactic antibiotics seems an appropriate next investigatory step.
Exenatide once weekly versus placebo in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial
The diabetes drug exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist which increases glucose-level-dependent insulin secretion, decreases glucagon secretion, and delays gastric emptying (7). Previous Parkinson’s research in murine models has demonstrated that exenatide has led to improvements in motor performance, behavior, learning, and memory through unclear mechanisms. In the most recent edition of The Lancet, investigators published a trial further studying the effects of exenatide on the motor-associated symptoms of Parkinson’s disease (7).
In a single-center, randomized double-blind, placebo-controlled trial, 62 patients with moderate Parkinson’s disease were randomly assigned to receive subcutaneous injections of exenatide or placebo weekly for 48 weeks in addition to their regular medication. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Motor Sub-scale (MDS-UPDRS) at 60 weeks.
In the exenatide group MDS-UPDRS scores improved by 1.0 point, and in the placebo group scores worsened by 2.1 points, an adjusted mean difference of -3.5 points (CI -6.7 to -0.3; p = 0.03). There were not significant differences noted in assessments of cognition, mood, dyskinesia, non-motor symptoms, or quality of life. Frequency and severity of adverse events also did not differ significantly between the two groups.
This trial is a milestone in Parkinson’s research. Remarkably, exenatide leads to improvement in motor symptoms even 12 weeks after its last administration. Whether this represents an enduring effect on disease progression is yet to be determined. Regardless, this is an encouraging example of drug repurposing, a strategy which is increasingly being used by pharmaceutical companies.
Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis
Adrenomedullin (ADM) is a 52-amino acid peptide that has been associated with several disease processes (8). In addition to the increased circulating levels associated with myocardial injury, shock, cellular hypoxia, and oxidative stress, significantly increased levels of ADM have been reported in patients with sepsis. Its exact role in sepsis is unclear. In cell culture models, it’s been shown to reduce endothelial hyperpermeability and vascular leakage, and exogenous administration has been demonstrated as protective in animal models. However, at higher levels of ADM are associated with worse patient outcomes, and administration of anti-ADM antibodies has mitigated sepsis-induced multi-organ failure in rodent models (8).
Until recently, ADM has been considered an unreliable biomarker, because several fragments of the precursor pro-hormone circulate which don’t necessarily reflect its activity. However, an immunoassay that specially measures the biologically active form of ADM (bio-ADM) has been developed that has already been shown to be predictive of clinically relevant outcomes in acute heart failure. In this month’s edition of CHEST, investigators sought to describe the relationship between bio-ADM and outcomes in patients with sepsis (8).
As a subset of the Albumin Italian Outcome Sepsis (ALBIOS) multi-center, open-label, randomized trial, 956 patients with severe sepsis or septic shock were recruited from 40 ICUs to participate in the bio-ADM study. Venous blood was collected 1, 2, and 7 days after enrollment, or upon discharge.
As expected, authors found that plasma concentration of bio-ADM was high, particularly in patients with septic shock. Interestingly, higher bio-ADM levels predicted the degree of hemodynamic support treatments, organ failure and shock. The trend of bio-ADM levels during the first week of treatment predicted 90-day mortality (HR [95% CI], 1.3 [1.2-1.4]; P < .0001), and its reduction below 110 pg/mL on the 7th day was associated with reduced 90-day mortality.
Will physicians in our ICUs be ordering bio-ADM levels on our septic patients in the future? While this study didn’t elucidate the mechanistic roles of ADM in sepsis, it clearly has a significant role in the pathophysiology of severe sepsis and septic shock. However, additional studies will be necessary to demonstrate whether it has a role individualizing therapies.
Minicuts:
Childhood intelligence and adult disease
A cohort study with a 68-year follow-up published in the BMJ found that higher scores on a childhood intelligence test were associated with lower risk of mortality ascribed to coronary heart disease and stroke, cancers related to smoking, respiratory diseases, digestive diseases, injury, and dementia (9).
Expanding the role of non-specialists in Hepatitis C treatment
A non-randomized clinical trial published in the Annals of Internal Medicine found that Hepatitis C treatment with ledipasvir-sofosbuvir by non-specialist providers was as safe and effective as that provided by specialists, suggesting that PCPs and NPs could substantially expand the availability of community-based provision of Hepatitis C therapy (10).
Neuroimaging and borderline personality disorder
A cohort study published in JAMA Psychiatry last week examined the use of 2-person neuroimaging to compare neural coupling (a stereotypical activation of cortical areas which occurs during face to face interactions) between pairs of healthy controls and patients with borderline personality disorder (BPD). Neuro coupling between the pairs that included a participant with BPD was significantly lower than in the healthy pairs, suggesting a role for new quantifiable markers in the study of a disorder that’s been historically difficult to measure and treat (11).
Dr. Jonathan Whitehouse is a NYU Langone Health
Peer Reviewed by Dr. Daniel Taupin, Inpatient Chief Resident, NYU Internal Medicine Residency Program at NYU Langone Health
Image courtesy of Wikimedia Commons
References
- Goodman D. De Blasio’s Push for Tax on Wealthy Helps Put Pressure on Cuomo. The New York Times. August 7 2017, pg A18. https://www.nytimes.com/2017/08/07/nyregion/de-blasio-push-tax-on-wealthy-fix-subway.html?rref=collection%2Fsectioncollection%2Fnyregion&action=click&contentCollection=nyregion®ion=rank&module=package&version=highlights&contentPlacement=5&pgtype=sectionfront
- Fessenden F, Fitzsimmons E, Lai R, Pearce A. New York’s Subway Are Not Just Delayed. Some Trains Don’t Run at All. The New York Times, August 7, 2017. https://www.nytimes.com/interactive/2017/08/07/nyregion/new-yorks-subways-are-not-just-delayed-some-trains-dont-run-at-all.html?rref=collection%2Fsectioncollection%2Fnyregion&action=click&contentCollection=nyregion®ion=rank&module=package&version=highlights&contentPlacement=1&pgtype=sectionfront
- Nessen, S. All aboard the 24-Hour Subway Listening Tour. WYNC Radio, August 3, 2017. http://www.wnyc.org/story/24-hour-subway-listening-tour/
- Friedman, L. Government Report Finds Drastic Impact of Climate Change in the U.S. The New York Times, August 8th, 2017, Page A1. https://www.nytimes.com/2017/08/07/climate/climate-change-drastic-warming-trump.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=first-column-region®ion=top-news&WT.nav=top-news
- Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. New England Journal of Medicine 2017;377:419-30. http://www.nejm.org/doi/full/10.1056/NEJMoa1704154
- Lv J, Zhang H, Wong M, et al. Effect of oral methylprednisolone on clinical outcomes in patients with iga nephropathy: The testing randomized clinical trial. JAMA 2017;318:432-42. http://jamanetwork.com/journals/jama/article-abstract/2646717
- Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. The Lancet 2017; pii: S0140-6736(17)31585-4. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31585-4/fulltext
- Caironi P, Latini R, Struck J, et al. Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis. Chest 2017;152:312-20. http://journal.chestnet.org/article/S0012-3692(17)30704-3/fulltext
- Calvin CM, Batty GD, Der G, et al. Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study. BMJ (Clinical research ed) 2017;357:j2708. http://www.bmj.com/content/357/bmj.j2708
- Kattakuzhy S, Gross C, Emmanuel B, et al. Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial. Annals of internal medicine 2017. [Epub ahead of print 8 August 2017] http://annals.org/aim/article/2647669/expansion-treatment-hepatitis-c-virus-infection-task-shifting-community-based
- Bilek E, Stossel G, Schafer A, et al. State-Dependent Cross-Brain Information Flow in Borderline Personality Disorder. JAMA psychiatry 2017. [Epub ahead of print 2 August 2017] http://jamanetwork.com/journals/jamapsychiatry/article-abstract/2646393