Search all rapid responses

All rapid responses

Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on thebmj.com. Although a selection of rapid responses will be included online and in print as readers' letters, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window. Letters are indexed in PubMed.

Re: Trade is central to achieving the sustainable development goals: a case study of antimicrobial resistance Johanna Hanefeld, Mishal Khan, Göran Tomson, Richard Smith. 358:doi 10.1136/bmj.j3505

The suggestions in this article for stronger regulation of substandard “counterfeit” antimicrobial drugs through intellectual property provisions in trade agreements is wrong and dangerous. It is based on the erroneous assumption that IP protection relates to higher quality standards of medicines and that IP enforcement can effectively prevent quality-compromised medicines from reaching the market. This article wrongly conflates issues of IP protection with issues of quality, safety and efficacy of medicines. Such conflation has inspired regulations and actions in the EU that has led to wrongful seizures of generic medicines in transit through European ports, which have been challenged by developing countries in the WTO. Member States of the WHO have agreed to keep away any consideration of IP issues in addressing quality, safety and efficacy of medicines and not use the term “counterfeit” with regard to quality compromised medicines, as the term refers to IP rights.

Competing interests: No competing interests

17 October 2017
NIRMALYA SYAM
Programme Officer
Viviana Munoz Tellez
Development. Innovation and Intellectual Property Programme at the South Centre, Geneva. The South Centre is an intergovernmental research organisation of developing countries that undertakes research and analysis on various international policy areas that are relevant to the development interests of developing countries.
Chemin du Champ d'Anier 17, 1211 Geneva 19
Re: Indications for anticoagulant and antiplatelet combined therapy Christopher N Floyd, Albert Ferro. 359:doi 10.1136/bmj.j3782

Dear authors,

Thank you for this highly informative article. I was wondering if there are any guidelines regarding management of patients on antithrombotics and dual antiplatelets who go on to develop a major/minor bleed. In case such a situation arose, how do we decide between either class of medications if the need arises to either stop treatment or to continue it, keeping in view the indications for instituting the treatment in the first place?

Competing interests: No competing interests

17 October 2017
Ghassan Ahmed Fazili
Doctor
Queen Elizabeth University Hospital, Birmingham
Re: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13 Ashlyn Pinto, Ajay Aggarwal, et al. 359:doi 10.1136/bmj.j4530

I wish to respond to the person from the EMA.

Dr. Pignatti states it is “well known” that in many situations showing survival or quality of life benefit is not feasible. Unfortunately, the arguments he gives are not universally agreed upon, they are merely oft repeated.

Dr Pignatti states that survival benefits may be difficult to detect because subsequent lines of therapy “dilute” them. Step back and consider this argument. Even though median survival with metastatic cancer is short, and life limiting, and even though a new drug approved is a novel, costly therapy, that drug cannot improve survival because all of the prior drugs are good enough to result in the same survival. An analogy would be: you were running a marathon, and purchased a 100,000 pound energy drink and drank it at mile 2. Unfortunately, you complete the marathon in the exact same time you otherwise would. A critic points out that the drink had no value. It didn’t change the outcome. You then argue that is only because the effect of the energy drink was diluted over all the other miles. But that is precisely an argument why the energy drink was a waste. Its cost and side effects are not justified unless it improves an outcome that matters.

Dr. Pignatti also argues prolonging progression free survival (PFS) may delay the onset of symptoms. Here, he uses PFS as a surrogate for symptoms, and fails to provide data—in the form of surrogate validation studies—that proves PFS gains are accompanied by reduction in symptoms.

It is important to remember that PFS and response rate are typically based on the arbitrary change in tumor size on a CT scan. Either an increase of 20% (progression) or decrease of 30% (response). Almost no patient says “I feel bad” the moment their tumor grows from 19% to 21%. Nor do they sudden exclaim "I feel better" if the tumor is 31% rather than 29% smaller. Moreover, studies show variability in the measurement of tumors on scans by different readers [1]. For this reason, it is impossible to contend either of these metrics is something inherently valuable to patients. They are radiographic surrogates.

Dr. Pignatti argues that “dramatic activity” in the form of response rates may make further randomized trials non-feasible. This argument is unsound for a few reasons. First, the response rate in early clinical trials is almost always inflated over later trials [2]. The response rate tends to be smaller if you test the drug again. Second, there have been drugs with impressive response rates (>60%) that have failed in every single randomized trial they have latter been tested in, resulting in market withdrawal [3]. Most cancer drugs offer marginal benefits, and can and should be tested in randomized trials. In fact, gains in PFS are always measured in randomized trials, only response rate can be single armed.

Dr. Pignatti states quality of life is hard to measure. I agree, and support better and fairer ways to measure it. Moreover we have to acknowledge that good drugs improve both survival and quality of life, and this is the goal. Simply because quality of life is hard to measure however, does not justify allowing drugs to remain on the market for years with proof they only change imaging results.

Dr. Pignatti says that drugs that offer incremental benefits are still worthwhile. The major finding of the paper by Davis is that far too often we don’t know if drugs offer benefits at all. I personally support the use of provisional approval based on surrogates in certain situations, but that must come with a responsibility to show survival benefit post approval. You cannot have both lax approval and lax post-marketing commitments, which is what Davis and colleagues show.

Finally, Dr. Pignatti engages in speculation. The world is better off by having surrogate approvals. The truth is we do not know if allowing surrogate approvals benefits or harms patients because we do not know the counterfactual. While some may believe a world without surrogate approvals will result in delays for drug approval, the unanticipated consequence may be the industry will no longer pursue targets that merely result in changes to imaging scans, and instead focus on truly promising compounds. We may have fewer drugs, but the ones we have might be better. I do not know know this is true, and neither does anyone else. But just as we can speculate the world will be worse, we can also speculate it might be better. Both are just speculation.

The major point of Davis and colleagues is that while it may be ok to allow cancer drugs on the market based on a surrogate, it seems illogical to allow them to remain on the market 3, 5, or 7 years without proof of survival or quality of life benefit. At some point in the lifecycle of these drugs, this must be shown. The EMA has the obligation to make that happen. These comments raises concern that the EMA views their role differently.

[1] https://academic.oup.com/jnci/article/106/12/dju331/922126/Use-and-Misus...
[2] https://www.ncbi.nlm.nih.gov/pubmed/26259493
[3] https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/1...

Competing interests: I am the editorialist

16 October 2017
Vinay Prasad
Physician
none
OHSU
Portland, OR
Re: Margaret McCartney: Hydration, common sense, and evidence Margaret McCartney. 359:doi 10.1136/bmj.j4642

Common sense means paying attention to the obvious. This is not as easy as it sounds, because we all have vivid imaginations, and we tend to get lost in our fantasies.

When fantasy replaces common sense, life becomes farcical and even tragic. Life is a series of ordinary events that follow the laws of logic and probability. These ordinary events are indifferent to our fantasies and require the careful, accurate navigation of common sense.

I learned the lesson of common sense as a third-year medical student. I was doing an internal medicine rotation at a VA (Veterans Affairs) hospital, while working with interns, residents, and attending physicians.

One day, on morning rounds, we examined a patient with a black tongue. The intern assigned to that patient had researched all the causes of a black tongue and was eager to impress us. As the intern started to lecture us, the attending physician interrupted him and asked the patient if he uses black cough drops. The patient smiled, opened the drawer of his night table, and took out a package of Smith Brothers black cough drops.

The intern's face turned red, and we all laughed. The intern was so focused on science, that he forgot to ask his patient an obvious question. It's been 45 years since I was a third-year medical student, but I still have a vivid memory of that day and that lesson: use common sense, and pay attention to the obvious.

Being a physician has taught me the lesson of common sense again and again. Eventually, I realized that we all lack common sense, and this is why we can't solve our problems. So let's seek common sense and apply it to everything, because knowledge plus common sense is wisdom, but knowledge minus common sense is nonsense.

Competing interests: No competing interests

16 October 2017
Hugh Mann
Physician
Retired
New York, NY, USA
Re: David Oliver: How much information should patients’ families expect on acute wards? David Oliver. 359:doi 10.1136/bmj.j4295

The MDU report of 2015 recorded the fact that 30% of complaints were related to poor communication. David points out very well the impossibilities of being available at the right place and time for relatives.

General practice has a new method - allowing patients and relatives (with patients' consent) to access the complete contemporaneous record. This will become possible soon in hospitals and certainly the Queen Elizabeth Hospital in Birmingham is allowing patients to access the digital hospital record already.

When patients opt to use data for their personal or domestic use the data is no longer subject in that personal use to the DPA, freeing doctors of worry about breaches of the DPA and confidentiality.

Personal data processed by an individual only for the purposes of that individual’s personal, family or household affairs (including recreational purposes) are exempt from the data protection principles and the provisions of Parts II and III.

So no extra work for doctors and nurses and maybe fewer complaints.

Here is one patient's story about record access recently:

http://www.bmj.com/content/358/bmj.j4126/rr-2

I read with interest the recent editorial on ‘Implementing Person Centred Approaches’, (BMJ 2017;358:j4126). I must first of all clearly state that I am neither an academic nor a health professional, I am a builder. A builder with a chronic disease (Ulcerative Colitis) that I have lived with for the last 5 or so years.

I am also aware, to an extent, of the pressures facing the NHS and the medical profession. Only what I see in the hospitals that I visit and hear through mainstream media channels, but enough to understand that to succeed the system needs to evolve and I think that the person centred care approach is a positive step.

It is encouraging to hear of building communication and relationships between healthcare professionals and the people receiving care as this can surely only serve to improve engagement and mutual understanding. (The healthcare professional’s understanding of the patient and the patient’s understanding of their condition/treatment).

I do however feel that in an organisational and system context (as well as a patient context) the article neglects to acknowledge an extremely valuable tool, that of the ability to share patient data. I refer not only to the appropriate and controlled sharing of patient data within and across relevant organisations which has its own merits, but also and importantly the sharing of patient data directly with the patient to which it relates.

During the years following my own diagnosis my relationship with my healthcare professionals (doctors, nurses and consultants) has quite suddenly and accidentally become more ‘patient centred’.
Two years ago I was at a stage in my understanding of my condition and treatment that was so limited it placed the entire weight of responsibility for my care on the doctors treating my condition. At that point in time I had lived with my diagnosis for three years and I was a passenger, along for the ride feeling I did not have a part to play.

Quite by chance I was then offered the opportunity to sign up for digital access to my records through ‘Patient Access’ by EMIS.

I have found that access to my medical data, including test results, consultation details, diagnosis history etc. has empowered me as a patient and given me a platform for the sort of communication with my healthcare professional that Person Centred Care appears to seek to achieve. I ask questions, discuss options for treatment and associated side effects, as well as assisting with the management of my regular scheduled treatments. I am able to feel a better level of care with less contact with the surgery. I can manage prescriptions and view test results without the need to take up time talking to the surgery staff. I can review treatment dates to ensure that my blood tests and treatments are scheduled appropriately without the stress of wondering when they are due. The access to EMIS has allowed me to take some ownership of my condition and work pro-actively with my various healthcare professionals in the management of my disease and its treatment both short and long term.

I have no doubt that I would not have had the confidence required to begin discussions with my doctors without the access to my records as a basis for communication.

I find the quarterly visits to my Consultant at hospital are also now far more useful. I am able to discuss the results of my GP surgery visits and test results and draw directly upon them at the consultation from my smartphone if required, adding depth to our discussions.

In short I am no longer a passenger, I am now very much part of the management team for the effective treatment of my condition and I am pleased to say that I am managing to remain in good health.
I understand that not everyone will have the capacity to use their data in this way but there are very many who will and I can see access to patient data being a very powerful tool indeed in achieving patient centred care.

Competing interests: No competing interests

16 October 2017
Richard Peter Fitton
Retired GP
Tameside and Glossop CCG
Glossop
Re: Indications for anticoagulant and antiplatelet combined therapy Christopher N Floyd, Albert Ferro. 359:doi 10.1136/bmj.j3782

Thanks for a good clear summary. In my experience though this is not what happens and many people remain on both anti platelet and doac treatment with no review or end date and when clarifying with their cardiologist the view is to continue

Related to this and not too clear - if someone with previous intervention and on aspirin then develops af can the aspirin be stopped once on a doac, assuming more than 1 year post stenting?

Competing interests: No competing interests

16 October 2017
john sharvill
gp
deal kent
Re: Europe steps up action against vaccine hesitancy as measles outbreaks continue Rebecca Coombes. 359:doi 10.1136/bmj.j4803

Dear Dr Coombes and Dr Ammon

I am pleased to read that somewhere in Europe, doctors will start answering Face Book users posting questions and concerns.

England too is in Europe. If you look up the rapid responses, you will find that a very few of us (myself included and indeed some parents) have posted questions and concerns. You will also find that no one, but no one has responded to us.

Some of us - certainly I - have been vigorous proponents of immunisation here in England. Certainly I, in my working life in public health, did answer questions from the public and the press about imm and vacc.

Will you be able to persuade the public health experts, the immunologists and the manufacturers of the vaccines, to answer the specific points that have been raised in the BMJ RAPID RESPONSES?

Let us not muddy the discussions by bringing in matters which we have not raised.

If I ask, “Is it now raining in Whitehall?” I want to know - YES or NO.

If you reply, "Now it is raining in Cardiff”, you can falsely claim to have answered my question.

Thank you

JK Anand

Competing interests: No competing interests

16 October 2017
JK Anand
Retired doctor
Free spirit
Peterborough
Re: Diagnosis and management of postpartum haemorrhage Edwin Chandraharan, Archana Krishna. 358:doi 10.1136/bmj.j3875

We would like to thank Chandraharan and Krishna for their recent article highlighting the challenges of postpartum haemorrhage (PPH). The article provided a comprehensive review of the causes of PPH and the pharmacological and surgical interventions that may be required. However, we felt that the article did not adequately address the importance of early recognition of PPH and multidisciplinary team working that together make a difference to outcome; nor did the article reflect the recent RCOG guidance and research that has increased our understanding of coagulation changes which occur during PPH.

The management of postpartum haemorrhage requires a well-trained, effective multidisciplinary team with a defined escalation strategy. Team working and training is essential to achieve an optimal outcome in a rapidly deteriorating clinical situation (1). In Wales we have developed a national quality improvement project working to improve the care of women experiencing postpartum haemorrhage (OBS Cymru (2)). Our key themes are multidisciplinary team working, risk assessment, measurement of blood loss and point of care testing to guide blood product administration. None of these issues were addressed adequately in the review, yet we feel that they are the cornerstones of successful PPH management.

The authors describe the inaccuracy of estimating blood loss which can lead to underestimation of large blood loss and overestimation of smaller bleeds. Both situations have a significant impact on the care of a bleeding mother. We have found that the gravimetric measurement of blood loss after all deliveries is easy to perform, requires minimal equipment and reflects the fall in postpartum haemoglobin in larger bleeds (3). When undertaken cumulatively during a bleed this technique allows the clinical teams to escalate appropriately and act in a timely fashion. Measuring blood loss is often said to be difficult or impractical, yet we now have an 80% compliance rate after all vaginal deliveries and 90% after Caesarean deliveries across the 12 consultant led delivery units in Wales.

Our additional concern was the recommendation that red blood cells should be replaced in a 1:1 ratio with fresh frozen plasma (FFP). This is not in-line with current RCOG guidance and does not reflect the recent research that has increased our understanding of the coagulation changes occurring during PPH (4,5).

The RCOG guidance now specifies that if no haemostatic results are available and bleeding is continuing, then, if bleeding is continuing after 4 units of red blood cells have been given then 15 ml/kg of FFP should be infused until haemostatic test results are known. The RCOG only advise early FFP administration if haemostatic tests are not available for conditions such as placental abruption or amniotic fluid embolism where coagulopathy is an early feature. There is a clear recommendation not to give 1:1 plasma to red cell transfusion for all bleeding. 1:1 resuscitation is a practice supported by data derived from studies in major non obstetric trauma and there is no data that support its use during PPH. We have recently published a study reporting on the use of point of care visco-elastometric testing of coagulation during severe PPH. Women were stratified during the bleed based on their fibrinogen levels. It was found that a rapid point of care test of coagulation was practical and that very few women needed coagulation product support based on the results of the bedside test. Point of care testing of coagulation is described in the RCOG guidance and we have found that if used, very few women receive FFP, thus avoiding the many unnecessary infusions that would have resulted from 1:1 resuscitation (6).

References
1. Siassakos D, Fox R, Crofts JF, Hunt LP, Winter C, Draycott TJ. The management of a simulated emergency: better teamwork, better performance. Resuscitation 2011; 82(2): 203-6.
2. www.1000livesplus.wales.nhs.uk/obs-cymru
3. Lilley G et al. Measurement of blood loss during postpartum haemorrhage. Int J Obst Anesth 2015; 24(1): 8-14.
4. Mavrides E,Allard S,Chandraharan E,Collins P,Green L,Hun tBJ,RirisS,Thomson AJ on behalf of the Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage. BJOG 2016; 124: e106–e149.
5. Collins PW et al. Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. BJA 2017; 119(3): 411-421.
6. Collins PW et al. Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: OBS2, an observational study. BJA 2017; 119(3):422-434.

Competing interests: OBS Cymru is an all Wales Quality Improvement Project sponsored by Welsh Government, 1000 Lives and Werfen.

16 October 2017
Sarah F Bell
Consultant Anaesthetist
Professor R Collis and Professor PW Collins on behalf of the OBS Cymru project
University Hospital of Wales
University Hospital of Wales, Cardiff, CF14 4XW.
Re: WHO downgrades status of oseltamivir Mark H Ebell. 358:doi 10.1136/bmj.j3266

To the Editor:

We strongly disagree with the interpretation of the evidence on antiviral treatment of influenza as described by Ebell in “WHO downgrades status of oseltamivir” [1], and we would like to clarify the fundamental issue of how to interpret the available data from studies of oseltamivir treatment of influenza patients. This is critically important to avert confusion among clinicians providing care for influenza patients worldwide. As representatives of public health and professional medical organizations, we continue to recommend use of neuraminidase inhibitor antiviral drugs, including oseltamivir, as soon as possible for treatment of influenza patients.

The WHO 2017 Expert Committee on the Selection and Use of Essential Medicines considered a proposal by the Cochrane Review acute respiratory infections group to delete oseltamivir from the Essential Medicines List (EML) and EML in children (EMLc) [2]. The WHO EML and EMLc serve as guides for the development of national and institutional essential medicine lists worldwide. Oseltamivir was added to the EML and EMLc in 2011. Ebell wrote that “Removal of oseltamivir from the essential medicines list is better late than never.” In fact, importantly, the WHO did not remove oseltamivir from the EML. Rather, the “Committee recommended the listing of oseltamivir be amended and the medicine be moved from the core to the complementary list, and its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients” [2].

The Cochrane review of oseltamivir, mentioned by Ebell, considered data only from randomized controlled trials (RCTs) of early oseltamivir treatment (generally started within 2 days of illness onset) versus placebo that were conducted mostly in otherwise healthy non-high risk outpatients with mild illness. These studies demonstrated modest benefit of early oseltamivir treatment in reducing the duration of illness [3]. These trials were not intended or designed to assess complications, hospitalization or death, were therefore underpowered for these outcomes, and do not inform oseltamivir use in hospitalized influenza patients with more severe disease [4]. In order to increase statistical power to detect such outcomes, studies with much larger sample size, including participants with chronic co-morbidities and those at higher risk for complications from influenza are needed, but do not exist; therefore, meta-analyses of pooled existing clinical trial and observational data can be informative. Ebell did not mention the meta-analysis of RCTs in outpatients published by Dobson et al. that reported oseltamivir treatment of adults with laboratory-confirmed influenza versus placebo was associated with a reduction in clinician-diagnosed lower respiratory tract complications requiring antibiotics more than 48 hours after randomization, and fewer hospital admissions for any cause [5].

Post-licensure, non-randomized studies can also provide important insights into protection against more severe clinical end-points. For example, data from an observational study in China where persons with mild-to-moderate illness caused by laboratory-confirmed influenza A(H1N1)pdm09 virus infection were isolated in hospitals at the beginning of the 2009 H1N1 pandemic provided an opportunity to assess the effect of oseltamivir treatment in preventing complications. Oseltamivir treatment started 2 or more days after illness onset compared with no antiviral treatment was associated with reduced risk of developing radiographically confirmed pneumonia [6]. Furthermore, an individual patient data meta-analysis of more than 3000 outpatients with laboratory-confirmed influenza concluded that neuraminidase inhibitor (NAI) antiviral drug treatment significantly reduced the likelihood of hospital admission [7].

Ebell and others, including the Cochrane review of oseltamivir RCTs [3,8], commonly report results for the “intention-to-treat (ITT)” population, of which many participants had negative influenza testing results, but had overlapping signs and symptoms of the syndrome of ”influenza-like illness” that can be caused by influenza viruses and multiple other respiratory pathogens. Because oseltamivir and other NAI antiviral drugs only have activity against influenza viruses, but not other pathogens, the reporting of ITT results is misleading and biased toward not finding benefit. Rather, what is most important is whether oseltamivir treatment is beneficial to patients with illness caused by influenza virus infection, the “intention-to-treat-infected” (ITTi) study population. For example, the Cochrane review reported that in adult outpatients with influenza-like illness, oseltamivir treatment significantly reduced the time from first alleviation of symptoms by 16.7 hours versus placebo [3], whereas in the Dobson et al meta-analysis, oseltamivir treatment of adult outpatients with laboratory-confirmed influenza significantly reduced the time to alleviation of all symptoms by 25 hours versus placebo [5].

We take strong exception to Ebell’s statement “Of course, what really matters is how the drug performs for patients with influenza-like illness since near patient tests for influenza lack sensitivity and are little used in most European countries”[1]. Antimicrobial stewardship includes selection of the optimal antimicrobial drug regimen for treatment of an infectious disease. Oseltamivir and other NAI antiviral drugs block the release of influenza viral particles from infected cells, but have no effect and provide no benefit to patients with signs and symptoms of influenza-like illness caused by non-influenza pathogens. Therefore, it is important for clinicians to properly and promptly diagnose influenza in order to prescribe antiviral medications for influenza patients who can benefit, particularly those who are at increased risk for influenza complications or with severe illness. Influenza tests, for example during a respiratory illness outbreak or with an out-of-season case, along with local influenza surveillance data on the level of influenza activity in the community and thus the likelihood that an individual has influenza, are critical to inform clinical decision-making. Recently, rapid molecular assays with high accuracy have become available for use in outpatient settings [9].

Since no randomized controlled efficacy trials of NAI antiviral drugs versus placebo for treatment of hospitalized influenza patients exist, assessment of available data on the “real-world” effectiveness of oseltamivir treatment from observational studies is relevant and appropriate, despite the well-recognized inherent limitations of observational data. A recent review assessed the strengths and limitations of a variety of study designs and concluded that different study designs can provide “actionable data that are sufficient for clinical and public health action” to inform health decision-making [10]. Furthermore, a Cochrane review found “little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions” [11]. Just as the quality of RCTs may vary, observational studies that have attempted to reduce biases and confounding are better than studies that did not.

Ebell also did not mention a very large meta-analysis of individual patient-level data from more than 29,000 hospitalized patients (86% with laboratory-confirmed influenza, 14% clinically diagnosed with influenza) from 38 countries that reported survival benefit of NAI treatment (primarily oseltamivir) in adults compared with no treatment, with significantly greater survival benefit with early (within 2 days of illness onset) compared with later initiation (>2 days after onset) of NAI treatment [12]. NAI treatment (including started >2 days after onset) versus no treatment also had significant survival benefit in critically ill adults and in pregnant women [12]. In response to concerns raised after publication, the authors performed additional analyses utilizing other methodologies to address different biases and suggested that the association of NAI treatment with survival benefit remained [13]. This study, together with the Cochrane review and the review by Dobson et al were recently reviewed by the European Centre for Disease Prevention and Control and an assembled independent expert group in order to form a balanced expert opinion of available data on the effectiveness of NAIs [14]. They concluded that “available evidence provides support for the use of NAIs as prophylaxis and treatment and thus they can be considered a reasonable public health measure during seasonal influenza outbreaks, pandemics and zoonotic outbreaks caused by susceptible influenza” [14].

Clinicians managing influenza patients should consider whether the potential benefits of oseltamivir treatment outweigh any possible adverse effects. Ebell referred to oseltamivir adverse effects of nausea, vomiting and “psychiatric events” identified by the Cochrane review. However, it is notable that in their meta-analysis of RCTs in adults, Dobson et al did not find any effect on neurological or psychiatric disorders or serious adverse events [5]. Furthermore, it is well-established that there is a wide spectrum of neurologic complications associated with influenza virus infection of the respiratory tract [15-17]. Dobson et al and others have reported an increased risk of nausea and vomiting with oseltamivir treatment versus placebo. In the Cochrane review, the risk difference identified in adults treated with oseltamivir versus placebo was 3.66% for nausea, and 4.56% for vomiting [3,8]. Such risks seem low and should be weighed against the fact that influenza results in direct medical and opportunity costs from staying home from school or work. The burden of severe disease is high, particularly in the elderly and those with underlying chronic co-morbidities, and for persons with severe disease, the risks of gastrointestinal symptoms are unlikely to be relevant.

The purported “psychiatric events” identified by the Cochrane review were not statistically significant in recipients of oseltamivir treatment compared with placebo. The only significant finding of “psychiatric events” was not during exposure to oseltamivir for treatment (twice daily dosing) or chemoprophylaxis (once daily dosing), but late events after the drug was no longer being taken - only in a small number of participants who had received chemoprophylaxis when the observation period was extended to days when no drug was received (off drug periods) [3,8]. Additionally, a large administrative database study of outpatients with clinically diagnosed or laboratory-confirmed influenza found no evidence of an increased risk of neuropsychiatric or other adverse events with oseltamivir treatment compared with no treatment [18]. It should also be noted that a large multinational European registry of pregnant women who received NAIs (oseltamivir or zanamivir) during pregnancy found no increased risks of adverse neonatal outcomes or congenital malformations compared with infants without NAI exposure in utero [19]. This is particularly important for clinicians to understand because influenza virus infection of pregnant women can result in severe disease.

It is indisputable that seasonal influenza epidemics cause substantial public health impact in terms of medical visits, hospitalizations, and deaths worldwide. During 2002-2008, an estimated 40,880-160,270 influenza-associated deaths occurred in 35 Latin American countries [20]. During 2010-2015, the CDC estimated that 140,000-710,000 hospitalizations and 12,000-56,000 deaths were associated with influenza each year in the U.S. [21]. Early estimates suggest that in 19 European countries at least 137 excess deaths per 100 000 population were attributable to influenza during the 2016-17 season [22].

While more effective influenza vaccines are needed to prevent influenza, especially in the elderly where disease burden is high, we also need much better therapies with different mechanisms of action than oseltamivir and other NAIs. In addition, the world needs to be much better prepared for the next influenza pandemic that could be much more severe than the 2009 H1N1 pandemic. Currently, avian influenza A(H7N9) virus poses the highest pandemic threat [23]. Ebell mentions the issue of antiviral stockpiling for pandemic preparedness. The controversies in the interpretation of data on oseltamivir use for seasonal and pandemic influenza have been summarized well by Hurt and Kelly; they also highlighted the use of NAIs to control the impact of the 2009 H1N1 pandemic in Japan that was facilitated by the wide availability and access of NAIs for treatment of seasonal influenza [4]. In the U.S., an annual review is conducted of available drugs for potential stockpiling for pandemic preparedness. In Europe, 27 of 28 countries with publicly available pandemic preparedness plans specifically include antiviral policy as part of the plans [24]. A major gap is that no new drugs other than NAIs (zanamivir, peramivir) have been approved for treatment of influenza in the U.S. or the European Union since oseltamivir was approved in 1999. Until new therapies with different mechanisms of action are available, antiviral treatment of influenza patients worldwide will be based upon initiation of NAI treatment, including oseltamivir, as soon as possible, in addition to supportive management of the wide range of complications associated with influenza, and adherence to recommended infection prevention and control measures.

We agree with Ebell that data from “all trials be published, and that individual patient data be made available for independent re-analysis.” We also urge clinicians, public health colleagues, and decision-makers to understand all of the issues and details of the findings of the antiviral treatment studies (RCTs and observational studies), and to focus on outcomes for patients with laboratory-confirmed influenza. The U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, Public Health England, the World Health Organization, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists, all continue to recommend use of neuraminidase inhibitor antiviral drugs as soon as possible for influenza patients who are most likely to benefit from them: persons with suspected or confirmed influenza who have severe or progressive disease, are hospitalized, or are at high risk of complications from influenza.

Timothy Uyeki MD, MPH, MPP, Centers for Disease Control and Prevention

Pasi Penttinen MD, PhD, MPH, Mike Catchpole MB, European Centre for Disease Prevention and Control

Richard Pebody, MBChB, PhD, Maria Zambon PhD, FRCPath, F Med Sci, Jake Dunning MBBS, MRCP, PhD, Public Health England

John Watson MB BS, MSc, FRCP, FFPH, Department of Health, U.K.

Henry (Hank) Bernstein DO, MHCM, Flor M. Munoz MD, MSc, David W. Kimberlin MD, American Academy of Pediatrics

Richard Beigi MD, MSc, Laura E. Riley MD, American College of Obstetrics and Gynecology

Andy Pavia MD, William Powderly MD, Infectious Diseases Society of America

Paul Spearman MD, Pediatric Infectious Diseases Society

Nikki Shindo MD, PhD, World Health Organization, Geneva, Switzerland

Disclaimer: The views expressed are those of the authors and do not necessarily represent the official policy of the Centers for Disease Control and Prevention.

References
1. Ebell MH. WHO downgrades status of oseltamivir. BMJ. 2017 Jul 12;358:j3266. doi: 10.1136/bmj.j3266.
2. World Health Organization. The Selection and Use of Essential Medicines. Report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Accessed at: http://www.who.int/medicines/publications/essentialmedicines/EML_2017_EC...
3. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014 Apr 9;348:g2545. doi: 10.1136/bmj.g2545.
4. Hurt AC, Kelly H. Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza. Emerg Infect Dis. 2016 Jun;22(6):949-55
5. Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. 2015 May 2;385(9979):1729-37.
6. Yu H, Liao Q, Yuan Y, Zhou L, Xiang N, Huai Y, Guo X, Zheng Y, van Doorn HR, Farrar J, Gao Z, Feng Z, Wang Y, Yang W. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. BMJ. 2010 Sep 28;341:c4779.
7. Venkatesan S, Myles PR, Leonardi-Bee J, Muthuri SG, Al Masri M, Andrews N, Bantar C, Dubnov-Raz G, Gérardin P, Koay ESC, Loh TP, Memish Z, Miller E, Oliva ME, Rath BA, Schweiger B, Tang JW, Tran D, Vidmar T, Waight PA, Nguyen-Van-Tam JS. Impact of Outpatient Neuraminidase Inhibitor Treatment in Patients Infected With Influenza A(H1N1)pdm09 at High Risk of Hospitalization: An Individual Participant Data Metaanalysis. Clin Infect Dis. 2017 May 15;64(10):1328-1334.
8. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;(4):CD008965. doi: 10.1002/14651858.CD008965.pub4.
9. Merckx J, Wali R, Schiller I, Caya C, Gore GC, Chartrand C, Dendukuri N, Papenburg J. Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction: A Systematic Review and Meta-analysis. Ann Intern Med. 2017 Sep 5. doi: 10.7326/M17-0848. [Epub ahead of print]
10. Frieden TR. Evidence for Health Decision Making - Beyond Randomized, Controlled Trials. N Engl J Med. 2017 Aug 3;377(5):465-475.
11. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014 Apr 29;(4):MR000034. doi: 10.1002/14651858.MR000034.pub2.
12. Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Báez C, Bassetti M, Beovic B, Bertisch B, Bonmarin I, Booy R, Borja-Aburto VH, Burgmann H, Cao B, Carratala J, Denholm JT, Dominguez SR, Duarte PA, Dubnov-Raz G, Echavarria M, Fanella S, Gao Z, Gérardin P, Giannella M, Gubbels S, Herberg J, Iglesias AL, Hoger PH, Hu X, Islam QT, Jiménez MF, Kandeel A, Keijzers G, Khalili H, Knight M, Kudo K, Kusznierz G, Kuzman I, Kwan AM, Amine IL, Langenegger E, Lankarani KB, Leo YS, Linko R, Liu P, Madanat F, Mayo-Montero E, McGeer A, Memish Z, Metan G, Mickiene A, Mikić D, Mohn KG, Moradi A, Nymadawa P, Oliva ME, Ozkan M, Parekh D, Paul M, Polack FP, Rath BA, Rodríguez AH, Sarrouf EB, Seale AC, Sertogullarindan B, Siqueira MM, Skręt-Magierło J, Stephan F, Talarek E, Tang JW, To KK, Torres A, Törün SH, Tran D, Uyeki TM, Van Zwol A, Vaudry W, Vidmar T, Yokota RT, Zarogoulidis P; PRIDE Consortium Investigators, Nguyen-Van-Tam JS. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014 May;2(5):395-404.
13. Leonardi-Bee J, Venkatesan S, Muthuri SG, Nguyen-Van-Tam JS, Myles PR; PRIDE research consortium. Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. Lancet Respir Med. 2014 Jul;2(7):e10-2. doi: 10.1016/S2213-2600(14)70137-7.
14. European Centre for Disease Prevention and Control. Expert opinion on neuraminidase inhibitors for the prevention and treatment of influenza - review of recent systematic reviews and meta-analyses. 14 August 2017. Accessed at: https://ecdc.europa.eu/sites/portal/files/documents/Scientific-advice-ne...
15. Britton PN, Blyth CC, Macartney K, Dale RC, Li-Kim-Moy J, Khandaker G, Crawford N, Marshall H, Clark J, Elliott E, Booy R, Cheng AC, Jones CA; ACE study investigators, FluCAN investigators and PAEDS network. The Spectrum and Burden of Influenza-Associated Neurological Disease in Children: Combined Encephalitis and Influenza Sentinel Site Surveillance from Australia 2013-2015. Clin Infect Dis. 2017 Apr 29. doi: 10.1093/clinid/cix412. [Epub ahead of print]
16. Goenka A, Michael BD, Ledger E, Hart IJ, Absoud M, Chow G, Lilleker J, Lunn M, McKee D, Peake D, Pysden K, Roberts M, Carrol ED, Lim M, Avula S, Solomon T, Kneen R. Neurological manifestations of influenza infection in children and adults: results of a National British Surveillance Study. Clin Infect Dis. 2014 Mar;58(6):775-84.
17. Mizuguchi M. Influenza encephalopathy and related neuropsychiatric syndromes. Influenza Other Respir Viruses. 2013 Nov;7 Suppl 3:67-71.
18. Greene SK, Li L, Shay DK, Fry AM, Lee GM, Jacobsen SJ, Baxter R, Irving SA, Jackson ML, Naleway AL, Nordin JD, Narwaney KJ, Lieu TA. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007-2010. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):335-44.
19. Graner S, Svensson T, Beau AB, Damase-Michel C, Engeland A, Furu K, Hviid A, Håberg SE, Mølgaard-Nielsen D, Pasternak B, Kieler H. Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study. BMJ. 2017 Feb 28;356:j629. doi: 10.1136/bmj.j629.
20. Cheng PY, Palekar R, Azziz-Baumgartner E, Iuliano D, Alencar AP, Bresee J, Oliva O, de Souza Mde F, Widdowson MA. Burden of influenza-associated deaths in the Americas, 2002-2008. Influenza Other Respir Viruses. 2015 Aug;9 Suppl 1:13-21.
21. CDC. Estimated Influenza Illnesses, Medical Visits, Hospitalizations, and Deaths Averted by Vaccination in the United States. Accessed at: https://www.cdc.gov/flu/about/disease/2015-16.htm
22. Vestergaard LS, Nielsen J, Krause TG, Espenhain L, Tersago K, Bustos Sierra N, Denissov G, Innos K, Virtanen MJ, Fouillet A, Lytras T, Paldy A, Bobvos J, Domegan L, O’Donnell J, Scortichini M, de Martino A, England K, Calleja N, van Asten L, Teirlinck AC, Tønnessen R, White RA, P Silva S, Rodrigues AP, Larrauri A, Leon I, Farah A, Junker C, Sinnathamby M, Pebody RG, Reynolds A, Bishop J, Gross D, Adlhoch C, Penttinen P, Mølbak K. Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017. Euro Surveill. 2017;22(14):pii=30506. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.14.30506
23. Uyeki TM, Katz JM, Jernigan DB. Novel influenza A viruses and pandemic threats. Lancet. 2017 Jun 3;389(10085):2172-2174.
24. European Centre for Disease Prevention and Control. Influenza pandemic preparedness plans. Accessed at: https://ecdc.europa.eu/en/seasonal-influenza/preparedness/influenza-pand...

Competing interests: None of the co-authors has any competing financial interests to declare with respect to oseltamivir or the content of our response. As stated in our response, all co-authors are representatives of organizations that provide recommendations for antiviral treatment of influenza or are supportive of such recommendations. Timothy M. Uyeki (on behalf of all co-authors) October 10, 2017

16 October 2017
Timothy Uyeki
Chief Medical Officer
Pasi Penttinen , Mike Catchpole (European Centre for Disease Prevention and Control); Richard Pebody, Maria Zambon, Jake Dunning (Public Health England); John Watson (Department of Health, U.K.); Henry (Hank) Bernstein, Flor M. Munoz, David W. Kimberlin (American Academy of Pediatrics ); Richard Beigi, Laura E. Riley (American College of Obstetricians and Gynecologists); Andrew Pavia, William Powderly (Infectious Diseases Society of America); Paul Spearman (Pediatric Infectious Diseases Society); Nikki Shindo (World Health Organization)
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30329, USA
Re: Which pain medications are effective for sciatica (radicular leg pain)? Rafael Zambelli Pinto, Annemieke J. H. Verwoerd, Bart W. Koes,. 359:doi 10.1136/bmj.j4248

BMJ Rapid Response

Pain Medication for Sciatica.(BMJ 2017;358:j4248)

Those of us working in back pain clinics are well aware that sciatica can last a long time, and analgesia can be a problem.

Almost all sciatica will settle given time, and during this time the physician must be optimistic and try and prevent the slide into inactivity and depression, with the accompanying deconditioning and sensitivity.
Appropriate surgical referral can prevent months of suffering, but to be put on a long waiting list, and eventually to have surgery declined because "there is no nerve root compression" makes the situation worse.

Since 2001 there has been a Community Back Pain Service in Plymouth, run in GP surgeries, and manned by GPs with a special interest, Osteopaths and Extended Scope Physiotherapists. After the first two years a sub-acute clinic was added where patients thought to be in danger of becoming chronic were re-assessed, and could be offered referral for CBT and a non-impact aerobic exercise program.

Patients were of a working age, not making progress, and with symptoms of less than 6 weeks duration.

Treatments included lifestyle advice, manipulation, trigger point therapy, including acupuncture and HCIs. For resistant sciatica the GPwSI could provide Caudal Epidural injections at greater than two weekly intervals, up to a maximum of three. MRIs and surgical referrals were available.

Numbers treated have been over 1000 patients per year, of which the diagnosis in almost half was thought to be discogenic.

Between 2% - 5% annually have been referred to Neurosurgery, and the last acute clinic audited costs (excluding the block MRI contract) were £132 per patient.

The service ensures patients are being supervised by an interested clinician, while several modalities of treatment can be tried. During this time inappropriate referral is avoided, and therefore total referrals must have been reduced. There have been no serious adverse events.

Mike Hopkins Ex GPwSI and Osteopath.

Competing interests: No competing interests

16 October 2017
Michael J Hopkins
Retired GP/Osteopath
Plymouth Back Pain Clinics
Modbury

Pages