Episodi

  • Dr. Daniel Aronov

    Does dust mite avoidance improve asthma? 


    Asthmatics are commonly advised to do things to reduce dust mites in their environment: vacuum regularly, wash the curtains, avoid soft toys, wash bed linen regularly, etc.


    This is because there is a strong association between asthma and house dust mite allergy: Around 65% of asthmatics are also allergic to house dust mites (on skin prick testing) and it seems that higher exposures to house dust mite allergens are associated with worsening asthma. But is this relationship causal? Will reducing house dust mite allergens in the environment actually improve asthma?



    This episode looks at the evidence around reducing exposure to house dust mites and its impact on asthma management.
    Bottom Line:
    Using dust mite impermeable bed linen reduces asthma-related hospitalisations for 1 in 8 children per year (provided these children have already had an exacerbation that led them to go to hospital, and that they have a positive skin prick reaction to dust mites) This was shown in a randomised controlled trial (2017) of 286 children. There was, however, no difference in the number of children who required a course of oral steroids and no meaningful difference asthma control scores. Furthermore, other studies, albeit of generally poor quality, have failed to show a benefit with dust mite impermeable bedding.
    References:

    Cochrane review: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001187.pub3/full
    2003 RCT: http://www.nejm.org/doi/full/10.1056/NEJMoa023175
    2017 RCT: https://www.ncbi.nlm.nih.gov/pubmed/28282501?dopt=Abstract

  • Dr. Daniel Aronov

    A pregnant woman has come to you for her first antenatal appointment. She’s perfectly healthy with no signs or symptoms of thyroid disease. You arrange the gamut of blood tests: full blood exam, blood group, HIV, etc., but do you also check her Thyroid Stimulating Hormone levels (TSH) to screen for thyroid problems? And if she ends up having subclinical hypothyroidism, do you treat it? This week we look at the evidence, the guidelines and the history to try and answer this question.

    The story of treating subclical hypothyroidism in pregnancy unfortunately, follows a very common formula in medicine:

    Here’s how it goes:

    Step 1: Data from observational studies suggest a strong association between an abnormal blood test and disease.
    Step 2: Guidelines jump on this data very quickly and make strong recommendations to fix the blood test if it's abnormal to try and reduce said disease.
    Step 3: This practice quickly becomes the standard of care.
    Step 4: Only after this has become standard of care is a good quality randomised controlled trial finally conducted to actually test the recommendations by the guidelines - to see if fixing the abnormality on the blood test actually improves the disease.
    Step 5: The randomised controlled trial/s shows that fixing the abnormal blood test has absolutely no impact on the disease to which it is associated.

    The worst part about this formula is step 6: That it often takes years or decades for practice to change now that there is good evidence that what we were doing was wrong.

    Let’s follow the history of treating subclinical hypothyroidism and see how it fits this formula to a tea!

    But first let’s define our terms: Subclinical hypothyroidism is when the TSH is elevated, but the thyroid hormone or T4 is within the normal range. So there must be some low thyroid hormone process going on, because it’s stimulating TSH to make more but the system is compensating and maintaining normal thyroid hormone levels. Theres another term called hypothyroxinaemia - this is the reverse - where there is low T4 but the TSH is within normal range. Then you can get a low T4 plus a high TSH - and this would just be called straight up hypothyroidism. But I would argue that you could even split this into two: symptomatic hypothyroidism and non-symptomatic hypothyroidism. Non-symptomatic hypothyroidism would be where the patient has low T4 and a high TSH but feels completely fine with no symptoms or signs of hypothyroidism whatsoever.

    So let’s go through our little formula:

    Step 1: Data from observational studies suggest a strong association between an abnormal blood test and disease.

    We have known for over a hundred years that hypothyroidism is associated with adverse pregnancy and neonatal outcomes, like mental retardation. That’s when it was discovered that overt hypothyroidism, where patients were iodine deficient and had symptomatic hypothyroid disease was associated with impaired brain function in the baby. But what about if the women are totally asymptomatic but have a low thyroid hormone or a high TSH? Well, in 1999 two studies came out to show that even in these women, there is an association with poor brain development of the child.

    One study measured the TSH in 25,216 pregnant women and found that those with TSH levels in the top 0.3% ended up having children with lower IQ scores

    The second study followed 220 pregnant women and found that babies born to mothers with lower T4 at the time of pregnancy did worse on  psychomotor development scores.

    So there seems to be a pretty consistent association. The problem is, there was absolutely no evidence that fixing the thyroid hormone levels leads to better outcomes. But that didn’t stop Step 2 of our association formula from going full steam ahead.

    Step 2: Guideline committees make strong recommendations to fix the abnormal blood test to try and reduce the disease.

    Well,

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  • By Dr. Daniel Aronov

    A patient presents with acute urticaria (hives) and after your comprehensive assessment, you decide to give them an antihistamine. But do you also give them a corticosteroid? Maybe some prednisolone to speed up the recovery from their hives? It’s a pretty common practice, in a study of one emergency department in Italy, 93% of those presenting with acute urticaria where treated with steroids on top of their antihistamine. But does it actually add any benefit on top of antihistamines? This episode we explore the evidence

    Approximately 10% of the population will develop acute urticaria at some point and most of the time we have no idea what causes it. Idiopathic urticaria, where no trigger is identified, is actually the most common cause (60% of cases). When a trigger for the urticaria is identified, in about 40% of cases, most are due to drugs, then insect bites, then foods.

    There have only been 2 randomised controlled trials to answer today’s question. One done in the United States in 1995 and the other done in France in 2017.
    Pollack, 1995
    This was conducted out of one Emergency Department in Phoenix, Arizona in America. Anyone who came into this Emergency Department over a 7 month period with a generalised itchy, urticarial rash was enrolled in the study. The rash had to be present for less than 24 hours and if they had any signs of a more serious allergic reaction, like angioedema or stridor, then they were excluded. They were also excluded if it was only a local allergic reaction or if they had already used an antihistamine or steroid in the previous 5 days.

    They were all given a 50mg intramuscular shot of diphenhydramine in the emergency room and then randomised into two groups: This first group were sent home with an antihistamine (hydroxyzine)  and prednisolone (20mg twice per day for 4 days).  The second group were sent home with an antihistamine, plus a placebo to take twice per day for 4 days.

    They recruited 43 patients all together, 19 in the placebo group and 24 in the prednisolone group. The primary outcome was the average change in Itch Score (0-10 itchiness rating) at day 2 and day 5
    Results
    The average itch score when they presented to the ED was somewhere between 7.5 and 8. On day 2, the average itch score was 4.4 in the placebo group and 1.3 in the steroid group (a  3 point reduction in the 10 point itch scale with adding prednisolone to the antihistamine). At the 5 day mark, the itch score was 1.6 in the placebo group and 0 in the steroid group.
    Barniol, 2017
    This study recruited 100 participants presenting with acute urticaria to one of 2 emergency departments. Again they were excluded if they had angioedema or anaphylaxis. They had to have had the rash for less than 24 hours and they can't have used steroids or antihistamines within the last 5 days.

    They were randomised to either antihistamine plus steroid or antihistamine alone. The antihistamine they used this time was levoceterizine 5mg daily for 5 days and for the steroid, they used prednisolone 40mg once daily for 4 days.

     

    The primary outcome was how many people had an Itch Score of 0 out of 10 on day 2.. They also checked itch scores at 5 days, 15 days and 21 days.
    Results
    At  2 days: 79% of those in the placebo group had absolutely no itch (An Itch Score of 0 out of 10 ), But in the prednisolone group, 62% had an itch score of 0. This was the only statistically significant result. All other results: Itch Score at 5, 15 and 21 days and complete resolution of rash were not statistically different between the two groups.
    Bottom Line
    There have been 2 randomised controlled studies assessing the benefit of steroids on top of antihistamines for the treatment of acute urticaria. One study from 1995 with 43 patients found that steroids improved itch scores by 3 points on a 10 point itch scale by day 2.  The second study had 100 patients and was done in 2017.

  • Dr. Daniel Aronov

    This episode is a live broadcast from a lecture given at the Royal Australian College of General Practitioners conference. It is a collection of my favourite evidence-based clinical pearls for the most common presentation in primary care: respiratory tract infections. We'll cover antibiotics for otitis media, sore throat and bronchitis, steroids for sore throat, Tamiflu, treatments for cough and a few other random things in between.
    To watch this talk with the slides head on over to my YouTube channel (and subscribe while you're there ;-p): www.youtube.com/drdanMD
    References:

    Ebell, M., et al., How Long Does a Cough Last? Comparing Patients’ Expectations With Data From a Systematic Review of the Literature. Annals of Family Medicine  Feb 2013
    Thompson M, Vodicka TA, Blair PS, et al, for the TARGET Programme Team. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ 2013;347:f2027
    Smith SM,, Fahey T,, Smucny J,, Becker LA.. Antibiotics for acute bronchitis.. Cochrane Database of Systematic Reviews 2014,, Issue 3.. Art.. No..:: CD000245.. DOI:: 10.1002//114651858..
    Paul;, et al., Effect of honey, dextromethorphan (robitussin), and no treatment on nocturnal cough and sleep quality for coughing children and their parents., Arch Pediiatric Adolescent Medicine 2007
    Shadkam, et al., A Comparison of the Effect of Honey, Dextromethorphan, and Diphenhydramine on Nightly Cough and Sleep Quality in Children and Their Parents. Journal of Alternative Complementary Medicine, 2010.
    Cohen., et al. Effect of honey on nocturnal cough and sleep quality: a double blind, randomized, placebo-controlled study. Pediatrics 2012
    Paul, et al. Vapor Rub, Petrolatum, and No Treatment for children with nocturnal cough and cold symptoms. Pediatrics Nov 2010
    Centor, et al. The diagnosis of strep throat in adults in the emergency room. Medical Decision Making., 1981
    Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD000023. DOI: 10.1002/14651858.CD000023.pub4.
    Hayward G, Thompson MJ, Perera R, Glasziou PP, Del Mar CB, Heneghan CJ. Corticosteroids as standalone or add-on treatment for sore throat. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD008268. DOI: 10.1002/14651858.CD008268.pub2.
    https://www.theguardian.com/business/2014/apr/10/tamiflu-saga-drug-trials-big-pharma
    Vergison, et al., Otitis media and its consequences: beyond the earache. Lancet 2010
    Venekamp RP, Sanders SL, Glasziou PP, Del Mar CB, Rovers MM. Antibiotics for acute otitis media in children. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD000219. DOI: 10.1002/14651858.CD000219.pub4.

  • This episode takes a deep dive into the evidence for and against the lipid hypothesis. The lipid hypothesis states that abnormal blood cholesterol levels cause cardiovascular disease. But is this true? Does high LDL ("bad cholesterol") and/or low HDL ("good cholesterol") actually CAUSE cardiovascular disease or is it just an association? This episode was recorded live from a General Practitioner conference. To view the presentation with the slideshow visit: www.youtube.com/DrDanMD

  • The ALL-HAT trial is by far the most important clinical trial ever done in the management of hypertension. It answers the question: Which class of antihypertensive medication is the best for reducing cardiovascular disease? And it is the definitive source for the answer. They randomised a whopping 42,000 patients to get one of the four antihypertensive medications: an ACE-inihibitor, a calcium channel blocker, a thiazide or an alpha-blocker. The ACE-inihibitor they used was lisinopril, the calcium channel blocker was amlodipine,  the thiazide was chlorthalidone and the alpha-blocker was doxazocin. They followed for between 4-8 years and they where interested in how many in each group develop cardiovascular disease. Perhaps one class of antihypertensive is better than the others?

    The trial was started in the mid-90s, when the thiazide, chlorthalidone, had been around for ages and the case for lowering blood pressure was now well established.  Lot’s of new agents were coming to market and each being vastly more expensive chlorthalidone. So the authors were interested in whether the more expensive drugs at the time: ACI inhibitors, Calcium channel blockers or alpha blockers were actually any better than good old cheap chlorthalidone?
    Methods
    The 42,000 participants were recruited from 623 centres in the US, Canada and Puerto Rico between 1994 and 1998. There were three main inclusion criteria:

    They had to be 55 years old or older
    They had to have hypertension as defined as either a systolic BP greater than 140 or a diastolic BP greater than 90.
    They had to have one additional risk factor for cardiovascular disease on top of hypertension. And this could be: Either a previous heart attack, type 2 diabetes, currently smoking, left ventricular hypertrophy on ECG or echo or an elevated cholesterol.

    The only excluded those who had symptomatic heart failure. They did not exclude patients who were already taking antihypertensive, in fact, 90% of them were, but they stopped them all when the study started. On the day of randomisation, they stopped all of their antihypertensives, then the next day they started their study drug. That way they were testing that particular drug in the purest way possible.

    They concealed allocation and randomised to a 1.7:1:1:1 ratio so that more participants were in the thiazide group. Around 15,000 were randomised to chlorthalidone and around 9000 to each of doxazocin, lisinopril and amlodipine. They stopped the trial in 2002 so those who were recruited in 1994 were followed up for 8 years while those were recruited in 1998 were followed up for 4 years. On average, the follow up was 5 years. They followed them up every 3 months in the first year then every 4 months in the following years. They would increase the dose of the study drug to get the BP to a target of below 140/90. If they couldn’t do that with maximal dose, then they would add in either atenolol, clonidine or reserpine and this was up to the doctor.

    The primary outcome was heart attack - either fatal heart attacks or non-fatal heart attacks. Secondary outcomes included: stroke, all-cause mortality, cancer, GI bleed, end-stage renal failure and a composite of all the bad cardiovascular outcomes.
    Results
    Baseline characteristics

    The average age was 67
    half of them were women
    the average Blood Pressure was 146/84,
    22% were smoking
    51% had established cardiovascular disease,
    36% had type 2 diabetes
    The average BMI was 29.2
    Around 30% were black, 70% white.

    Alpha-Blocker (Doxazocin)
    They stopped the doxazosin (Cardura) arm of the trial early because an interim analysis showed that it was inferior. They published this interim analysis on doxazosin in a separate article before the results of the main trial came out. It was in JAMA in the year 2000. After an average of 3.3 years of follow up for this interim analysis, they found that compared to the thiazide chlorthalidone:

  • By Dr. Daniel Aronov

    On average, children get about 8 upper respiratory tract infections per year. Most of which involve a cough which can be a nuisance. It can ruin the child’s sleep and the parents sleep and it can also be very distressing for the parents. A survey found that one of the common fears about their child’s cough is that they may die from asphyxiation. It’s no wonder then, that we spend a fortune on cough medications. In Australia alone, we spend $67 million per year on over the counter cough medications for kids. Yet, almost all guidelines and drug regulators warn against using them because they don’t work and they may be harmful. the Australian therapeutic guidelines, the Royal children’s hospital guidelines, the American Academy of Paediatrics guidelines, the FDA and the TGA, to name a few, all recommend against using cough medicines in kids under 6 years of age. So is there anything else we can use to combat cough in kids? Some cultures have an age-old tradition of giving honey to treat coughs, and believe it or not, honey as a treatment for cough has been tackled in the scientific literature 3 times! This week, we look at the evidence.

    By far, most of the over-the-counter cough medications have dextromethorphan as their active ingredient: Robitussin, Dimetapp (cough, cold and flu), Vicks, Codral (Cold&Flu and cough), Bisolvon, Mucinex, and others.
    Occasionally, like in Benadryl, Diphenhydramine is the antitussive ingredient.
    RCT 1 - (Paul, 2007)
    The first of our three randomised controlled trials compared honey, to dextromethorphan to usual care (doing nothing). It was done in Pennsylvania in the United States and was published in 2007 in the Archives of Paediatric and Adolescent Medicine.

    They recruited anyone between the ages of 2 and 18 who presented to a single pediatric clinic in Pennsylvania with a cough that was due to an upper respiratory tract infection, having been present for less than 7 days.

    All three of these RCT’s were just a one-day study. They did a cough survey on the day they presented to their doctor, then that night they got the honey pr the placebo, then the next day the would repeat the cough survey to quantify the difference in cough between the two nights. So as they came to their paediatrician, wanting them to fix their child’s cough, they were asked if they wanted to participate in the study. If they consented, they immediately had to fill out a questionnaire about the child’s cough from the night before (when they didn’t have any treatment for their cough). All three randomised controlled trials used the same questionnaire which had five questions, each with 7 possible tick box answers. The questions were:

    How severe was your child’s cough last night?
    How frequent was your child’s cough last night?
    How bothersome was your child’s cough last night?
    How much did your child’s cough affect the child’s ability to sleep?
    How much did the child’s cough affect the parent’s ability to sleep?

    The possible answers were:

    not at all
    not much
    a little
    somewhat
    a lot
    very much
    extremely

    Only parents who gave a score of at least 3,  (“somewhat”) for at least 2 of these 5 questions, were then able to be included in the study. They managed to recruit 130 kids, but only 105 completed the study for whatever reason. They were then randomised into three groups: The first group got an artificially honey-flavoured dextromethorphan preparation. The second group got honey. And the third group got nothing. The honey they used was buckwheat honey. Good on them for making an artificial honey flavoured dextromethorphan! So the no treatment arm were not blinded but the honey and dextromethorphan groups were. And the investigators were blinded from all three interventions. They gave the honey or dextromethorphan in an unlabelled syringe and were told to give it to their child 30 minutes before bed that night.

  • By Dr. Daniel Aronov

    14.5% of Australian adults smoke cigarettes - this is down from 22.4% at the turn of the century. The rates are similar in the US but much higher across Europe - with an average closer to 30%.
    There’s pretty much nothing we can do for a smoking patient that would improve their health as much as getting them to quit smoking would. So how do we do it? Firstly, are you more likely to quit successfully if you stop it “cold turkey”, or is it better to stop gradually? Secondly, can medications help? and by how much?
    This week we look at a randomised controlled trial that compared gradual smoking cessation to abrupt cessation. We'll then examine the evidence for each of the different pharmacological treatments used to help people quit.
    Etymology of "Cold Turkey"
    Given that it’s almost universally used to depict the sudden stopping an addiction suddenly, where in the world did this term come from?
    According to the Online Etymology Dictionary, it came from the fact that cold turkey is a dish that doesn’t require much preparation. So quitting "cold turkey", is quitting suddenly or without any preparation. But then dictionary.com reports it’s origin comes from a common phrase used in America in the 1950’s: “to talk turkey” which means to speak bluntly about something. …if only there was a peer-reviewed journal of etymology.
    Benefits of quitting smoking
    I think we are all sold on the benefits of quitting smoking, but it's worth mentioning one particular trial just to remind us. It was published in Chest in 2007 and the brilliance of this trial was that they were assessing the outcomes of a smoking cessation intervention, rather than whether they actually quit or not. Normally studies will tell us, say, the cardiovascular disease reduction in a group of people who quit smoking versus those who continued smoking. But this study just assessed the cardiovascular outcomes from whether you gave an intervention to help people stop smoking or whether you didn’, regardless of how many actually quit in each group.
    They recruited 209 smokers who had just been admitted to hospital for either heart failure or a heart attack. Everyone got about half an hour of counselling about the harms of smoking and how to quit and were given a lot of written information prior to discharge from hospital. They were then randomised into two groups: An intensive treatment group who got a further 12 weeks of counselling plus pharmacological therapy to help them quit like nicotine replacement therapy or bupropion. The second group was a usual care group who didn’t get further intervention outside of that 30 minute counselling session in hospital.
    At the end of 2 years, the mortality rate was 12% in the usual care group, but in the intensive smoking cessation group it was only 2.8%. So a 10% absolute reduction in all-cause mortality after 2 years just by providing an intervention to help patients quit. This is unheard of for any other intervention. Let’s compare it to aspirin for example, because no doctor in the world would not be firm about taking aspirin after a heart attack (unless they couldn’t take it for whatever reason). But giving aspirin for 2 years after a heart attack leads to a 1.4% reduction in mortality. So this 10% is huge.
    What’s encouraging to me, is that the rates of smoking cessation at 2 years were not fantastic. 9% in the usual care group and 33% in the intensive treatment group. So it’s nice to know that even if the majority of patients are not quitting despite your constant nagging, overall, it's still providing a very impressive benefit.
     Cold Turkey Versus Gradual Quitting
    A good quality randomised controlled trial has been conducted to see whether gradual smoking cessation is more or less effective than cold turkey. It was published in the Annals of Internal Medicine in May 2016.

    They took 697 adult smokers who were smoking at least 15 cigarettes per day and were addicted.

  • There’s no doubting that allergies are on the rise. We know it because when we were in school it was pretty rare, but for kids in school nowadays its all too common. The United States, who have been collecting data on the rates of peanut allergy over time, found that in 1997, 0.4% of people reported peanut allergy, and this had tripled by 2008 to 1.4%. Currently, it’s around 2%. Medicine has done a complete 360 in the way that it thinks about allergies and it’s all thanks to the LEAP trial. (...or is it a 180?)
    Guidelines
    Could it be that expert guidelines have contributed to this massive rise in allergies?

    Almost all guidelines, up until recently, have been recommending that we avoid giving babies any sort of allergic foods. The theory was that if babies don’t come into contact with their allergen early in life, they will be less likely to develop an allergy. The United Kingdom Department of Health commissioned a working group on allergies who issued the following recommendations in 1998: If the mother or father or any siblings of the baby have any sort of atopic disease (hay fever, asthma, eczema or allergies), they should avoid eating peanuts during pregnancy, avoid eating peanuts while breastfeeding and avoid giving any peanut products to the child until they are at least 3 years old!

    Meanwhile, in the US, the American Academy of Paediatrics, in the year 2000, issued the same recommendations. Here’s a quote from the guidelines: “Mothers should eliminate peanuts and tree nuts (eg, almonds, walnuts, etc) and consider eliminating eggs, cow's milk, fish, and perhaps other foods from their diets while nursing. Solid foods should not be introduced into the diet of high-risk infants until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, nuts, and fish until 3 years of age”

    Amazing that there was universal agreement on this despite no evidence to back up these recommendations.

    Unfortunately, making recommendations without any scientific evidence to back them up is all too common for guidelines. A group of researchers showed that only 6% of recommendations made by endocrinology guidelines were based on randomised controlled trial evidence. And Pierluigi Tricoci and colleagues (JAMA 2009) showed that for cardiology guidelines, this was 11%. Now that’s not the issue,  there are a lot of things in our practice that don’t have randomised controlled trial data to guide our decisions. Fine. But here’s the problem: This study also found that 50% of the recommendations were based on opinion only. So no evidence to back it up WHATSOEVER! Again, this is not necessarily a bad thing. But what is completely unacceptable, is that these recommendations are written with the exact same authority as the ones based on high-quality evidence. The same tone, the same language, the same style. And then these become absolute truths.  It's even more frightening when you consider that 50-80% of members in guideline committees have financial conflicts of interest (Neuman 2011). Guidelines need to be more humble when they are making recommendations that are based purely on expert opinion - they should change their wording to something like: “there is no evidence for this recommendation but the committee felt that this was the best approach to manage this situation”.  Therefore, patients and doctors can exercise their judgment when applying these recommendations to the very nuanced clinical scenario they are facing.

    Back to peanuts. What if the recommendations to exclude dietary allergens early in life was actually harmful? What if it contributed to the huge rise in allergies we've been facing?
    Early Evidence
    In 2008, a team of researchers, led by George Du Toit, published an interesting observational study that got everyone thinking.

    They surveyed 5,600 parents of Jewish kids in Israel to determine their rates of peanut allergy, and they also surveyed 5,

  • Almost all guidelines are recommending that we should reduce dietary fats and restrict saturated fats. The PURE study has called to question these recommendations and in this episode, we explore the evidence.

    It's very hard to find a guideline that does not recommend reducing total fat and saturated fat intake:

    The Australian Heart foundation guidelines
    The heart association guidelines
    The Australian dietary guidelines
    The RACGP and Diabetes Australia diabetes guidelines
    The American Heart Association Guidelines
    The NICE cardiovascular disease guidelines
    The World Health Organisation healthy diet guidelines
    The World Heart Federation guidelines

    ...and the list goes on and on. It seems that every single evidence based guideline has made a statement on limiting fat intake and on avoiding saturated fats, but are these statements evidence based? A study from the Lancet from the PURE trial has resurfaced this controversy and in this episode, we will explore the evidence.
    Ecological Evidence
    Saturated fats are in eggs, animal meats and milk products like milk, cream, cheese and butter. The recommendation to avoid saturated fats is so well known and so widely adopted that you’d think there was pretty solid evidence to back it.  Well you might be surprised - because the recommendation to decrease fat and avoid saturated fats actually came from pretty weak evidence from ecological studies. This is where you look at different populations, see what they eat and count their heart attacks. If a population is having more heart attacks, see if you can blame something in their diet. The most famous of these studies was the seven countries study by Ancel Keys. Here, Keys showed that the Countries which ate the most saturated fat had the most heart attacks. Fascinatingly, he actually collected data from 21 countries but only reported on the 7. When a guy called Jacob Yerushalmy analysed the data from all 21 countries, the association was no longer there. But it was too late, so to speak, the cat was out of the bag. Fats were deemed bad. And saturated fats…worse.

    For a more in depth discussion of the history of fats and diet and guidelines, there’s a book called “Good calories, bad calories” by Gary Taubes that goes into a lot more detail. If you can handle his passive aggressive and sort of salesman type tone, then give it a read.
    Surrogate Marker Studies
    The second piece of evidence used a few decades ago to launch the saturated fat recommendations, is that eating foods high in saturated fats increases cholesterol. (Actually, while it increases LDL it also increases HDL and some studies suggest it conveys a more favourable HDL:LDL ratio). Does it matter though? The reason we care about cholesterol is because of its link to cardiovascular disease.  It is a surrogate marker for cardiovascular disease. But there are plenty of drugs that lower cholesterol but have no impact on cardiovascular disease. So the fact that something lowers cholesterol doesn’t always mean it is good for us. Not only that, but treatments like the Mediterranean diet reduces cardiovascular disease without having any impact on cholesterol levels. So it’s best we use evidence that assesses the impact of low fat diets and low saturated fat diets directly on cardiovascular diseases, rather than on things like cholesterol.
    Cohort Studies
    Since this seven countries trial, studies that have tried to back up the claim that saturated fats are bad, have failed to come through with the goods.

    The next level of evidence, up from ecological studies, are cohort studies - this is where you take a population, ask them how much fat they eat (among other things), and then follow them up to see how many got cardiovascular disease and whether it was associated with their diet.

    A recent review of all of the studies that used this approach was published in the BMJ in 2015 (reference below). They found that there was NO association between saturat...

  • There’s a new cholesterol lowering drug in town and its ability to lower cholesterol is like nothing we’ve ever seen before. It’s called Evolocumab, (trade name Repatha) but is it any good at reducing cardiovascular disease? This week, we delve into the FOURIER trial - a humongous randomised controlled trial that will answer this question.
    Development of Evolocumab
    Evolocumab is a monoclonal antibody PCSK9 inhibitor. It's actually an interesting story how this drug came to be.  A group in Paris who do a lot of research on families with familial hypercholesterolemia had long known about a mutation on Chromosome 1 that was associated with some of these families. They had no idea where and what the gene did but they were aware of it. Then, in another part of the world, researchers in Canada had discovered a new protein involved in cholesterol regulation whose gene was also located on Chromosome 1. The two teams got together and eventually, in 2003, discovered it was all the same gene. The gene was for PCSK9 and certain mutations that over-activated this gene seemed to be linked to familial hypercholesterolemia.  But it was also discovered that people with mutations that de-activated this gene had very low levels of cholesterol and perhaps even reduced cardiovascular disease. The more PCSK9 the higher your cholesterol and the less PCSK9 the lower your cholesterol. So what if we could block PSK9? Well, this multi billion dollar idea was quickly developed by Amgen who made Evolocumab - a fully human monoclonal antibody that binds to PCSK9 and inhibits it. Early phase clinical trials have shown that its ability to reduce LDL is out of this world, like nothing we’ve ever seen before. but we’ve been waiting for big trials on whether it has any impact on cardiovascular disease.
    FOURIER trial
    Wait no longer! Because the FOURIER trial has arrived. It stands for Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk. .....bit of a stretch if you ask me.

    This trial was published in the NEJM in March of 2017.
    Methods
    They recruited 27,564 patients from 49 countries between he ages of 40 and 85 with cardiovascular disease. They had to either have had a stroke, a heart attack or symptomatic peripheral vascular disease. People with angina or stents were not considered having cardiovascular disease.

    The patients also had to have other risk factors that put them at even higher risk than your average secondary prevention patient, like diabetes or smoking.

    They had to have at least an LDL of 1.8mmol/L (70mg/dL) and they had to already be on a statin.

    They were then randomised to either evolocumab or placebo injections. If they were randomised to the evolocumab group, then they could choose between having a 140mg injection every 2 weeks or 420mg injections every month. And the gave the same choice to those in the placebo group to ensure blinding.
    Results
    They ended up with 27,564 patients. The average age was 63 and one-quarter of them were women. 80% of them had had a history of myocardial infarction and 20% had a history of stroke. 70% were taking a high dose statin and the rest were taking a moderate dose. 90% were on aspirin. 30% of them were smokers….even after having their heart attack or stroke!

    The average LDL was 2.4mmol/L (92mg/dL), and they were able to lower this by 60% with evolocumab….which is huge! Most were already on maximal dose statin so this is very impressive.

    They followed them up for just over 2 years.

    The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.

    So what did they find?

    The primary outcome occurred in 11.3% of the placebo group, and in the evolocumab group…it went down to 9.8%. So this gives a 1.5% absolute reduction. The relative risk reduction is 13%

    Where relative risk reduction is very useful is if the baseline risk is different for...

  • Night time leg cramps are very common and can ruin sleep. One study surveyed 490 veterans and found that 60% of them had suffered from night time leg cramps and 1/4 of those had them regularly. A lot of people use magnesium to ease their nocturnal cramps and they often swear by them, but do they actually work? This week, we delve into the evidence of magnesium for leg cramps.

    A study published in JAMA in May of 2017 has tried to answer this question.
    Methods
    This was a randomised, double blind, placebo controlled trial that was conducted in Israel. They first recruited people using flyers and posters inviting anyone who suffers from leg cramps. Then, for anyone who expressed interest, they put them through a 2 week screening phase where they didn’t give them any treatment but asked them to keep a diary where they had to document how many night time cramps they got and the nature of these cramps. They then used this diary to include or exclude people based on whether they matched the criteria. The criteria was that they had to have at least 4 episodes of nocturnal leg cramps during this 2 week screening phase. And the criteria for what they called a cramp was fairly strict: it had to be painful, occurring at rest, involuntary and causing a palpable knot in the muscle. They excluded pregnant women and those with renal failure.

    166 people responded to the ads, and 94 of those passed the 2 week screening phase and made it into the trial. On average these people were getting 8 night time leg cramps per week. 60% of them were women, and the average age was was 65.

    They were randomised, with concealed allocation, to receive either 865mg of magnesium oxide daily (520mg of elemental magnesium) or placebo to take at night before bed.

    The primary outcome was the change in the number of cramps per week. Secondary outcomes included severity and duration of the cramps, quality of life and quality of sleep. The way they got their data was again with that diary -  Every morning when they woke up they’d write down how many episodes they had, how severe it was from 1-10 and how long they went for. The investigators sent them a text message every morning to remind them to fill out their diary and investigators called them twice per week to see whether there were any adverse effects, to make sure they were taking the magnesium or the placebo and to make sure they were filling out their diary.

    They followed them up for 4 weeks and here’s what they found:
    Results
    Magnesium was able to reduce the number of cramps - there were 3.41 less cramps per week when the participants were taking magnesium. Coming from an average of 8 cramps per week that’s about a 40% reduction in the number of cramps. Which is pretty impressive.

    The problem is though….that in the placebo group there were 3 less cramps per week. Which is also pretty impressive. And while magnesium was able to reduce cramps by 0.4 episodes per week over placebo, this was not statistically significant.

    Now this doesn’t necessarily mean it isn’t true. It wasn’t powered with enough people to detect such a small difference. They designed the trial to have enough power to detect a difference of 1 episode of cramping per week, so they would have needed 2-3 times more people to accurately say whether this reduction of 0.4 episodes per week was true. But even if it is true is a reduction of 0.4 nocturnal leg cramps per week a significant one? This equates to 1 less cramp every 2-3 weeks. So in someone getting 8 cramps per week is this meaningful? I don’t think so.

    They also presented the results in a dichotomous way which is what you need to get a number needed to treat. They defined a "minimum clinically important difference" as a reduction in leg cramps by 25%. They found that in the placebo group, 63% of them reached this minimum clinically important difference, but in the magnesium group, 75% of them reached it. Again, this was not statistically significant,

  • Otitis media, or middle ear infection, is a very common issue. It is the second most common reason for a child to see a GP and is the most common reason antibiotics are prescribed to children. According to a large Australian database called the BEACH data, 80% of kids with otitis media are prescribed an antibiotic.
    The dilemma
    A study was published in the NEJM in December of 2016 by Hoberman, et al.,  that compared 10 days of amoxycillin/clavulanate to 5 days for treating kids with acute otitis media. They randomised 520 kids between the ages of 6 and 23 months and this was a very well designed trial. They found that 10 days was far superior to 5 days - Clinical failure occurred in 34% of those getting 5 days of antibiotics versus 16% in those getting 10 days. This makes a number needed to treat of 6 - so one in every six kids will avoid clinical failure if they are treated with 10 days of antibiotics versus 5 days. This paper got a lot of press - "should we be treating otitis media with antibiotics again?", "Did we get it wrong with the recommendation that we shouldn't treat?, "Should we change the guidelines to recommend 10 days of antibiotic use?"

    But this is weird! because when you compare antibiotics to placebo, the benefit is nowhere near as good.  So comparing antibiotics to less antibiotics was way better than comparing antibiotics to no antibiotics! How does this make sense. To put it more starkly, the exact same research team that did this study, did a different study in 2011, also published in the NEJM, where they compared 10 days of amoxycillin/clavulanate to placebo. And here there was no difference. So the same team of researchers with almost identical study design on the one hand showed that 10 days of antibiotics doesn't work, yet on the other hand showed that 10 days of antibiotics is better than 5 days! Whats going on here?

    The answer lies in a wonderfully written opinion article published in the BMJ by Paul Glasziou entitled: "How to hide trial results in plain sight"

    But before going into that, let's first cover the previous evidence on treating otitis media with antibiotics
    Cochrane Review
    A Cochrane review on antibiotics for otitis media was done in 2015 which found 13 randomised controlled trials that were of a low risk of bias making a total of 3,400 children with otitis media. These studies compared antibiotics versus placebo.

    They looked at a heap of outcomes but the main ones are:

    There was a reduction in symptoms at 2-3 days in those who took antibiotics. 84% of children had improved by 2-3 days in the placebo group versus 89% in those who took antibiotics. So antibiotics increase the chance of recovery by 5% making a number needed to treat of 20.
    There was no difference in hearing loss, no difference in suppurative complications like meningitis or mastoiditis.
    There was a reduction in ear drum perforations - this went from 5% in the placebo group to 2% in the antibiotic group.
    And in terms of adverse events, the number needed to harm for vomiting, diarrhoea or rash was 14 in those taking the antibiotic.

    The Answer
    Almost every other study had used the child's symptoms as their primary outcome, including the Cochrane review and even including the 2011 Hoberman study that compared 10 days of amoxycillin/clavulanate to placebo. This is the AOM-SOS score or the Acute Otitis Media Severity Of Symptoms Scale. This scale assesses things that parents and children really care about: Ear pain, ear tugging, irritability, decreased play, eating less and fever.  The 2016 Hoberman study that compared 10 days to 5 days of amoxycillin/clavulanate used a different primary outcome. Their primary outcome was any of these three things:

    If they still had otoscopic signs of infection
    If they did not have a complete or nearly complete resolution of signs and symptoms by the end of treatment
    Worsening infection

    There are three problems with this outcome:

  • Opioid addiction has been increasingly recognised as a public health crisis:

    Deaths from prescription painkillers have now surpassed the deaths from heroin.
    Opioid use disorder has risen 500% from 2010 to 2016 in the USA
    For the first time in history, the Surgeon General sent a letter to every single doctor in America. That’s over 2 million doctors! And the letter was a summary of the recommendations on opioid prescribing from the CDC. This clearly points to the importance of this issue. 

    The issue is that opiates can be a very good drug. They can be a life saver in terms of pain management and they can be used in patients with kidney disease or peptic ulcer disease when other pain killers, like NSAIDs, can’t.

    The scary thing about them though, is that some people become dependant.  I always have this strong fear in the back of my mind whenever I hand over an opioid script like ”am I going to ruin this patients life forever?”

    This week we look into a study that asks the question: "when handing a patient a script for opioids for the first time, what is the chance that they will become a chronic user?" It also asks: " Is there something that a doctor can do when giving a patient their first opioid prescription to reduce the risk of them becoming a chronic user?"

     

     
    Methods
    The state of Oregon in the USA has whats called a "Prescription Drug Monitoring Program” where they can track and monitor all prescriptions for controlled substances. Firstly, this is brilliant, because clinicians can use this data to see if a patient is drug seeking. In Australia we rely on doctors to report to a doctors shopper line, but a lot of drug seekers fall through the cracks with this system. The other reason why this monitoring program is amazing, is that it creates an unbelievable amount of great data on opioid use. The authors of this study used this data in a really genius way.

    They looked at every patient that was prescribed an opiate between the years of 2012 and 2013 who were otherwise opiate naive. They classified someone as being opiate naive if they had not filled a script for opiates for 12 months prior to this first script being filled. There were 536,767 of these patients who were prescribed an opiate for the first time. And this was all outpatient prescriptions, so it didn't include opiates dispensed in the hospital.

    They then checked how many of these became chronic users. They defined that as someone who filled 6 or more scripts for opioids over the subsequent 12 month period. They had good evidence to back this up as a good marker of chronic use.

    The opioids they included where analgesics, antitussives and migraine medications. They had to exclude tramadol and buprenorphine-naloxone combinations because they were not included in the prescription drug monitoring program during 2012 and 2013.
    Exclusions

    They wanted to exclude people who were prescribed opiates with the intention of being a long term prescription, like those with cancer pain or other palliate care patients. This is because the intention of the study was to find out how many people become long term users when we don’t want them to be long term users.  The problem is that this data set doesn’t include the patient diagnosis. To get around this, they excluded patients who died within 1 year of this first opioid prescription assuming that these patients might have been palliative care patients.
    They also excluded anyone under the age of 11 because they are thought to be at low risk of chronic use and because this age group would mostly be prescribed opiates in the form of antitussive medication. 
    Another issue they had with the data was that all they had to work with was the number of pills prescribed and the dose of the pills. So they couldn’t work out from that whether it was a PRN prescription or whether they were prescribed to take 2 tablets per day or 5 tablets per day. But they used a different approach to get around...

  • We want to reduce the use of antibiotics but at the same time we also want to keep our patients satisfied. Otherwise, they’ll just go and find another doctor.  This week we look into a really great study that compared refusing to give that antibiotic script, to giving them the script straight away, to a delayed prescription - which is where you tell them to only use the script if symptoms don’t get better in a few days. Which method is the best for reducing antibiotic use? and which method is best for keeping patients satisfied? Let’s take a look.

    Introduction

    There is a lot of antibiotic prescribing in primary care. A new report on the Australian BEACH data found that around 80 to 90% of all antibiotics prescribed by GP’s for respiratory tract infections were completely unnecessary. And this is likely to be an overestimate because the doctors volunteering to  participate in the BEACH study are probably different to the average GP.

    The whole issue of antibiotic resistance has been getting constant attention and is considered a massive public health threat. So simple methods to reduce antibiotic prescribing should be welcomed with open arms.

    One such method is called “delayed prescribing”  where the doctor writes out a prescription for the patient but in one way or another gets them to only use it if their symptoms don’t improve in a few days.

    I’m pulling out this particular trial published in the BMJ in 2014 out of the large body of evidence on delayed prescribing - mainly because I think it was one of the more excellent trials.  But there has been heaps of trials like this, and amazingly they all show similar results. They will be discussed later.

    Methods

    So this trial was published in the BMJ in 2014 and it randomised patients who didn’t need immediate antibiotics into 5 groups.

    They recruited 53 GPs in 25 different practices and they gave them each a bunch of envelopes. Anytime a patient would come in with a respiratory tract infection the GP would decide if the patient needed immediate antibiotics. If they didn’t need immediate antibiotics, they picked an envelope at random and in that envelope it would tell the doctor which group the patient should be assigned to. It also had an advice sheet to give to the patient based on which intervention they were getting.

    The five group were:

    No prescription - so here the doctor would read the envelope and use their own approach to not give them a prescription, but they had to offer advise to come back if things got worse. So they said things like: “this is viral, you don’t need antibiotics, this will get better on its own, etc.“
    The other 4 groups used different approaches to delayed prescription. The second group was given the script and asked not to use it unless they didn’t get better in the next few days.
    The third group was given the script for antibiotics like the other group, but the script was dated in the future, so they couldn’t fill it until that date had come some days later
    In the fourth group, the doctor left the script with reception and told the patient they could come at any time without booking an appointment to collect the script if their symptoms don’t pick up over the next few days.
    And finally, the fifth group had to actually call the clinic and leave a message for the doctor that things weren’t getting better and they wanted the script - then the doctor would leave it at reception for the patient to pick up.
    They also analysed the data together with the participants who got an immediate script. So really there were 6 groups: 1 immediate antibiotic group, 1 no antibiotic group and 4 delayed antibiotic groups.

    The advice on how long they should delay taking the antibiotics was different depending on the type of respiratory tract infection. So if it was an ear infection they would say: "if things don’t get better in 3 days then use the antibiotics", or "come pick it up from reception" or "call the clinic" (depe...

  • Introduction

    The reason doctors like to lower their patients cholesterol is to decrease their risk of developing cardiovascular disease. There is no point decreasing cholesterol levels if it has no impact on cardiovascular disease.

    Ezetimibe (Zetia, Ezetrol  or Vytorin when in combination with simvastatin), was on the market for 13 years before the manufacturers finally published a study to assess whether it actually had any benefit for cardiovascular disease. This was called the IMPROVE-IT trial and is the topic of this episode.

    Background

    The FDA approved Ezetimibe in 2002 without any evidence that it had patient oriented benefits like reducing cardiovascular disease. The approval was based entirely on trials that showed that it was able to lower LDL cholesterol over placebo.

    This drug was marketed so aggressively in the following years that it had managed to make $5 billion dollars in its first 5 years, well before any trials were done to test whether it reduces cardiovascular disease. Remember, we want to lower cholesterol for the sake of reducing cardiovascular disease….not just to make blood tests look better.

    Before the IMPROVE-IT trial came in 2015 the manufacturers of ezetimibe intermittently published studies - some on other surrogate markers like carotid artery wall thickness and other smaller ones on cardiovascular outcomes but they never looked good for ezetimibe. Let’s just go through some of these so we can get a complete picture of ezetimibe.

    In 2008 they published the ENHANCE trial where they compared simvastatin and ezetimibe versus simvastatin alone for carotid intimal thickening - which is a measure of atherosclerosis in the carotid arteries. Carotid artery thickening,  is just another surrogate marker for cardiovascular disease - the thought being that the thicker your carotid arteries, the more likely one is to develop cardiovascular disease, and you could argue that this is a bit better than just showing its impact on cholesterol levels. In this study, there was no difference between the two groups. In fact the carotid artery walls were actually thicker in the ezetemibe group but this was not statistically significant.

    Then, also in 2008, came the CEAS trial which compared ezetemibe plus simvastatin to simvastatin alone for 1,873 patients with Aortic Stenosis. They followed them up for 4.5 years to see if there were any differences in ischaemic events or aortic-valve events but there were none.  Concerningly, this trial showed a statistically significant increase in cancer with ezetimibe.

    In 2009 came another one of these carotid artery wall thickness trials. This time they compared statin plus ezetimibe versus statin plus niacin. Niacin being another drug that has shown to reduce LDL and increase HDL. Again they were looking at the thickness of the carotid artery - and with this the niacin was better than the ezetimibe.

    In 2011 there was finally a trial that showed benefits for hard outcomes with Ezetimibe, the SHARP trial. The problem, was that they compared statin plus ezetimibe versus nothing at all! ….Ezetimibe…together with a drug we already know reduces cardiovascular disease…..to nothing at all. So was it the statin doing all the work? Who knows? Its impossible to tease out how much of the benefit came from statins versus how much came from ezetemibe.

    So up to this point we have a bunch of trials showing ezetimibe lowers cholesterol, and it consistently does this, lowering it by about 20%. But any trials that have tested hard outcomes have either shown no benefit for ezetimibe or have been a rediculous comparison.

    IMPROVE-IT

    That was all until 2015. 12 years after they got approval by the FDA they published the IMPROVE-IT trial

    This came out in 2015 in the NEJM and was a multi-centre, international, double blinded placebo controlled trial to test whether ezetimibe with simvastatin is better than simvastatin alone in terms of cardiovascular outcomes.

  • Background

    Testosterone levels seem to naturally decline as men age. There has been an enormous rise in the amount of testing and treatment of this natural decline in testosterone.  Testosterone clinics have been popping up all over the place and promise that treatment will restore energy, improve depression, increase libido and enhance overall well-being.  In America, the direct to consumer advertising about low T is everywhere- on television, radio, magazines and billboards.  There has been a 100 fold increase in testosterone prescriptions over the past three decades and this is despite the complete lack of any new indications for the drug or any new evidence for the use of testosterone. A trial that looked through the medical records of 112,000 veterans who had been prescribed testosterone. found that only 3% of them met the laboratory  criteria to actually confirm the diagnosis of low testosterone. Around 13% had contraindications to testosterone therapy. Including 1.5% with prostate cancer! And 16% never even had their testosterone levels tested.

    So either doctors really believe in testosterone therapy or patients are pressuring doctors to prescribe it. And until now, there has been no good evidence to support OR discredit the treatment of age related testosterone deficiency. The  Testosterone Trials are the first well designed piece of evidence to shed some light on the correct approach. These trials assessed the impact of testosterone treatment on age related testosterone deficiency, not testosterone deficiency due to pathology of the reproductive system.

    Study Design

    This one study was actually a series of 7 studies. Each was a randomised, placebo controlled trial. They screened 51,085 but only 790 met criteria for inclusion. And then this group 790 men were used across the 7 studies. participants could be included in more than 1 of the trials depending on which inclusion criteria they matched. The general inclusion criteria included:

    Age >65
    Low serum testosterone levels on two seperate readings (<9.5nmol/L or <275ng/dL)
    No past history of prostate cancer and low risk for prostate cancer
    No cardiovascular disease and low risk for cardiovascular disease

    They randomised half of the participants to testosterone and the other half to placebo. The testosterone they used was 1% Androgel in a pump bottle, they initially started 5g topically, daily, but they titrated the dose to keep the serum concentration to a normal level. They considered a normal level as the normal range for someone aged 19 to 40. To maintain placebo, they also did fake dose titrations to those getting the placebo gel.

    Vitality Trial

    To be recruited to the vitality trial patients had to have low vitality as determined by a vitality scale called the FACIT-fatigue scale (Functional Assessment of Chronic Illness Therapy-fatigue). This is a scale out of 65 which assesses symptoms such as "I feel tired", "I have trouble starting things because I’m tired", "I feel weak all over", "I need help doing my usual activities", etc. Out of the 790 men in the overall study, 474 qualified for the vitality trial.

    The primary outcome was how many men in each group had a greater than 4 point increase in this vitality score. They chose 4 because that is supposed to be the minimally clinically important difference.

    Bottom Line: There was no difference in the number of people who had clinically important improvements in vitality with testosterone compared to placebo

    Physical Function Trial

    To be included in the physical function trial participants had to have difficulty walking or climbing stairs and they had to be slow -  with a gait speed of less than 1.2 metres per second on the 6 minute walk test. 387 patients out of the 790 were enrolled in this trial. The primary outcome was how many people achieved a 50 metre increase in their 6 minute walk test.  This is what was considered to be a clinically important improvement in t...

  • Calcium channel blockers and alpha blockers are both smooth muscle relaxants and so could theoretically relax the smooth muscle of the ureter and speed up the passage of kidney stones. Given that kidney stones can take several weeks to pass and often are rated as 10/10 pain, treatments to speed up the passage of stones would be greatly welcomed.

    A Cochrane meta analysis in 2014 found 32 studies, making a total of 5864 patients with kidney stones, and showed that alpha blockers, mainly tamsulosin, increased the likelihood that a stone would pass by 4 weeks with a number needed to treat of 4. Tamsulosin was better than the calcium channel blocker, nifedipine, in this review.

    The problem is that the 32 trials in the review are of fairly poor quality. They were small, the largest having 150 patients and the others have less or much less than that. And most of the studies had an unclear risk of selection bias, which as we discussed last week, is one of the most important measures of trial quality. A lot of the trials also didn’t do any blinding.

    Since this Cochrane review a very high quality randomised controlled trial has been published in The Lancet in 2015. They randomised 1, 167 patients with kidney stones less than 10mm to one of three group: One groups were given the alpha-blocker tamsulosin at 400micrograms per day, the second group got the calcium channel blocker nifedipine at 30mg per day and the third group got a daily placebo.

    On average, these patients were 43 years old, 80% were men and 20% were women. The average stone size was 4.5 mm, though 25% were greater than 5mm.

    The primary outcome was how many people had passed their stone by 4 weeks in each group.

    The results were very different to the Cochrane review. They showed no difference - about 80% had passed the stone by 4 weeks no matter whether they got tamsulosin, nifedipine or placebo. There was a 10% absolute increase in stone passage with tamsulosin if the stone was greater than 5mm. It went from 61% with placebo and nifedipine to 71% with tamsulosin, though this was not statistically significant. You could argue that as only 25% of the patients in the trial had stones bigger than 5mm, this analysis was not powered to detect a 10% difference in outcomes. This improvement in stone clearance with tamsulosin for larger stones certainly fits with what the Cochrane review had showed. What we really need now is a large, well designed study, like this one but only looking at stones greater than 5mm to see whether this holds true.

    In terms of adverse events, 3 people developed serious adverse events in the nifedipine group and 1 in the placebo group. There were no serious adverse events in the tamsulosin group.  In terms of how many people stopped due to adverse events, for nifedipine the number needed to harm was 10 and for tamsulosen the number needed to harm was 25

    So what do we do with all this?

    We now have a very high quality, well designed trial that shows that tamsulosen and nifedipine are of no benefit in improving stone passage rates or reducing the need for some sort of intervention, but we have data from 32 other smaller and crappier studies saying that it does. Which is the better evidence - a large, well designed randomised controlled trial or a meta analysis of smaller studies?

    And while this can frustrate some people I think this is the beauty of evidence based medicine. Evidence is not black and white. It's often grey.  And we can use our own opinions or our patients opinions to guide what you do based on the scenario in front of us

    You could easily argue:  1) There didn’t seem to be any major adverse events with tamsulosen, there is some evidence that it works, especially for stones greater than 5mm, it’s only for 4 weeks, maybe I’ll give it a try. Or 2) If they couldn’t find a benefit in a large well done study it probably doesn’t work.  And I guess both would be right.

    It's a beautiful thing.

  • For show notes including all the results for this trial: http://www.ebmpodcast.com/breech

    The Term Breech Trial is one of the most important clinical trials in the history of obstetrics and has changed the way we manage breech presentation across the world.

    The term breech trial was as randomised controlled trial comparing planned caesarian section to planned vaginal delivery for management of breech presentation at term.

    2088 pregnant women, who were presenting in a breech presentation at 37 weeks or more, were randomised to one of two groups: planned vaginal delivery OR planned caesarian section. Women were recruited from 26 different countries using 121 clinical centres.

    The women could either have frank breech or complete breech, but they were excluded if they had a footling presentation. Women were also excluded if they were having very large babies -  They defined really big as an estimated weight of 4kg or more which is 8.8 pounds (for the Americans)

    Allocation was concealed and the plan would be that if they were randomised to the C-section group, they would schedule it in at anytime from 38 weeks onwards. On the day of the C-section, they would make sure the baby was still in breech, and if it had managed to move to be in cephalic presentation they would then just plan a normal vaginal delivery.  About 40% of the mums where randomised at the time of labour, and so they would have been pretty quickly rushed off to get their Caesarian section after being randomised to that group. If they were randomised to the planned vaginal delivery group, they would just wait for them to labour spontaneously, unless for whatever reason they needed induction of labour and they had a whole protocol on how induction of labour was to be managed.

    The primary outcome was the death of the baby either during labour or in the first 28 days of life, or like really bad things happening to the baby. And there was a heap of these: birth trauma, which included subdural haematoma, intracerebral haemorrhage, spinal-cord injury, basal skull fracture and peripheral-nerve injury or clinically significant genital injury; seizures occurring at less than 24 h of age or requiring two or more drugs to control them; Apgar score of less than 4 at 5 min; cord-blood base deficit of at least 15; hypotonia for a least 2 h; stupor, decreased response to pain, or coma; intubation and ventilation for at least 24 h; tube feeding for 4 days or more; or admission to the neonatal intensive care unit for longer than 4 days.

    Of those assigned to C-section - 90% were actually delivered by C-section. The 10% who were delivered vaginally, did so either because they managed to turn to cephalic presentation, or they had progressed too quickly in labour that it was too late for C-section, or because the mother changed her mind last minute and decided against a C-section.

    Of those assigned to the planned vaginal birth - only 56% ended up delivering vaginally. The rest were delivered via C-section and the most common reason being that they just weren’t progressing in labour or the baby was too big for the pelvis.

    So what were the results? Well that composite primary outcome - with all the bad stuff that can happen to a new born baby, coupled with some less bad stuff - went from 5% in the planned vaginal delivery group to 1.6% in the C-section group. So there was a 3.4% decrease in what they called serious neonatal morbidity or neonatal/perinatal mortality with planned C-section over planned vaginal delivery. The number needed to treat was 30, which means for every 30 breech babies we deliver via planned C-section instead of planned vaginal delivery, we will prevent 1 bad thing happening to the baby.

    So let’s look at the breakdown of the components of this primary outcome:

    Starting with perinatal or neonatal death - this went from 1.3% with planned vaginal delivery, to 0.3% with planned C-section, so a 1% decrease in baby death with planned C-se...

  • This episode delves into the highest quality trial ever done on the treatment for warts. This randomised controlled trial published in the CMAJ compared cryotherapy with liquid nitrogen to salicylic acid wart creams to doing nothing.

    250 patients were recruited in primary care and follows up for 13 weeks, The primary outcome was complete resolution of the wart by that time.

    The bottom line was that for plantar warts there was no difference between cryotherapy, salicylic acid cream or doing nothing in terms of cure rates or patient satisfaction at 13 weeks. For other warts, there is a 35% absolute increase in cure with using cryotherapy over salicylic acid and a 46% absolute increase in patient satisfaction. The prognosis is worse for warts that have been there for longer than 6 months, and for plantar warts, the prognosis is worse if the patient is 12 years old or older.

    In this episode we also discuss the importance of allocation concealment.

    Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952009/

    music by Polyrhythmics, song El Fuego