502 - Meds for Chronic Constipation, Tamiflu for Influenza?, Let us Rejoice
Take 3 – Practical Practice Pointers©
From the Guidelines
1) Pharmacological Management of Chronic Idiopathic Constipation
Constipation is a widespread problem in primary care medical practice, with multiple primary and secondary causes, often including medication side effects. Chronic idiopathic constipation (CIC) affects approximately 8%–12% of the US adult population. CIC is a lower gastrointestinal (GI) tract disorder commonly defined by the Rome diagnostic criteria. It has a significant negative impact on patient quality of life and medical costs related to the management of it are estimated to be between $2,000 and $7,500 per patient per year.
Nonpharmacological interventions often represent the initial step in management of CIC and may include dietary (such as increased fluid intake and increased dietary fiber) and behavioral changes (such as exercise). Despite these interventions, patients often require pharmacological management with one or more agents in order to attain improvement in their symptoms.
To that end, the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) recently published a joint evidence-based guideline which aims to provide recommendations for the pharmacological management of CIC in adults, updating a guideline published by the AGA in 2013. These recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Conflicts of interest were identified and managed according to AGA, ACG, the National Academy of Medicine, and Guidelines International Network standards. Development of this guideline was wholly funded by the AGA and ACG with no support from the industry.
The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, strong recommendations were made for the use of polyethylene glycol, bisacodyl/sodium picosulfate, linaclotide (linzess), plecanatide (trulance), and prucalopride (motegrity) for CIC in adults. Conditional recommendations were made for the use fiber, lactulose, senna, magnesium oxide, lubiprostone (amitiza).
Limitations noted in the guideline include that the reviewed clinical trials did not uniformly evaluate interventions for patient important outcomes on efficacy, adverse effects, and tolerability. Additionally, there was a paucity of data for the most commonly used treatments of CIC such as fiber, lactulose, senna, and docusate. There was also variance in acceptable clinical trial length by regulators over time. Most of the included studies followed the patients for the short term, and the safety and tolerance of these medications in the long term is not well studied. Although it is noted that “cost was considered” during the evidence to decision-making process, the panel did not perform formal cost-effectiveness analyses.
Mark’s Comments:
National data indicates that in general the US adult population falls far short of the recommendations for daily fiber intake, which goes a long way to explain the prevalence of CIC. For a nice primary care-focused review of the topic, see the 2nd reference from the American Family Physician journal, which provides an algorithm that emphasizes non-pharmacological and OTC interventions as first line treatment, noting that it will often take a combination of interventions to achieve the desired outcome. That article also provides more detail on cost. Not surprising, many of the newer prescription medications are quite expensive, while most of the recommended first line treatments are quite affordable. Remember, there’s really no financial incentive for pharmaceutical companies to fund studies looking at any of those more affordable options, explaining the paucity of efficacy data.
References:
· Chang L, et al. AGA-ACG Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation. Am. J. Gastroenterol. June 2023. 118(6):936-954. Link
· Stadler K, Arnold F, Dean S. Management of Constipation. Am Fam Physician. September 2022;106(3):299-306. Link
From the Literature
2) Oseltamivir to Prevent Influenza Hospitalization?
One of the more interesting evidence-based medicine stories (OK, I think it’s interesting…) is that of the 2014 Cochrane review about antivirals (oseltamivir (Tamiflu) and zanamivir (Relenza)) for influenza. The lead author, Tom Jefferson (!), felt as though he was not getting the full story of the effectiveness of the antivirals from the published randomized controlled trials. So, he instituted a media campaign to ask the government pharmaceutical regulators in several countries to release the regulatory documentation that allowed the drug’s approval. He received 166,000 pages of data about 46 trials. His review team deemed that most of the trials had methodological problems, and ultimately, the only effectiveness shown from these medications was shortening of viral symptoms by less than a day. Hospitalizations were not reduced, and complications (pneumonia, asthma exacerbations, etc.) were not reliably enough reported to make solid conclusions. This episode generated a temporary rallying cry against industry influence, but its ultimate effect was minimal.
Now, an independent systematic review has been undertaken to include the more recent investigator-initiated (i.e., not industry-supported) trials of oseltamivir for influenza in adolescents and adults. They did not include zanamivir in this review. The review searched for published articles from multiple databases that looked at trials of oseltamivir vs. placebo/non-active control for confirmed influenza. Unpublished reports from the manufacturer of oseltamivir were obtained from a BMJ-sponsored repository (an artifact of the Jefferson, et al. review). Validity of the studies was evaluated using the Cochrane Risk of Bias tool, the GRADE framework was used to interpret the results and the meta-analysis was well-detailed and included an assessment of heterogeneity.
From over 2300 published studies, only 7 met inclusion criteria. Another 8 unpublished studies were found in the manufacturer’s clinical study report archives. Nine of the studies were found to have low risk of bias, five were moderate risk, and 1 study was at high-risk. The overall rate of hospitalization in the control groups was 0.6%. There was no decrease in hospitalization in the oseltamivir group (risk difference (RD) −0.14%; 95% confidence interval (CI) −0.32% to 0.16%). There was no heterogeneity in this pooled outcome. In the planned subgroup analyses, the only positive finding was that the industry sponsored studies showed a 50% reduction in hospitalizations (which would yield an NNT of 333!), but the non-industry-sponsored trials showed no effect. The subgroups of high-risk, elderly, high vs. low quality trials all showed no difference. Oseltamivir did result in more nausea (RR 1.43; 95% CI 1.13-1.82) and vomiting (RR 1.83; 95% CI 1.28-2.63) than placebo/control. Diarrhea was reduced (RR 0.76;95%CI 0.57-1.00) in the oseltamivir group, however, and serious adverse events were no different between groups.
John’s Comments:
I think we give oseltamivir to our influenza patients because influenza can be a bad illness for those at high-risk and we do not have many options. But there is precious little evidence to back us up on this. I am going to be using this medication for influenza treatment even less than I do currently, given this data.
References:
· Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database of Systematic Reviews. 2014;(4). Link
· Hanula R, Bortolussi-Courval É, Mendel A, Ward BJ, Lee TC, McDonald EG. Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients with Influenza. JAMA Intern Med. Published online June 12, 2023:e230699. Link
From PeerRxMed ( www.PeerRxMed.org ) and PeerARTx
3) Therefore, Let Us Rejoice
In 1982, cardiologist, essayist, poet and professor John Stone, MD, delivered the medical school graduation address for the class of Emory University in the form of a poem titled “Gaudeamus Igitur” which is translated as “therefore, let us rejoice.” That same poem was published in JAMA in April of 1983, and this year marks the 40th anniversary of it being shared with a wider audience.
As a writer, Dr. Stone is perhaps best known for On Doctoring: Stories, Poems, Essays (1991), an anthology of literature and medicine that he co-edited with Richard Reynolds, former executive vice president of the Robert Wood Johnson Foundation. Since 1991, every U.S. medical student has received a copy of this book as a gift from the foundation and it has served as a reminder to a generation of medical students that anchoring ourselves in the humanities will make us much better in our calling to the art and science of the practice of medicine. Unfortunately (and ironically), the poem Gaudeamus Igitur was not included in this anthology.
Fortunately for us, the poem lives on, most recently republished along with a commentary in the June 9 issue of JAMA. Below are excerpts from the poem and you can find full poem here. As you read the excerpts, and hopefully the entire poem, consider how you might recapture or rekindle some of the joy, wonderment, humility, and love that you experienced as a newly minted physician (or other clinician), whenever that might have been for you.
For the trivial will trap you and the important escape you
For the Committee will be unable to resolve the question
For there will be the arts
and some will call them
soft data
whereas in fact they are the hard data
by which our lives are lived
For everyone comes to the arts too late
For you can be trained to listen only for the oboe
out of the whole orchestra
For you may need to strain to hear the voice of the patient
in the thin reed of his crying
For you will learn to see most acutely out of
the corner of your eye
to hear best with your inner ear
For there are late signs and early signs
For the patient's story will come to you
like hunger, like thirst
For you will know the answer
like second nature, like first
For the patient will live
and you will try to understand
For you will be amazed
or the patient will not live
and you will try to understand
For you will be baffled
For you will try to explain both, either, to the family
For there will be laying on of hands
and the letting go
For love is what death would always intend if it had the choice …
For the heart will lead
For the head will explain
but the final common pathway is the heart
whatever kingdom may come
For what matters finally is how the human spirit is spent …
For this is the beginning
Therefore, let us rejoice
Gaudeamus igitur.
· Hanula R, Bortolussi-Courval É, Mendel A, Ward BJ, Lee TC, McDonald EG. Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients with Influenza. JAMA Intern Med. Published online June 12, 2023:e230699. Link
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Mark and John
Carilion Clinic Department of Family and Community Medicine
Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.
Email: mhgreenawald@carilionclinic.org