Primecuts – This Week In The Journals

By Benjamin Geisler, MD MPH

Peer reviewed

With the first Ebola patient being treated in the New York City area in one of our own training institutions, the viral disease is, understandably, on all our minds. Now a week and a half ago, Bellevue’s atrium was the setting for a press conference that featured the mayor, the city’s health commissioner, and the governor. Since then, the governors of New York, New Jersey, and Maine have instituted a quarantine for returning health care workers from the Ebola-ridden parts of West Africa. This move has been opposed by many in the clinical and scientific communities – including the head of the National Institute of Allergy and Infectious Diseases, Dr. Anthony Fauci. The concern is that a quarantine will make health care workers less likely to volunteer for work trips to West Africa, although it is also conceivable that the associated stigma outweighs the actual quarantine.

Last week’s New England Journal featured a case report[1] of Ebola in a 36-year old male W.H.O. epidemiologist who contracted the disease in Sierra Leone but was treated in Germany. Unique about this article was that it contained a significant amount of data from the patient’s course, which has not been routinely available from patients in previous outbreaks. What stood out from this article was the quantity of intravenous fluids the patient received (about ten liters daily in the first three days) and that the patient was found to have an extended spectrum beta-lactamase-containing organism in their blood, which may have been a hospital-acquired infection as he had received third-generation cephalosporins even before being airlifted or, as speculated in the article, from gut translocation. Other notable components of the patient’s course of illness were diffuse volume overload, respiratory failure from unclear etiology, gastroparesis and ileus, thrombocytopenia, and encephalopathy. In addition the patient was found to have Ebola virus RNA in his urine and semen.

While the patient described in this case did not receive any experimental therapies, Ebola patients in other developed countries continue to be treated with Ebola survivors’ plasma (“convalescent serum” – unclear if it contains coagulation factors) in the hopes that these patients developed antibodies against Ebola structures. Some have argued that the serum needed to be given at the very beginning of the symptomatic period to make a difference. Further, it is unclear whether this is a feasible strategy to be employed in West Africa given the lack of infrastructure including cold storage and blood banks. It is also likely that even without these therapies the case fatality rate could be decreased if basic chemistry lab capabilities were in place and more patients would be treated with enough intravenous fluids and electrolyte repletion. Once patients go into single or multiple organ failure though, they might require more intensive care that will likely be impossible to deploy.

While there has not been additional news regarding research into the monoclonal antibody and small molecule products (including ZMapp and TKM-Ebola) for some time, work has resumed on a vaccine that had previously been shelved

Lastly, this week the Food and Drug Administration has issued an emergency authorization for rapid rt-PCR-based tests for blood or urine samples with a turnaround time of around an hour.

And then this week’s New England Journal brings us a small observational study of n=106 EBV patients in Sierra Leone[2]. The overall case fatality was 75% and differed by age (57% for <21 years vs 94% for >45 years, p=0.03), number of virus copies in the blood, presenting symptoms (statistically significant differences were found for temperature, weakness, dizziness, and diarrhea), and lab values corresponding to end organ dysfunction (BUN and creatinine, as well as aspartate aminotransferase). The incubation period was estimated to be 6 to 12 days. What was also interesting was that only one single patient had overt bleeding which seems to be unique for the strain responsible for the current outbreak. These and similar subsequent study will help characterize the characterizing signs and symptoms better.

Shifting gears, there is a new observational study[3] in JAMA Internal Medicine that confirms what your cardiology fellow has been saying all along: treatment with metoprolol succinate and carvedilol lead to equivalent results in heart failure with an ejection fraction of equal or less than 40% (adjusted hazard ratio for mortality carvedilol vs metoprolol 0.99; 95% confidence interval [CI] 0.88 to 1.11). Previously, the COMET study[4], a randomized controlled trial from 2003, had shown that carvedilol was superior to metoprolol tartrate (34% vs. 40%; p=0.0017) but more recently it was speculated that the long-acting metoprolol was non-inferior , as the MERIT-HF study[5] also studied metoprolol succinate and also because the target dose of metoprolol was only 100 mg/day.[6] Nevertheless, this was an observational study only. On the other hand, one has to wonder what would happen if a drug-manufacturer developed a daily carvedilol preparation?

Back to infectious diseases as three NEJM trials of four-month long respiratory fluoroquinolone (moxifloxacin and gatifloxacin)-containing compared to standard tuberculosis regimens were negative (absolute risk difference for a “favorable outcome” of 1.7 to 10.5% for INH and 6.7 to 16.1% for ethambutol in the first moxifloxacin study, a risk difference of an “unfavorable” response of 13.5% [90% CI 8.1-19.1], and very heterogeneous results in the gatifloxacin study that were interpreted as not non-inferior) [7-9] However, there was a treatment arm where high-dose rifapentine (a rifamycin, similar to rifampin) and moxifloxacin were only weekly administered, but for six months, and this arm was as effective as your standard 6-months RIPE regimen. The weekly administration could be easier although the cost consequences for developing countries are unclear.

Prescription opioid dependence is a growing problem, and could be considered a non-communicable disease epidemic. A new Archives of Internal Medicine study[10] compared a buprenorphine taper regimen with ongoing maintenance therapy in a primary care setting. Not surprisingly, the authors found that maintenance was superior in terms of more negative urine samples (75% versus 82%, p=0.04), less days of illicit opioid use (1.27 versus 0.4 days, p=0.02) and fewer maximum consecutive weeks of opioid abstinence (2.70 versus 5.2 weeks with non-overlapping confidence intervals).

In the field of oncology, a trial in the New England Journal of patients with metastatic colon cancer comparing fluorouracil/leucovorin, oxaliplatin, and ironectan (FOLFOXIRI) plus bevacizumab against fluorouracil/leucovorin, oxaliplatin, and ironectan (FOLFIRI) plus bevacizumab11 showed superiority of the former regimen in terms of progression free survival (12.1 versus 9.6 months; hazard ratio 0.75; CI 0.62 to 0.90). Oxaliplatin is known to have mostly synergistic effects. The overall survival was only borderline significant, however (31.0 versus 25.8 months; HR 0.79 with a CI of 0.63-1.00 and a p=0.054), which raises the question if the difference is clinically significant. Oxaliplatin is an old an inexpensive drug, and progress in oncology is known to be incremental, so its appeal for utilization is understandable.

For more interesting articles contained in this week’s JAMA’s special edition on Price, Cost, and Competition in Health Care, see http://jama.jamanetwork.com/issue.aspx?journalid=67&issueid=930974

Primecuts – This Week In The Journals

November 4, 2014

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