Death of a Blogger

The Economist is generally a good read. But it is the obituaries that are especially well written. Recently the obituary made a moving sketch of Dr Mags Portman,[1] proponent of Pre-exposure Prophylaxis for HIV or PrEP. I had not realised how much resistance there had been to adoption of this effective method to reduce risk. I guess there must be some debate about long-term effects on condom use, but the short-term benefit is large at 86% relative risk reduction. Mags was a tireless campaigner and it was tragic to read that her life was cut cruelly short by the disease mesothelioma. Mesothelioma is usually the result of exposure to asbestos. One might have thought that exposure to asbestos was a thing of the past, but Mags believed that she had been exposed while working in a hospital in London. Her life was short but inspiring.

— Richard Lilford, CLAHRC WM Director

Reference:

1. The Economist. One tablet, taken daily. The Economist. 16 March 2019. p86.

Cannabis and Schizophrenia: Which Way Around Does Causality Run?

Does cannabis lead to schizophrenia or does schizophrenia lead to the use of cannabis? That there is a strong, dose-related, association between the use of cannabis and the development of schizophrenia is not in doubt. But association studies cannot prove causality. Furthermore, a dose response can be seen where exposure to the putative causative agent and the true causative agent are correlated.

Genes to the rescue! Power and colleagues looked to see whether genetic polymorphisms that are associated with cannabis use are also associated with schizophrenia in people not exposed to cannabis.[1] They found that genes that pre-disposed to cannabis use also pre-disposed to schizophrenia, independently of whether the person actually used cannabis. The strength of the association between cannabis use predisposing genes and schizophrenia was the same in people who used cannabis, as in those who have never used this substance. Moreover, the risk was the same irrespective of the dose of cannabis consumed. The genetic predisposition to consume cannabis explained less than one-tenth of the variance in cannabis use. Nevertheless, this finding suggests that it is the predisposition to use cannabis, rather than the cannabis itself, that causes the psychiatric symptoms. If corroborated, then this study has important implications for policy.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Power RA, Verwij KJH, Zuhair M, et al. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatr. 2014; 19: 1201-4.

Reducing Risk of Postpartum Haemorrhage in LMICs

­Worldwide around 127,000 women die each year due to postpartum haemorrhage (the loss of 500ml of blood within the first 24 hours after giving birth), making it the most common cause of maternal death.[1] It is especially prevalent in low- or middle-income countries (LMICs). The standard treatment is administration of oxytocin – however, the drug needs to be kept at 20-25°C, which can be difficult in some countries where refrigeration isn’t reliable in either the hospital or whilst being transported. Thus, there is a need for an alternative option. Widmer and colleagues conducted a double-blind RCT of nearly 30,000 women across ten countries comparing postpartum administration of oxytocin with carbetocin, a heat-stable oxytocin analogue that can be stored at room temperature.[2] Both groups of women showed similar frequencies of blood loss – 14.4% of those given oxytocin lost >500ml of blood, compared to 14.5% given carbetocin (relative risk 1.01, 95% CI 0.95-1.06); while, respectively, 1.45% and 1.51% lost >1000ml of blood (relative risk 1.04, 95% CI 0.87-1.25). There were also no significant differences in necessary interventions or adverse events.

Carbetocin could even perform better than oxytocin in LMICs as the oxytocin was stored in optimum conditions, which may not accurately reflect real-life settings. It will be interesting to track the implementation to uptake of this new finding – any takers?

— Peter Chilton, Research Fellow

References:

1. World Health Organization. Making Pregnancy Safer. Issue 4. Geneva, CHE: World Health Organization; 2007.
2. Widmer M, Piaggio G, Nguyen TMH, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. New Engl J Med. 2018.

Non-Antibiotic Medicines May Increase Antibiotic Resistance

Alexander Fleming predicted the emergence of antibiotic resistance, and he was soon proved right. The increase in antibiotic resistant bacteria has been at least partially due to the over prescribing of antibiotics by GPs, healthcare centres, etc.[1] Steps have been taken in­­ recent years to combat this,[2] though a recent database study by Smieszek, et al. estimated that between 8.8%-23.1% of antibiotic prescriptions in English primary care were inappropriate,[3] and the situation is much worse in low- and middle-income countries.[4] Now, a study published in Nature by staff from the European Molecular Biology Laboratory has found potential risk from prescribing non-antibiotics.[5]

Previous research has found that medication that targets human cells, as opposed to microbes (for example, anti-diabetics, proton pump inhibitors, non-steroidal anti-inflammatory drugs) may alter the composition of the gut flora. In order to determine the extent of such effects the authors tested over 1,000 drugs against 40 human gut bacterial strains. They found that 24% of those with human targets inhibited the growth of at least one of the strains (and 5% affected at least ten strains). While this could offer new avenues for future drug-therapy research and personalised medicine, the authors also found strong correlation between resistance to antibiotics and to drugs that target human cells, likely due to common mechanisms conferring resistance. This means there is a potential risk of non-antibiotics promoting antibiotic resistance in some bacteria – a concern with the large amount of non-antibiotics taken on a regular basis by a large number of people.

— Peter Chilton, Research Fellow

References:

1. Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, Laxminarayan R. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis. 2014; 14(8): 742-50.
2. Hoffman SJ, Outterson K, Røttingen J-A, et al. An international legal framework to address antimicrobial resistance. Bull World Health Organ. 2015; 93(2): 66.
3. Smieszek T, Pouwels KB, Dolk FCK, et al. Potential for reducing inappropriate antibiotic prescribing in English primary care. J Antimicrobial Chemo. 2018; 73(s2): ii36-43.
4. Das J, Chowdhury A, Hussam R, Banerjee AV. The impact of training informal health care providers in India: A randomized controlled trial. Science. 2016; 354: aaf7384.
5. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555: 623-8.

Antibiotics Work!

Yes, an RCT of antibiotics vs. an anti-inflammatory drug in people with lower urinary tract infection shows clearly that the antibiotic is superior in reducing (in fact halving) the mean duration of symptoms.[1] I have worried before [2] about long-term effects of withholding antibiotics in conditions often caused by bacteria – quinsy in throat infections, for example. In this trial the risk of pyelonephritis (kidney infection) was higher in the group from whom antibiotics were withheld. Appropriate targeting of antibiotics is important. And I prefer high dose, short duration therapy regimes.[3] [4]

— Richard Lilford, CLAHRC WM Director

References:

1. Kronenberg A, Bütikofer L, Odutayo A, Mühlemann K, da Costa BR, Battaglia M, Meli DN, Frey P, Limacher A, Reichenbach S, Jüni P. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. 2017; 359 :j478.
2. Lilford RJ. Protocol to Test Hypothesis That Streptococcal Infections and Their Sequelae Have Risen in Incidence Over the Last 14 Years in England. NIHR CLAHRC West Midlands News Blog. 13 January 2017.
3. Lilford RJ. Not Taking a Full Course of Antibiotics. NIHR CLAHRC West Midlands News Blog. 29 September 2017.
4. Lilford RJ. More Evidence for Short Doses of Antibiotics in Infection. NIHR CLAHRC West Midlands News Blog. 5 June 2015.

Preventing Strokes

Strokes affect over 100,000 people each year in the UK,[1] with atrial fibrillation (AF) being a contributing factor in around 20% of these cases.[2] In total there are around 1.2m people in the UK living with AF,[3] though estimates suggest another 500,000 remain undiagnosed,[4] and they have a five-fold risk of a stroke.[5] Most of these people are prescribed long-term anticoagulants as a preventive method, predominantly warfarin. However, use of warfarin requires regular monitoring to avoid complications, such as clot formation or uncontrolled bleeding. Therefore there is a need to improve the clinical utility of using anticoagulants as a preventive method – either by using direct-acting oral anticoagulants (DOACs) instead, or improving the use of warfarin.
A number of RCTs have been conducted, which showed that DOACs were the better option in terms of key indicators, having a wider therapeutic range, and as their use did not require regular monitoring. As such, NICE updated their guidance in 2014, advising that both DOACs and warfarin should be given equal weight at consultations. From this there has been an increase in the use of DOACs in clinical practice, and a corresponding increase in expenditure – more than £100 million in the NHS in 2015/16, and £400 million in 2016/17.[6] An article by Sir John Burn and Munir Pirmohamed published in Open Heart takes a look at the evidence for DOACs vs. warfarin,[6] and argues there are a number of major concerns with the use of DOACs:

• RCTs generally have a younger study population, with fewer comorbidities, and thus fewer adverse events. Further, there is not enough evidence on the impact of drug-drug interactions with DOACs.
• Analysis of prescription issuance shows that patients are less likely to adhere to regimes of DOACs, perhaps due to the lack of routine monitoring and that some of the drugs need to be taken twice a day.
• Evidence suggests a possible link between DOACs and myocardial infarction.

Instead, the authors argue that it is possible to improve the effectiveness of warfarin using a simple genotype guidance that identifies patients more suited to warfarin treatment, and by increased adoption of home monitoring technology. This would also reduce the rising expenditure facing the NHS.

— Peter Chilton, Research Fellow

References:

1. Royal College of Physicians Sentinel Stroke National Audit Programme (SSNAP). Is stroke care improving? Second SSNAP Annual Report prepared on behalf of the Intercollegiate Stroke Working Party November 2015. 2015.
2. Royal College of Physicians Sentinel Stroke National Audit Programme (SSNAP). National clinical audit annual results portfolio March 2015-April 2016. 2016.
3. NHS Digital. Quality Outcomes Framework (QOF) – 2015-16. 2016.
4. Stroke Association. State of the Nation. 2017.
5. Savelieva I, Bajpai A, Camm AJ. Stroke in atrial fibrillation: Update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. Ann Med. 2017; 39: 371-91.
6. Burn J, Pirmohamed M. Direct oral anticoagulants versus warfarin: is new always better than the old? Open Heart. 2018; 5: e000712.

Psychotropic and Anti-Addictive Medication After Release from Prison and Risk of Reoffending

Another great Scandinavian linkage study compares methods to reduce violent reoffending after release from Swedish jails, both across and within individual ex-prisoners.[1] The results confirm the results of RCTs in non-prisoner populations – psychotropic drugs reduce violent reoffending by about a third, and drugs to combat addiction by about 40% (using within person analysis to control for many sources of confounding, such as genetic predisposition, adverse upbringing, etc.). Similar results were obtained in the (potentially more confounded) between person analysis. Anti-depressant drugs had no apparent effect on reoffending in any analysis. Of course, this is an observational study and reverse causality, even within individuals is possible, but it is the best information we are likely to have for some time, and is relevant to attempts to reduce the duration of incarceration in many countries, including England. The fact that the results mirror experimental studies in at-risk people who had not been to prison adds verisimitude to the findings.[2]

— Richard Lilford, CLAHRC WM Director

Reference:

1. Chang Z, Lichtenstein P, Långström N, Larsson H, Fazel S. Association Between Prescription of Major Psychotropic Medications and Violent Reoffending After Prison Release. JAMA. 2016; 316(17): 1798-1807.
2. Chen Y-F, Hemming K, Chilton PJ, Gupta KK, Altman DG, Lilford RJ. Scientific hypotheses can be tested by comparing the effects of one treatment over many diseases in a systematic review. J Clin Epidemiol. 2014; 67: 1309-19.

Legalisation of Marijuana

Having borne down heavily on tobacco, it seems like everyone is now campaigning to make marijuana legal – are they mad?

A libertarian would say that there is no case to ban tobacco (or effectively ban it by draconian taxes on consumption). All tobacco can do is kill you, and as long as you know this you may use it. Marijuana is a different case altogether. It appears that it does not just kill you, it maims you – and not just your body, but you – your personality, your memory, your intelligence, i.e. your essence. And it is particularly attractive to teenagers – those with the most precious and vulnerable brains. Use is increasing in the US and has increased in association with decriminalisation, even if cause and effect is hard to prove.[1] Meanwhile a recent longitudinal cohort study found that persistent cannabis dependence was linked to downward socioeconomic mobility, financial difficulties, workplace problems, and relationship conflict.[2] It gets worse, the concentration of psycogenic compounds is increasing in the plant due to selective breeding. The attitude and fashion among liberal metropolitans “tobacco is vulgar, but marijuana is cool.” Have we gone mad? If we could confine the need to people over 18, and campaign against it, then over time we could reduce use. But a chemical that actually alters the structure of the adolescent brain and is more ubiquitous than boxing? We urgently need more information on the effects legalising cannabis has on usage. Also, more research on its effects on the brain using functional MRI. I wonder if Mendelian randomisation could shed light on causality?

— Richard Lilford, CLAHRC WM Director

References:

1. Azofeifa A, Mattson ME, Grant A. Monitoring Marijuana Use In the United States: Challenges in an Evolving Environment. JAMA. 2016; 316:1765-6.
2. Cerdá M, Moffitt TE, Meier MH, et al. Persistent Cannabis Dependence and Alcohol Dependence Represent Risks for Midlife Economic and Social Problems: A Longitudinal Cohort Study. Clin Psychol Sci. 2016; 4(6): 1028-46.