Through Russian Snows by HENTY, G. A.: Recent Episodes
Dr. Dan
There are few campaigns that, either in point of the immense scale upon which it was undertaken, the completeness of its failure, or the enormous loss of life entailed, appeal to the imagination in so great a degree as that of Napoleon against Russia. Fortunately, we have in the narratives of Sir Robert Wilson, British commissioner with the Russian army, and of Count Segur, who was upon Napoleon's staff, minute descriptions of the events as seen by eye-witnesses, and besides these the campaign has been treated fully by various military writers. I have as usual avoided going into details of horrors and of acts of cruelty and ferocity on both sides, surpassing anything in modern warfare, and have given a mere outline of the operations, with a full account of the stern fight at Smolensk and the terrible struggle at Borodino. I would warn those of my readers who may turn to any of the military works for a further history of the campaign, that the spelling of Russian places and names varies so greatly in the accounts of different writers, that sometimes it is difficult to believe that the same person or town is meant, and even in the narratives by Sir Robert Wilson, and by Lord Cathcart, our ambassador at St. Petersburg, who was in constant communication with him, scarcely a name will be found similarly spelt. I mention this, as otherwise much confusion might be caused by those who may compare my story with some of these recognized authorities, or follow the incidents of the campaign upon maps of Russia.. (Introduction by G.A.Henty)
By Dr. Daniel Aronov
Daniel is available for talks, workshops or seminars
Before any sort of surgery, its routine to clean the skin with antiseptic. The point is to kill the microorganisms on the skin and so hopefully reduce the chance of infection. The two most common preoperative skin antiseptics are povidone-iodine and chlorhexidine. Both of these come in an alcoholic or aqueous preparation. So which is better for preventing wound infections? Iodine or chlorhexidine? And does it matter if it’s in alcohol or in water?
Bottom Line: According to the best available evidence, cleaning the skin with chlorhexidine seems to be superior to iodine in terms of reducing surgical site infections. The evidence for chlorhexidine with alcohol versus iodine in water is strong, while the evidence for chlorhexidine in alcohol versus iodine in alcohol is of poorer quality but nonetheless in favour of chlorhexidine. Furthermore, for simple skin excisions done in the general practice setting, it doesn’t matter if you use chlorhexidine in alcohol or chlorhexidine in aqueous solution. Despite all of this, rates of surgical site infections with simple skin excisions are pretty uncommon regardless of what you use and so if you love operating on jaundiced looking skin, you could make a case for iodine.
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548541/
http://www.nejm.org/doi/full/10.1056/NEJMoa0810988
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003949.pub4/full
Dr. Daniel Aronov
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. So is this relationship causal? Will reducing contact with house dust mite allergens improve asthma?
This week, we look 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 are asthmatics who get exacerbations that lead them to go to hospital, and who have a positive skin prick reaction to dust mites. This was shown in a randomised controlled trial 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 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, it certainly hasn’t been universally accepted in all guidelines, but some big guidelines have definitely taken this information and said every pregnant women should be tested with a thyroid function test, and any high TSH or any low T4 should be corrected, even if they are completely asymptomatic. In 2005, for example the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society came out with a joint statement that every pregnant women should be screened for subclinical hypothyroidism and treated. One review found that based on the thresholds that some of these guidelines were recommending treatment, 15% of all pregnant women would need to take thyroid hormone.
Step 3: This practice becomes standard of care.
Certainly in my experience, I have noticed that pregnant women get treated for their subclinical hypothyroidism, especially if they end up under the care of an endocrinologist. I’m sure it’s not universal but I think it is very common.
Step 4: randomised controlled trials are finally done to test whether fixing said blood test abnormalities will actually reverse or improve the disease to which they are associated
Let’s start with the CATS study or the Controlled Antenatal Thyroid Screening study, which was published in NEJM in 2012.
They study took 21,846 pregnant women and checked their TSH and T4 levels within the first 16 weeks of pregnancy. They were then randomised into two group:
The first group was the screening group: in this group the treating team were given the results of the TSH and T4 tests straight away, and if the TSH was high or the T4 was low or both, they were put on thyroxine.
The second group was the control group and in this group, they took the blood sample but froze it straight away, stored it at -40 degrees Celsius, and only after delivery, thawed it out and measure the TSH and T4.
390 women in the screening group tested positive for hypothyroidism, either with a high TSH or low thyroid hormone or both, and so were treated, while 404 women in the control group tested positive for hypothyroidism but were not treated because the results were only available after delivery.
The primary outcome was cognitive function of the the babies born to these mothers at age 3.
And….there was no difference between the groups. The IQ score was the same whether you had abnormal thyroid hormone levels and you got treatment or whether you had abnormal thyroid hormone levels and you didn’t get treatment. There was also no difference in preterm birth, birth weight, etc.
In March of 2017, the second randomised controlled trial looking into this had come out. It was also published in the New England Journal of Medicine, and Brian Casey was the lead author.
It was actually 2 trials: One trial was testing whether treating subclinical hypothyroidism during pregnancy improves cognitive function in their baby. While the second trial was testing whether treating hypothyroxinaemia in pregnancy improves cognitive function in their baby.
They screened 97,228 pregnant women with thyroid function testing before 20 weeks gestation. 3057 of them ended up having subclinical hypothyroidism (TSH>4mU) and of these, 677 fit all the inclusion criteria, gave consent and underwent randomisation to either get thyroid hormone therapy or not. That was study 1 – The subclinical hypothyroidism study. Study 2 was the hypothyroxinaemia study. 2805 of the 100,000 women ended up having hypothyroxinaemia, where the T4 level was low but TSH was normal. 526 of those underwent randomisation.
They were all randomised to either take levothyroxine or placebo. Every month they got a blood test and adjusted the levothyroxine dose if they needed, in order to keep the TSH level (study 1) or T4 level (study2) in the normal range. They did sham dose adjustments in the placebo group as well. For every real dose adjustment they did in the levothyroxine group, they did a sham dose adjustment to someone in the placebo group. It’s great. The goal was to keep the TSH level between 0.1mU/L and 2.5mU/L for study 1. For study 2, the goal was to keep the T4 level between 0.86 and 1.9 ng per decilitre (11 and 24.5 pmol/L).
The primary outcome was a full scale IQ test at age 5 in the baby that eventuated from this pregnancy. Secondary outcomes were other cognitive, motor and language scores at 12 and 24 months and a bunch of other developmental tests like behaviour and social competence were done at different stages of follow up. They also looked at a bunch of pregnancy and neonatal outcomes as well.
So what did they find? Let’s start with the pregnancy and neonatal outcomes: There was absolutely no difference. In preterm birth, preeclampsia, placental abruption, apgar scores, admission to NICU, nothing! No difference in either of the studies. So if you treat a low T4 or a high TSH with thyroid hormone, there is absolutely no impact on pregnancy or neonatal outcomes.
Now let’s move onto the neurodevelopment and behavioural outcomes. They were able to follow these kids up to the age of 5 in 96% of the cases. There was no difference in IQ scores and no difference in any of the other developmental scores either. Nothing. And again, this was in both trials. So whether you had a high TSH or a low T4, doesn’t matter…fixing it does not help anything to do with pregnancy.
Bottom Line Treating either subclinical hypothyroidism (high TSH, normal T4) or hypothyroxinaemia (low T4, normal TSH) with levothyroxine in pregnancy does not have any impact on pregnancy outcomes (such as preterm birth, preeclampsia, gestational diabetes or placental abruption), it does not have any impact on neonatal outcomes (such as apgar scores, admission to NICU, stillburth, miscarriage, or neonatal death) and it does not have anyone impact on the childs neurodevelopment or behaviour.
References
Website: www.ebmpodcast.com
Videos: www.youtube.com/DrDanMD
Casey 2017: http://www.nejm.org/doi/full/10.1056/NEJMoa1606205
CATS study 2012: http://www.nejm.org/doi/10.1056/NEJMoa1106104
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. It showed that steroids DID NOT improve recovery from acute urticaria when added to antihistamines.
So what should we do?
Option 1: The better study showed that steroids did not improve outcomes so stop using them for acute urticaria.
Option 2: Even if the first study is true and steroids speed up recovery from acute urticaria by a little bit, they all eventually got better anyway so it’s not worth the potential for side effects with systemic steroids.
Option 3: There is some evidence steroids improve recovery so we should use them.
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 favorite 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
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.ebmpodcast.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:
Those getting doxazocin had a 25% increase in adverse cardiovascular outcomes – it went from 21.67% in the chlorthalidone group to 25.45% in the doxazocin (NNH 27). Which means that for every 27 patients you decide to treat with doxazocin over chlorthalidone, 1 will develop a cardiovascular event.
Congestive heart failure doubled. It went from 4.45% in the chlorthalidone group to 8.13% in the doxazosin group making a number needed to harm of 27.
Now, this was the first ever decent study to compare an alpha blocker to another class of antihypertensive and while it should have spelt the end of doxazosin for the treatment of hypertension…it didn’t! Pfizer, who brought doxazosin to market under the brand name “Cardura”, was also one of the sponsors of the ALLHAT trial. So they became aware of these results before the trial was published. So what do you do when one of your drugs is found to be harming people? Do you pull it from the market? Or perhaps you put a little warning on the box? No. You create a marketing and damage control campaign. In fact, the sales of Doxazosin or Cardura where completely unscathed after this trial was published with virtually no change in the $800 million dollars of sales per year for this drug.
Some internal documents leaked from Pfizer to show the techniques they used. They got an external research agency to study the doctors’ awareness of this preliminary report from the ALLHAT trial. When the agency found that “knowledge of the trial’s preliminary results is minimal for all specialities,” they took great steps to make sure, as best as possible, that word did not get out. Firstly, Pfizer deliberately did not issue a statement about the ALLHAT results, because it “would likely draw more media attention to the situation.” Secondly, they taught their drug reps to provide information about the ALLHAT trial “only when asked.” And how’s this for a bit of genius: At the American College of Cardiology conference in California in the year 2000, Dr. Furberg, who is the lead researcher of the ALLHAT trial, was set to give a presentation on the ALLHAT results. So what did Pfizer do? They brought in the top big shots in cardiology to do a tour at the same time as the presentation. Therefore keeping doctors who attended the conference from attending the talk on the ALLHAT trial. In fact, a document leaked where the two Pfizer employees who came up with this idea were praised as being “quite brilliant” by their management.
The blood pressure reductions between chlorthalidone and doxazosin were pretty much the same – Around 2mmHg between them. So I think this is an important lesson that blood pressure reduction is not equal. A 10mmHg reduction in blood pressure with one class of drug will impact on cardiovascular disease differently than a 10mmHg reduction with another drug. And this is the same for everything: cholesterol, HBA1c, and it’s why we need to ask for clinical trials to show us the impact on hard outcomes rather than these surrogate markers.
Calcium Channel Blockers (Amlodipine) The primary outcome, which was fatal or non-fatal heart attacks was the same in all three groups. It occurred in 11.5% of the participants regardless of which antihypertensive they got.
But, it’s in the secondary outcomes where some differences lie. And seem to be in favour of chlorthalidone:
There was a 40% relative increase in heart failure with amlodipine compared to chlorthalidone it went from 7.7% to 10.2% (NNH 40).
There was an increase in coronary revascularization with amlodipine as well, it went from 9.2% to 10%, (the P-value was 0.06 though).
Peripheral vascular disease decreased by 0.4% with amlodipine – from 4.1% to 3.7% (again the P-value was 0.6 – just short of that arbitrary cut off for statistical significance).
All the other outcomes: stroke, end-stage renal disease, cancer and all-cause mortality were the same between the two. And it didn’t matter if they were male or female, older or younger, black or white or diabetic or non-diabetic, the results were consistent across all those groups.
ACE Inhibitor – Lisinopril Here again, chlorthalidone came out on top.
There was a 15% relative increase in stroke with the ACE inhibitor compared to the thiazide: It went from 5.6% to 6.3% (NNH of 143).
The combined cardiovascular outcome was also worse for the ACE inhibitor – it went from 30.9% to 33.3%, (NNH 41).
Heart failure was also worse with lisinopril (NNH 100).
More people developed angina with lisinopril, (NNH 67), and more coronary revascularization.
End-stage renal failure was not different between the groups – it was 2% for those taking lisinopril versus 1.8% in those taking chlorthalidone.
There was also no difference in all-cause mortality, peripheral arterial disease or cancer.
They did a lot of subgroup analyses and did show that within certain age ranges and within certain races, lisinopril was not worse than chlorthalidone:
Age: When they looked at those under the age of 65 there was no difference in the combined cardiovascular disease outcome between lisinopril and chlorthalidone. It was only in those over the age of 65, where lisinopril was worse.
Race – lisinopril was worse in black people. There was a 40% increase in stroke in black people taking lisinopril, but no increase in stroke rates in white people taking lisinopril. Similarly, with the combined cardiovascular outcome, it increased by 20% in black people taking lisinopril but only increased by 6% in white people taking lisinopril.
Diabetics status: The outcomes were consistent with the overall findings
Gender: The outcomes were consistent with the overall findings
Blood Pressure Targets The blood pressure achieved in each of the three groups were actually statistically difference. Whether they were clinically or meaningfully different is another story. So at 5 years, the systolic BP was 134 for chlorthalidone, 134.7 for amlodipine and 135.9 for lisinopril. So a 2mmHg difference between chlorthalidone and lisinopril. Could that be the sole reason for the worse outcomes with lisinopril? I highly doubt it but could be. And even if it is, it still puts thiazides ahead in my books because great…it’s better at reducing blood pressure than the others.
Side Effects At the end of 5 years, 20% of those in each of the chlorthalidone and the amlodipine group were no longer actually taking those drugs. While 27% were no longer taking lisinopril by this time. The most common reason was that of adverse effects or the patient refused to take it after a certain point. So it seems more people were stopping the lisinopril. They did collect some limited data on other adverse events. Angioedema occurred 4 times more in the lisinopril group than the other groups but it was still pretty rare occurring in about 1 in every 250 people taking lisinopril. They measured potassium levels and found that hypokalaemia occurred more commonly with chlorthalidone. At the start of the study, before any of them were given their study drug, around 3% had a potassium less than 3.5. In those randomised to chlorthalidone, 8.5% developed a potassium less than 3.5, while only 1% did with lisinopril and 1.9% with amlodipine.
Statin Arm Of the Trial For everyone who had elevated cholesterol in this study, of which there were 20,000, they randomised them to either get a statin or a placebo. I guess they thought: “well, we’re spending billions of dollars recruiting and following these people up, we might as well check if statins work as well”. This arm of the study will not be discussed here,
Bottom Line: The ALLHAT study is the most definitive study to compare different classes of antihypertensives in terms of their ability to reduce cardiovascular disease. They found that the alpha-blocker – doxazocin (Cardura) was significantly inferior, causing double the rate of congestive cardiac failure and a 25% relative increase in cardiovascular disease compared to chlorthalidone. The calcium channel blocker, Amlodipine was equivalent to chlorthalidone in terms of heart attacks, strokes and cardiovascular disease, but in terms of heart failure, Chlorthalidone was superior – treatment with amlodipine resulted in a 40% increase in congestive cardiac failure (NNH 40). Chlorhalidone seemed to be superior to the ACE-inhibitor lisinopril as well – treatment with lisinopril resulted in a 15% relative increase in stroke compared to treatment with chlorthalidone. It also resulted in an increase in cardiovascular disease (NNH 41) and heart failure (NNH 100). This increase in adverse cardiovascular outcomes with ACE-inhibitors where much less profound in a subgroup analysis of only white people.
Guidelines So how did the guidelines respond to this piece of evidence?
American guidelines (JNC 8): “In the general nonblack population, including those with diabetes, initial anti-hypertensive treatment should include a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB). In the general black population, including those with diabetes, initial treatment should include a thiazide diuretic or calcium channel blocker.
Australian Heart Foundation Hypertension guidelines: “In patients with uncomplicated hypertension ACE inhibitors or ARBs, calcium channel blockers, and thiazide diuretics are all suitable first-line antihypertensive drugs, either as monotherapy or in some combinations unless contraindicated”.
UK NICE guidelines
For under 55 they recommend starting with an ACE or an ARB. For over 55 or for black people they recommend starting with a calcium channel blocker. If a calcium channel blocker is not tolerated then a thiazide diuretic. For under 55 they recommend starting with an ACE or an ARB. For over 55 or for black people they recommend starting with a calcium channel blocker, if a calcium channel blocker is not tolerated then a thiazide diuretic. They actually recommend using chlorthalidone or indapamide as the thiazide of choice rather than hydrochlorothiazide. NICE also recommend to: ” Prescribe non-proprietary drugs where these are appropriate and minimise cost”
And while we’re on the topic of cost, here is a quote from the conclusion of the ALLHAT trial article:
“One of the stated objectives of ALLHAT was to answer the question, “Are newer types of antihypertensive agents, which are currently more costly, as good or better than diuretics in reducing CHD incidence and progression?”18 Consideration of drug cost could have a major impact on the nation’s health care expenditures. Based on previous data that showed that diuretic use declined from 56% to 27% of antihypertensive prescriptions between 1982 and 1992, the health care system would have saved $3.1 billion in estimated cost of antihypertensive drugs had the pattern of prescriptions for treatment of hypertension remained at the 1982 level”
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. They then called them the next day and asked them to answer the exact same cough questionnaire that they did the day before.
The average age of the child was 5, the oldest person in the study was 17 and they were sick for an average of 4.5 days before presenting to the clinic. The primary outcome they were assessing, was the difference in cough frequency from the night they didn’t take anything to the next night when they had either the honey, dextromethorphan or nothing. The other outcomes were the other 4 questions in the survey: cough severity, cough bothersome-ness, child’s sleep and parental sleep. They determined that a clinically meaningful change in score would be 1. So dropping from “very much” to “somewhat” or from “somewhat” to “a little”.
A the start of the study, the average cough score for each of the 5 questions in the survey, was about 4 out of 6 which means, on average, they were ticking the “a lot” box. So my child’s cough effected my sleep “a lot” last night. How severe was your child’s cough last night? “a lot”. And so on and so forth.
So what did they find?
Well for all five of the outcomes, the greatest reduction in score was seen with honey, then dextromethorphan, then doing nothing. Important to note that the doing nothing group did improve, because as we know, these things just get better with time. No need to go into the exact results of all five of these outcomes because they were all pretty much the same (and I don’t want to put you to sleep). But let’s look at the primary outcome: “cough frequency” as an example. “how frequent was your child’s cough last night?”. The night before, when they didn’t get any treatment, the average score for this question was 4 representing “a lot”. Giving them no treatment on the night of the experiment took their score down by 0.92. So it took the average response to this question down from “a lot” to “somewhat” just by doing nothing. Giving honey took the score down by 1.89 points, so from “a lot” to “a little”. While dextromethorphan took it down to somewhere in between, 1.39 points – so somewhere in between “somewhat” and “a little”. And that was the pattern for all their outcomes. Doing nothing leads to some improvements, giving honey lead to greater improvements and giving dextromethorphan disguised as honey was somewhere in between the two. But despite the fact that this pattern was easily visible for all five questions, only one of them reached statistical significance when camparing honey to doing nothing, and that was for cough frequency. The difference in score was 0.97…so just shy of that minimally clinically important difference of 1.
So that’s the first study. Yes some benefits, but questionable whether these benefits were meaningful. And this study was funded by the National Honey Board! RCT 2 – (Shadkam, 2010) This one was done in Iran in 2010 and was published in the Journal of Alternative and Complementary medicine. Here, they were comparing honey versus dextromethorphan versus diphenhydramine versus usual care. They recruited 141 children, between the ages of 2-5 and randomised them into 4 groups. The first group got 2.5mL of honey. The second group got 2.5mL of dextromethorphan syrup, the third group for 2.5mL of diphenhydramine and the fourth group got usual care. This was again, an overnight study – On the day they came into the paediatric clinic, they were given that same cough survey, then that night they had the intervention, and this time they came back into the clinic the next day where they did the questionnaire again.
Importantly, the methods used in this study were really poor. There was no blinding, which, granted is difficult to do with honey, but at least in the other study, they made an effort with honey flavoured dextromethorphan preparation. And while blinding patients is important, what’s even more important is blinding the researchers. There was no blinding of the researchers. There was no allocation concealment which always makes you wonder whether there was actually any randomization. But perhaps the weirdest part of this study was, and I quote: “Any ambiguous question for the mother, if any, was answered by a paediatrician” …what the? So the investigators were answering questions if the mothers didn’t know the answer? This makes it even more alarming when you consider that the investigators were not blinded. So if they had a personal belief that honey was better, they could very easily influence the results, even if only subconsciously.
The starting score for each of these questions was around 4 (which was the same as the other trial) and the results were pretty much identical to the other study. In the usual care group, the score went down to about an average of 2.5 across the outcomes from the questionnaire. In the honey group the score went down to about 1.5. And for dextromethorphan and the diphenhydramine, the score went down to 2. This time, when comparing honey to usual care, the improvement was statistically significant for all of the outcomes and they were all also clinically meaningful having at least a difference of 1 point between the two for each of the outcomes.
So that’s two down and what do we have so far: We have one study which showed a benefit for honey but only reaching statistical significance for 1 of 5 outcomes and questionable clinical significance and this second study which shows a statistical and clinically meaningful difference but at a high risk of bias. Let’s put all our eggs in the third study basket. RCT 3 – (Cohen, 2012) This one was done in Israel and compared eucalyptus honey, to citrus honey to labiatae honey to placebo. Which is awesome because as someone who does use honey in general practice, I always get asked, “which honey is best?” This was the best designed out of the three trials. They recruited children between the ages of 1 and 5, from 6 paediatric clinics who were presenting with a nocturnal cough due to an URTI. They used the exact same cough questionnaire as the other two studies. They managed to recruit 270 kids and blinded both the patient and their family as well as the investigators. They also concealed allocation. They randomised them to 4 groups – 3 of them were honey but different types of honey (eucalyptus, citrus and labiatae honey) and the fourth group was placebo. For placebo, they used Silan date extract – which they report looks and tastes similar to honey. They were all packaged in little 10 gram packets and you couldn’t tell the difference between them. Like the other two studies this study was only an overnight study – so they took the survey on the day of presentation, gave them the honey or placebo that night (30 minutes before bed), then redid the survey the next day – like the first study, an investigator called them and they did the second day questionnaire over the phone. These kids were just over 2 on average and were sick for about 3 days when they presented. Again, they used the five separate questions of the cough survey as an individual outcome. The primary outcome was cough frequency and the other 4 were secondary outcomes.
So what did they find?
Well firstly, there was no difference between the 3 types of honey for any of the 5 outcomes.But, honey was superior to the placebo date syrup for all 5 of the outcomes. And this was statistically significant. The reductions were very similar to the other two trials. On average, across the five outcomes, the date extract had a 1 point reduction in the cough score, while the 3 different honey’s had about a 2 point reduction in cough score. Bottom Line Honey reduces the frequency and severity of cough in children associated with upper respiratory tract infections. It also improves child’s sleep and parental sleep. When compared head to head, it is superior to the vast majority of cough medications which either contain dextromethorphan or diphenhydramine as their active ingredient.
Adverse effects Cough medications have had a lot of serious adverse effects reported in the literature. Firstly, 15% of all childhood overdoses in America are from cough medications. One-third of the time it’s because the incorrect dose was given to the child by the parent, but in two-thirds of the time, it’s because the child found it, went “hmmmm…This tastes nice”….and drank the whole thing. But even with standard doses, dystopias have been reported, as has anaphylaxis, hallucinations, mania. But it’s not only these studies which show they don’t work, a separate Cochrane review has also found no benefit with dextromethorphan. Well now we have honey! Kids love it. minimal risk and more effective than the medications out there. But do not give honey to babies <1 years old because of the risk of botulism. References: Paul 2007: https://www.ncbi.nlm.nih.gov/pubmed/18056558 Shadkam 2010: https://www.ncbi.nlm.nih.gov/pubmed/20618098 Cohen 2012: https://www.ncbi.nlm.nih.gov/pubmed/22869830
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 councelling 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 morality 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. They made sure they were addicted by conducting a survey called the Fagestrom Test for Nicotine Dependance (FTND), which asks things like: how soon after waking do you have your first cigarette, do you find it hard to refrain from smoking in places it’s forbidden like a library or church, and do you smoke even if you’re so sick, that you stay bed the whole day? It’s a score out of 10, where a score above 5 is considered moderately dependant.
They were randmoised into 2 groups: All of the participants in both groups were told to set a quit date for 2 weeks time. The cold turkey group where told to smoke as normal and not reduce the number of cigarettes they smoked until that quit date. The gradual cessation group were told to aim to half the number of cigarettes they smoked in the first week, then half them again in the second week and then quit after the second week. The second group were given nicotine replacement therapy during those 2 weeks as they were reducing their cigarettes. They could get either nicotine gum, nasal spray, mouth spray, lozenges, inhalers, or sublingual tablets. Both groups received counselling and support during the 2 weeks before the quit date. After the quit date both groups got a daily 21mg nicotine patch plus a short acting nicotine replacement therapy that they could choose (inhaler, gum, mouth spray, lozenge)
They followed them up for 6 months and the primary outcome was how many were abstinent from cigarettes by 4 weeks. They confirmed abstinence by using a tool called the Russell Standard, which incorporates exhaled carbon monoxide concentrations to confirm abstinence. They also did this at 8 weeks and 6 months. Results The average age of the patients was 49, half of them were men, and they were smoking an average of 20 cigarettes per day. The average FTND addiction score was 6 indicating that they were moderately addicted. 94% were white.
At 4 weeks, abstinence was achieved in 39% of those in the gradual cessation group, but in the cold turkey group, this increased to 49%. So a 10% absolute reduction in smoking rates making a number needed to treat of 10 in favour of cold turkey quitting. By 6 months, as you’d expect with these things, the rates of abstinence were much lower – but they were still better for the cold turkey quitters. They were 15.5% in the gradual cessation group versus 22% in the cold turkey group. making a number needed to treat of 16. They asked all the patients at he start of the study whether they would prefer gradual or sudden smoking cessation. Interestingly, of those who preferred gradual cessation, they were still more likely to quit when they stopped abruptly compared to if they stopped gradually. Pharmacological treatment of smoking addiction There are 4 agents that have good evidence to improve smoking cessation rates in smokers who are willing to quit. They are: Nicotine Replacement Therapy (NRT), nortryptaline, bupropion and varenicline (Champix or Chantix) Nicotine Replacement Therapy There ’s been a cochrane review on this. In fact there’s a cochrane review for each of these 4 medications. Firstly, what would you predict the actual quit rate is for someone who is motivated to quit? (i.e.they’re in the “action” phase of that Pracheska-Diclemente cycle of change). It’s around 10%! And this was consistent among all the placebo arms in all of these Cochrane reviews. It just shows how addictive these things are. Mark Twain wrote: “giving up smoking is easy, I’ve done hundreds of times” The Cochrane review was able to find 117 RCT’s making up over 50,000 patients assessing the benefits of nicotine replacement therapy. In the no intervention group, 10% were able to achieve abstinence and this went up to 16% in the NRT group. And it didn’t seem to matter which NRT you used whether it was gum, patches, inhalers, sprays or lozenges. They had some really great analysesto help get the best out of patches. Here are the highlights:
In studies that compared short duration of nicotine replacement therapy versus longer duration – there was no difference in abstinence rates. The authors of the cochrane review recommend 8 weeks.
Using a combination of a long acting NRT like a patch, together with a short acting NRT, like gum, spray or inhalers (to control sudden cravings), seem to be better than either one alone. It was about 15% abstinence with just a long acting or short acting, versus 20% when using a combination of both.
There was a slight benefit to starting the nicotine replacement therapy before the actual quit date rather than starting after.
The harms of NRT seemed to be local reactions like skin irritation from the patch, hiccups and sore throat in the mouth spray, and bad taste with the gum. They couldn’t find any increase in cardiovascular disease but they did find an increase in palpitations or chest pain which occurred in 1.4% of the placebo groups versus 2.6% in the NRT group.
Bupropion The Cochrane review that looked into the efficacy of bupropion for smoking cessation found 44 RCT’s making up 13,700 patients The abstinence rate in the placebo group, was 11.5% and this went up to 18.7% with bupropion. So very similar to nicotine replacement therapy. In fact in the hand full of trials that directly compared bupropion to nicotine replacement therapy there was no difference in effectiveness. The main side effects with bupropion are insomnia, which occurring in 25% compared to 15% in placebo; dry mouth and nausea. More alarmingly, it does increase seizures but this is very rare, in the order of 1 in 1000, but obviously wouldn’t want to give it anyone with epilepsy. Nortriptyline This Cochrane review found 11 studies making up 2 and a half thousand patients, and showed very similar results to the others – 10% abstinence rates for placebo versus 20% for nortriptyline. In the trials that compared it to nicotine replacement therapy it was maybe slightly better but not statistically significant. In terms of side effects, they are mainly the anticholinergic side effects like sedation, dry mouth, constipation, difficulty urinating and blurred vision. The main fear with the tricyclic antidepressants is their often fatal in overdose so I you’d need to be confident the patient doesn’t have any risk of suicidality. Varenicline (Champix) This Cochrane review found 27 RCT’s making up around 12 thousand patients. Those who attempted to quit smoking with placebo had an 11% chance of remaining abstinent in these trials. But if they quit using varenicline, this went up to 25%. There have also been studies comparing varenicline to some of the other smoking cessation medications:
8 trials compared varenicline to nicotine replacement therapy – For NRT abstinence was achieved in 19% versus 23.7% with varenicline. So the chance of successfully quitting was 4% higher with varenicline over nicotine replacement therapy.
5 trials compared varenicline to bupropion finding varenicline to be superior by about 6.5% – it was 17% versus 24%.
In terms of adverse effects, the major concern has been about neuropsychiatric harms: things like depression, suicide, strange behaviours, anger and things like that. In fact, in 2009, the FDA put a black box warning on Champix with regards to these adverse events. But in 2015 a large meta analysis specifically looking at these side effects was published in the BMJ and with 39 RCT’s, found no difference in depression, suicide ideation, attempted suicide, aggressive behaviours or irritability. Since then there has also been a large, good quality trial with 8000 patients of which 4000 had a psychiatric disorder, and the main aim of the study was to detect any neuropsychiatric effects. This was called the EAGLES study and they also couldn’t find any increase in psychiatric issues with varenicline. The harms they could find were: nausea occurring in 25% of people, abnormal dreams occurring in about 12%, more fatigue and insomnia as well. Bottom Line Cold turkey seems to be a better approach to smoking cessation achieving a 10% increase in abstinence rates at 4 weeks over gradual cessation. The chance of achieving abstinence in a motivated person without any help is about 10%, and this can be doubled with either nicotine replacement therapy, bupropion, nortriptyline or varenicline (Champix). Champix seems superior to the other methods achieving a 4-6% improvement in abstinence over NRT and bupropion. References:
Chest 2007: https://www.ncbi.nlm.nih.gov/pubmed/17296646
Cold turkey versus gradual smoking cessation: https://www.ncbi.nlm.nih.gov/pubmed/26975007
Nicotine Replacement Therapy: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000146.pub4/full
Bupropion: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000031.pub4/full
Varenicline: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006103.pub7/full
EAGLES study: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30272-0/abstract
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 issues 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 when they didn’t have any evidence to back up these recommendations.
Unfortunately, making recommendations without any 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. 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.
So 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 the rates of peanut allergies over there, and they also surveyed 5,100 parents of Jewish kids in the UK so that they could compare the difference in peanut allergies rates. The thinking was that as they share a common heritage, any difference in peanut allergy rates, would likely be due to environmental influences rather than genetic factors. They also did surveys on both of these populations on how they weaned, when they introduce peanuts and when they introduced other solids to their children. They found that peanut allergies were more than 10 times higher in Jewish kids in the UK compared to Jewish kids in Israel. The prevalence was 1.85% in the UK compared to only 0.17% in Israel. So whats the difference between these two populations that lead to such a massive discrepancy in the rates of peanut allergy?
Well interestingly, while in the UK parents were not giving their children any peanut products, presumably to comply with the guidelines, in Israel, they were giving their babies heaps of peanuts products. Most babies had been introduced to peanuts by 7 months of age. It turns out that Israel has a peanut snack called Bamba – it’s like a dissolving cheese puff- similar to Cheeze Doodles, but it’s made from peanuts and is marketed in Israel for babies as well as adults.
Interestingly, the rates of egg and milk allergy where pretty similar between the two groups which reflects the fact that they both populations introduced them to the diet at similar times.
The researchers who did this study got thinking: perhaps we got it wrong – perhaps the early introduction of allergenic foods protects kids from developing allergies to those foods?
LEAP trial This led those same researchers to conduct the LEAP study (Learning Early About Peanut Allergy).
Methods This was a very well designed, randomised controlled trial. It was “open-label”, which means it was not blinded, which is reasonable given that it would be very difficult to blind parents who are giving their children regular peanut products. The peanut product they used was this Bamba snack, but if they couldn’t tolerate that they could use smooth peanut butter, and they did not receive any money form the manufacturers of any of these products. They recruited 640 babies between the ages of 4 and 11 months and then randomised them to either receive regular peanuts (Bamba) – 6 grams of peanut protein every week (divided into 3 meals) until the age of 5. Or to avoid peanut products entirely until the age of 5. Now the authors didn’t call it five years old….they called it 60 months old. I just translated it for you. I’m good at that because I’m always translating my wife: “how old’s your boy?” “29 months” my wife would say. And as I stand there, watching them looking like they’re trying to solve a calculus equation, I swoop in with: “2 and a half” and watch the sigh of relief come over their face. These babies were all at very high risk of developing an allergy – they had to have either an already established egg allergy or severe eczema.
When it comes to allergy prevention there’s “primary prevention” and “secondary prevention”. Primary prevention is when the child has no evidence of an IgE mediated reaction to the allergen. In other words, they have a completely negative skin prick test or RAST test. Secondary prevention is when a child does have an IgE related reaction to the allergen – so they do have a positive reaction to skin prick testing or RAST testing but you want to prevent them getting a clinical allergy (i.e a rash, tissue swelling, angioedema or anaphylaxis when actually eating the allergen)
The researchers were keen to find out if the early introduction of peanuts could prevent the development of an allergy in both primary and secondary prevention. So for each of the 640 babies in the study, they first did a peanut allergy skin prick test. They then divided the babies into two groups: those that had absolutely no reaction to the skin prick test and those that did have a reaction. The reaction had to be wheal greater than 1mm in diameter but less than 4mm. They excluded anyone who had a wheal greater than 4mm in diameter.
Anyone who was randomised to the peanut group had to have a peanut challenge – This is where they gave the babies peanut products (under strict clinical monitoring and with resuscitation equipment on standby). If they had an allergic reaction to the peanut challenge then they were told to avoid peanuts. But if they didn’t have an allergic reaction they could continue with the study. Interestingly, 87% of those who had a positive skin prick test did not have a reaction to the peanuts when given the food challenge.
At the end of the study, all 640 babies got a peanut challenge after they turned 5. The researchers were keen to find out how many babies in each group developed a proper peanut allergy.
Results The average age of the baby was just over 7 and a half months. 98 of the 640 kids did have a positive skin prick test and the rest did not. The families in the peanut group were very good at giving their babies peanut products – with an average of 7.7 grams of peanut protein per week across the group.
So what did they find?
Of those who were told to avoid peanuts: 17.2% had a confirmed peanut allergy by 5 years of age. Of those who were given peanuts form an early age, only 3.2% developed a peanut allergy. So there was a 5 fold increase in peanut allergies in those who avoided them. Or to put it another way, an 82% relative reduction in peanut allergies with early and regular exposure to peanuts.
These were the results of the intention to treat analysis. They also did a per-protocol analysis where they excluded people who didn’t follow the protocol either because they had an allergic reaction to the initial food challenge and so couldn’t get peanuts even though they were randomised to the peanut group, or for whatever reason. And as expected with sort of analysis the results were even more impressive – a similar amount of those who avoided peanuts got allergies – 17.3% but much less in the peanut exposure group – 0.3% making it a 57 fold decrease in the rate of peanut allergy with early exposure, or a relative risk reduction of 98%.
They also separated the results based on whether there was a positive skin prick test initially or not. And the results were very similar.
Other Research The authors of the LEAP study did a follow on study after this, which they called the LEAP-on study. They followed these children up for another 12 months (or 1 year for all those engaging in calculus) to see whether the benefits persisted and they did.
There’s been other studies as well. Most of them for peanut and egg allergy – all showing early exposure to be beneficial. One particular study, also published in 2016 in the NEJM, randomised 1,300 to either start giving their kids allergenic foods at 3 months, or to start giving them at 6 months. The foods included milk, peanuts, eggs, fish and wheat. And here they found that starting at 3 months was better than at 6 months 2.4% had any allergy in the 3 month exposure group versus 7.3% in the 6 months exposure group.
Bottom Line Among kids with a high risk of atopic disease, introducing peanuts into their diet before 11 months and giving it to them regularly results in an 86% reduction in the development of peanut allergies compared to when they avoid peanut altogether. The benefits hold true even in children who have a positive reaction to peanut on skin prick testing. Guidelines should be more upfront when making recommendations that do not have a basis in the evidence. This may have prevented some of the massive increase in peanut allergies that we have witnessed.
References:
Evidenced videos on common health topics: www.youtube.com/DrDanMD
American Academy of Paediatrics 2000 guidelines: http://pediatrics.aappublications.org/content/106/2/346.long
LEAP trial: http://www.nejm.org/doi/full/10.1056/NEJMoa1414850#t=article
Conflicts of interests in guidelines: http://www.bmj.com/content/343/bmj.d5621
Scientific basis of endocrinology guidelines: https://www.ncbi.nlm.nih.gov/pubmed/22624723
Scientific basis of cardiology guidelines: https://www.ncbi.nlm.nih.gov/pubmed/19244190
Observational study: https://www.ncbi.nlm.nih.gov/pubmed/19000582?dopt=Abstract
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 saturated fats and death, heart attacks, strokes or diabetes.
Randomised Controlled Trials The highest level of evidence are randomised controlled trials, where you actually randomise a group of people to either reduce their saturated fat intake or keep it the same. By far the biggest of these studies was the Women’s Health Initiative. If you look at systematic reviews like the Cochrane Review, this trial contributed to about 60% of the power of the review. This is a complicated trial that needs its own episode, but in one of the arms of the trial, 50,000 women were randomised to two groups: The first group simply continued their usual diet, and the second group got a very intensive program of dieticians and eduction to reduce their total fat and saturated fat intake. They followed them up for 8 years and found absolutely no difference in cardiovascular disease whether they continued their usual diet or reduced their fat and saturated fat.
The PURE Study The PURE study is the latest to stab this saturated fat theory in the back. It’s a huge prospective cohort study – and probably the highest quality one we have to date.
They recruited 156,424 people and got them to complete surveys at the start of the study and then every 3 years after that. They were interested in things like smoking, physical activity, medications, socioeconomic things like education and income and a full medical history.
They recruited people from 18 countries getting a good mix of third world and first world countries. This is what sets it apart from other studies.
They recruited from three high income countries – like Canada and Sweden, 11 middle income countries – like Brazil, China, Poland and South Africa, and four low-income countries like India and Pakistan. And they based this on the World Bank classification.
They also tried to get the most accurate representation of what each of these people were eating. They did this by making participants fill out food questionarres on their diet. Every country had its own questionarre that was specific to that country but the questionnaires were standardized across the countries. The problem with this method is that there is good evidence that food questionaries are often not an entirely accurate depiction of what someone is actually eating. Imagine if I asked you what sorts of foods you eat – How different would your answer be if you were in a good mood compared to being in a bad mood – your diet might not be different, but you might feel guilty and self loathing and inflate all the bad things you eat. If you just got out of gym, on the other hand, and are feeling amazing, you might inflate all the fruits and vegetables you eat. And then there’s the problem of recall – who can remember how many times they added salt to their food? And how are you to know how much butter or oil was in that eggs Benedict you ordered from the restaurant. This is one of the big limitations of any diet study, be it a cohort or even a randomised controlled trial. In order to verify the accuracy of the answers to these questions, they got a sample of about 50-250 participants from each country to keep a 24 hour food diary every now and then. That way they could compare how well matched their actual food intake was to what they had written on their food questionnaire – and they could try and adjust for this.
This PURE study is still ongoing. They are following this population continuously and publishing studies about them left right and centre. The specific study from the PURE data that we’re looking at today was titled: “Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. It was published in the Lancet in August 2017.
Out of the 156,424 people in the PURE cohort, only 135,335 could be included in this study because they didn’t have all the data they needed. They also excluded people who had a history of cardiovascular disease. The average follow up was for 7 and a half years.
The aim of the study was to see if they could make any associations between diet and cardiovascular disease. They followed each patient up every single year to see if they had a heart attack or a stroke or any other cardiovascular outcomes.
They calculated the proportion of carbohydrates, fats and protein in everyone’s diet. They did this by converting the foods they ate into nutrients. They then split up the population into quintiles for each of these macronutrients. So for example, with saturated fat intake, they split the population into 5 groups based on the proportion of saturated fat they were eating. The top 20% – who ate the most saturated fats – were put in the highest quintile and the 20% who ate the least amount of saturated fat were put in the lowest quintile and so on and so forth. They did this for all the macronutrients. And then for each quintile, they checked to see how many died, how many got strokes, heart attacks and so on.
Results Saturated Fats Put that skinny flat white down and and take a seat for this one because you could be in for a bit of a shock. The recommendation is that we eat less than 6-10% of our total energy intake from saturated fat, it differs slightly depending on the guideline. The lowest quintile of saturated fat consumers in this study were eating 2.8% of their total energy intake from saturated fat – so they were well and truly within all the guidelines. And they were the most likely group to die! They were also the most likely group to develop stroke! And while it wasn’t statistically significant, they seemed to be at the greatest risk of all the other cardiovascular outcomes.
There was no difference between any of the other quintiles, only this lowest quintile of saturated fat consumers where at a higher risk. So it didn’t matter if you were getting 13.2% of your total energy from saturated fat or 9.5% or 7.1% or 4.9% – there was no difference in death or cardiovascular disease. But if you were eating a really low amount – 2.8%, then your risk significantly increased. All cause mortality was 7.2% in the lowest saturated fat eaters and this went down to around 4.5% as you increased the amount of saturated fat in your diet.
Total Fats Again, the lower your total fat intake the more likely you are to die or develop a stroke. The highest quintile of fat eaters were getting 35.3% of their energy from fat and they were the least likely to die. Total death and stroke was more common when total fat made up 10% of your diet compared to if it was 35.3%.
Carbohydrates This is where things get interesting. When I was in primary school there was a national program to teach kids about the food pyramid. On the bottom of this food pyramid – the foods we should be eating the most – were all carbohydrate foods – breads, cereals and pasta. Well, what does the PURE study have to say about that? It showed that as your intake of carbohydrates increased, your risk of death and cardiovascular disease also increased. And if you look at the graph it really looks like it’s in a linear fashion. So in the lowest quintile of carbohydrates eaters (those who obtained 46.4% of their total calories from carbs) – 4.1% died during the follow-up period. But among those who ate the most carbohydrates (77.2% of their total calories) – 7.2% of them died.
Other Macronutrients Interestingly, animal protein intake was associated with lower rates of mortality.
Discussion
Why do we insist on making recommendations when we don’t have sound evidence to support these recommendations. Especially when they involve a radical change in lifestyle. Using a different example, most dietary guidelines, up until recently, used to strongly recommend that parents should avoid giving their babies foods that are allergenic. The American Academy of Pediatrics told all mothers not to eat peanuts during pregnancy, while breastfeeding and not to give them to their child until they reach 3 years of age. Then the LEAP trial came along in 2015 and showed that actually, the earlier you give peanut products to babies, the less likely they are to develop allergies. It is clear that these recommendations had actually caused a lot of food allergies. The difference is that the paediatric nutritional guidelines have been quick to adjust their recommendations after the LEAP trial came out, but the total fat and saturated fat recommendation don’t seem to show any signs of slowing down despite an increasing body of evidence that we were probably wrong.
This isn’t perfect evidence. Nothing beats a randomised controlled trial in terms of telling us whether something is causative, but it’s almost impossible to do a good quality randomised controlled trial on diet. Firstly blinding is impossible. Secondly, if I told you to stop eating saturated fats, or you start eating much more saturated fats, would you be able to do that? For 5 years? It’s very tricky. This is one area of medicine that you argue that cohort studies are probably better at giving us answers than randomised controlled trials – just because it’s so hard to control the bias in RCT’s. But even still, we do have randomised controlled trials – which do not find any benefits from a diet low in saturated fats. It would be very unusual not to pick up an association from cohort studies if there was something very bad about saturated fats as the guidelines suggest. When you look at cohort studies of smoking – there was like 8-10 times higher rates of lung cancer in those who smoked. It was a very robust association. But here, cohort studies just don’t seem to find an association.
One might argue that people who are health conscious might exercise more, smoke less and choose their diet carefully – therefore skewing the results. But if anything, this would skew the results towards low-fat diets looking better. Because healthy people are eating less fat and less saturated fat – because that’s what society has been telling them to do – so if the people in the low-fat group are exercising more – this would make the results look even more impressive.
Perhaps people who can’t afford meats which are high in fat are more likely to die not because they are eating less fat, but because they don’t have money to pay for healthcare, etc. Interesting potential bias. So the researchers did additional analyses where they adjusted for socioeconomic status and found the same results.
Bottom Line This is a direct quote from the conclusion of the study:
Global dietary guidelines should be reconsidered in light of the consistency of findings from the present study, with the conclusions from meta-analyses of other observational studies and the results of recent randomised controlled trials.
References and Links
Evidence based videos: www.youtube.com/DrDanMD
PURE study: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32252-3/abstract
Womens Health Initiative: https://www.ncbi.nlm.nih.gov/pubmed/16467234
Systematic review of observational studies: http://www.bmj.com/content/351/bmj.h3978
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. Its actually an interesting story how this drug came to be. A group in Paris who do a lot of research on families with familial hypercholesterolaemia 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 about it. Then, in another part of the world, researchers in Canada had discovered a new protein involved with 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 hypercholesterolaemia. 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 Well 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, hospitalisation for unstable angina, or coronary revascularisation.
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 everyone. So in this study, it showed that evolocumab rhad.an absolute risk reduction of 1.5%….but that’s only if your baseline risk is 11.3% over 2 years. If your baseline risk is 5% over 2 years, then this number is no longer true. And this is where relative risk is useful. Because we can apply it to people’s baseline risk to determine their individual absolute risk reduction. Using the relative risk reduction of 13%, if our patient has a 5 year cardiovascular risk of 10%, then giving evolocumab for 5 years will reduce that by 13% to 8.7% – making an absolute risk reduction of 1.3% for that patient. But if our patient has a 5 year risk of 3%, then evolocumab will only reduce it down to 2.6% – making an absolute risk reduction of 0.4%.
Relative risk is also good when comparing it to other drugs. Compare Evolocumab’s 13% relative risk reduction to high dose statins which reduce risk by 35%!. Or to ezetimibe which reduces risk by 6%. Or antihypertensives which reduce risk by about 25%. So hopefully that puts evolocumab in perspective.
Now, its important to see exactly where this 13% risk reduction came from. Because it was a 13% reduction in any of heart attacks, strokes, unstable angina or revascularisation, and I think we can all agree that a 13% reduction in risk of revascularisation or angina is very different to a 13% reduction in cardiovascular death.
So firstly, there was absolutely no reduction in death – cardiovascular death or death from any cause. Not even a signal of benefit there – it was 3.1% in the placebo group and 3.2% in the evolocumab group. There was a reduction in non-fatal myocardial infarction, this went from 4.6% down to 3.4%, and stroke also went down from 1.9 to 1.5
In terms of harms – they could not find any difference. And they looked at a lot: cognitive impairment, muscle aches, bleeding, allergic reactions. There was a slight increase injection site reactions but this was rare.
Discussion
Sponsorship: The manufacturer of the drug sponsored the trial – they were involved in designing the trial and collecting the data. They then gave the raw database with all the data to an independent group called the TIMI group and they were responsible for analysing the data. So industry was involved but this trial would never have happened and probably wouldn’t have been as robust if not for industry funding.
Lipid Hypothesis: This trial and the positive results of the trial, has re-opened this whole debate about the lipid hypothesis. This is the debate as to whether lowering cholesterol is important – no matter which drug…or whether the drug is important and it doesn’t matter what it does to cholesterol. There is probably no bigger debate in evidence based medicine than this. A lot of proponents for the lipid hypothesis consider this trial a great victory to their belief system but I wouldn’t be so quick to jump on the band wagon because there are a few holes to the theory in this trial. Firstly, the investigators divided the patients in this trial based on their starting LDL. In the lipid hypothesis, we would expect a greater benefit from reducing cholesterol in those who have a very high cholesterol – The higher the cholesterol the greater the risk and so the greater the reduction in cardiovascular disease with treating such high cholesterol. We see this in hypertension, reducing blood pressure from 180 systolic with an antihypertensive gives you much greater benefit that reducing a 140 systolic with that same antihypertensive. But this was not seen…there was the exact same benefit if your starting LDL was 3.4mmol/L or if it was 1.8mmol/L. Secondly, there’s a group called the cholesterol trialists who did a big meta-analysis of cholesterol lowering in 2012, and their conclusion was that it doesn’t matter what you use to lower cholesterol, every 1mmol/L reduction in LDL will result in a 23% relative reduction in cardiovascular events over 5 years. This trial showed that evolocumab reduced LDL by 1.6mmol/L – so if we apply this rule of the clinical trialists, this should equate to a 37% reduction in cardiovascular disease. But it didn’t – It led to a 13% reduction in cardiovascular disease. So clearly the impact of cholesterol lowering is not consistent across the different drugs.
Another point to mention is that these were not your average secondary prevention patients. It’s very common for a drug to be released onto the market with a very narrow indication but this tends to expand overtime. It’s difficult to say whether this medication will benefit your average secondary prevention case. After all, not only had these patients already had a heart attack or a stroke, but they also had risk factors on top of that like smoking or diabetes. Even worse, my fear is that this drug will creep into the primary prevention space even though its very doubtful it has any meaningful effects in primary prevention.,
Cost: Evolocumab currently costs 14,300 USD per year of treatment. So lets make a calculation. This study showed a number needed to treat of 67 over 2.2 years. So if you multiply 14,300 by 2.2 and then by 67 – this drug costs 2.1 million dollars to avoid one non-fatal heart attack or non-fatal stroke. That will not save any lives, just reduce a heart attack….for 2.1 million dollars. Can you imagine how many heart attacks you would avoid by putting 2.1 million dollars into exercise programs? Currently the Government in Australia will pay for the medication in those with homozygous familial hypercholostorolaemia.
Bottom line: We now have 3 medications that lower cholesterol and reduce cardiovascular disease. The latest is the monoclonal antibody, Evolocumab (Repatha), which is able to reduce cardiovascular disease by a relative reduction of 13%. Compare this to high dose statins which reduce cardiovascular disease by 35% and ezetimibe which reduces CVD by 6% (relative). Evolobumab does not reduce death. It currently costs 14,000 US dollars per year, which equates to 2 million dollars per non-fatal heart attack avoided.
References & Links:
Dr. Dan Videos: www.youtube.com/drdanmd
FOURIER trial: http://www.nejm.org/doi/full/10.1056/NEJMoa1615664
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, the P value was 0.21, but again, that doesn’t mean it isn’t true – it just means that there is a 20% probability that these results occurred by chance.
Therefore, in this study, 12% more people obtained a minimum clinically important improvement in their symptoms in the magnesium group compared to placebo. If this is true, it means the number needed to treat for magnesium over placebo is around 9.
There was no difference between magnesium and placebo for any of the secondary outcomes, like quality of life or sleep quality.
In terms of side effects, there was no difference between magnesium and placebo. But other studies have shown increased rates of diarrhoea with magnesium.
Other Evidence There have been 4 other randomised controlled trial looking at magnesium for idiopathic leg cramps (Cochrane), and they all showed pretty much the same thing. That amazingly, there was a great improvement with placebo, but no greater improvement with magnesium. 1 of the trials also showed this very slight improvement with magnesium over placebo but it also was not statistically significant.
There have also been three trials looking at using magnesium specifically in pregnant women and while one found it was better than placebo, the other 2 didn’t.
Bottom Line In those who suffer nocturnal leg cramps, placebo and magnesium are very affective at reducing the number of cramps, reducing them by almost half. There was a non-statistically significant improvement with magnesium over placebo which, if true, equates to a reduction in the number of leg cramps by 0.4 episodes per week or a number needed to treat of 9 for a minimum clinically important improvement (P=0.21).
So should we stop using magnesium? Well, given that the placebo response is so good for this condition, and given there is absolutely no other effective treatment for nocturnal leg cramps and given that the side effects are minimal….perhaps magnesium is a reasonable option. What are your thoughts? Leave a common
References and Links:
Dr. Dan Youtube videos: www.youtube.com/drdanmd
JAMA 2017 study: https://www.ncbi.nlm.nih.gov/pubmed/28241153
Cochrane review: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009402.pub2/full
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:
Who cares about how the ear looks otoscopically? This is a disease oriented outcome rather than a patient oriented outcome. As a parent I care if my child is eating, if they’re not in pain and if they’re not miserable. I really couldn’t care less if their ear drum was still red or not.
This outcome is very subjective “if they did not have complete or nearly complete resolution of signs and symptoms”.
All the other trials have used the AOM-SOS scale as their primary outcome which is a patient oriented outcome, why did they change it?
The authors did also use the AOM-SOS scale but used it as a secondary outcome, and it was very difficult to find the results for this – you had to look at different rows from two different tables to find this result. Paul Glasziou has done that for us in his article and has even draws us a nice graph comparing the severity of symptoms over time. And when you compare this change in symptoms, there was really no difference between the 10 days or the 5 days.
Harms
1 in 3 kids in this trial had diaper dermatitis (nappy rash). Now as a parent of 2 kids who are still in nappies – this is a nightmare. They’re in pain when you wipe them, you’re forever putting creams on and getting peed on all the time as you try to maximise nappy-free time.
1 in 3 had diarrhoea.
Other Issues This study was done out of hospital setting, so these kids were going to the emergency department. And they had very strict criteria for which kids were allowed into the study. They had to have obvious bulging of the tympanic membrane and the presence of middle ear effusions. A lot of the children had a fever as well. So if we struggle to show a benefit for antibiotics in these patients, how much more so will they be useless in those with a slightly red drums, a bit grizzly, coming to their GP and not hospital.
The lead author, Hoeberman, apparently has a patent on an amoxycillin clavulate combination. And this doesn’t make the data wrong, but given that there is potential gain by him proving more amoxycillin/clavunate is better, it definitely warrants a more skeptical eye when looking at the methods and results.
Bottom Line: The evidence suggests that antibiotics will increase the chance of recovery by 5% over placebo, it will decrease the risk of ear drum perforation by 3%, but has no impact on long term hearing or other complications like mastoiditis or meningitis. Using amoxycillin/clavulanate for 10 days will improve otoscopic signs compared to 5 days of use but will not impact patient symptoms. 1 in 3 children will develop diarrhoea and 1 in 3 will develop nappy dermatitis with the use of amoxycillin/clavulanate (whether for 5 days or 10 days).
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 this. A good marker of what dose they were using was how many times they refilled a script within the first 30 days of this first script. So they know the dose of the pills and the amount of pills that were prescribed, and they know now how long it took them to refill the script they could now figure out what dose they were using.
Results
Of the 536,767 patients who were prescribed an opiate for the first time, 26,785 became long term opioid users. Which makes 5%.
85% of these first prescriptions were combinations of opiates with paracetamol. In Australia we have a combination product of paracetamol and codeine known as Panadein or Panadein Forte. America seem to have a lot more combination options: they have acetaminophen and hydrocodone, acetamenophine and oxycodone as well as acetaminophen and codeine.
The more repeat fills they had in the first 30 days after the initial prescription, the more likely they were to become chronic users: The risk of chronic use went from 2.9% if they just filled that first script in the first 30 days, to 10% if they had another refill in the first 30 days, to 26.1% if they had 4 or more refills in the first 30 days.
Now here is possibly the most interesting finding in the entire study: those who were started on long acting opioids had a much higher chance of chronic use than those started on short acting opiates. It was 25% versus 3.5%.
Bottom Line There is a 5% risk that a patient will become a chronic opioid user after being given their first script for an opioid medication. The likelihood of long term use increase greatly as the number of script refills within the first 30 days increased – From 2.9% with just that 1 opioid script fill, to 26% if they filled 4 or more. Initial prescribing of extended release preparations are associated with much higher chronic use rates compared to immediate release forms (25% versus 3.5%)
References:
https://link.springer.com/article/10.1007%2Fs11606-016-3810-3
Links: youtube.com/drdanmd
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” (depending on which group they were assigned to). If it was a sore throat the delay was for 5 days, and if it was for an acute bronchitis, the delay was for 10 days.
They managed to recruit 889 respiratory tract infection suffering patients but 333 were given immediate antibiotics because the doctor thought they needed them. So only 556 were randomised into the five delayed prescribing groups.
The outcomes they assessed were symptom severity – to see if those with delayed prescriptions had worse symptoms, they also looked at how much antibiotic was actually being used in each group, and patient satisfaction. Anyone over the age of 3 with any respiratory tract infection was included in the study. Including: cold, flu, sore throat, middle ear infection, bronchitis or sinusitis.
Results
Severity of Illness
In terms of severity of illness, there was no difference between the groups. There was also no difference in the duration of the respiratory tract infection nor in the amount of analgesia used. Even those who were given the antibiotics to take immediately had no difference in their illness compared to the others. So telling your patient: “no, you can’t have these antibiotics” or offering them one of the four different delayed prescription strategies did not effect their actual illness compared to giving them the antibiotics straight away.
Antibiotic Use
There was a massive reduction in the amount antibiotics used with the delayed prescriptions:
Of those who were given the immediate antibiotic script, 97% ended up taking the antibiotics. This is remarkable because in general, if a doctor gives a patient a script for almost anything else, study after study has shown that only about 70% ever go and fill that script. So there is something special about antibiotics. Or maybe there is something special about respiratory tract infections and the desperation to get rid of them as quickly as possible.
If the patient was denied a script for antibiotics 26% of them used antibiotics. And this is very interesting. Many just went to a different doctor and got their script. Makes you think hey?
In the delayed groups, there was no difference in antibiotic use no matter which method of delayed prescribing you used. Around 37% took antibiotics in the delayed groups: whether they were given a script and told to only fill it if they didn’t get better in a few days, whether they had to come to reception to collect their script, whether they had to call the doctor a few days later if they wanted their script or whether they got a script which was dated in the future, it didn’t matter. 37% of them used antibiotics.
So offering a delayed antibiotic script reduced antibiotic use by doctors 60%. And denying them a script only reduced antibiotic use by 10% over what a delayed script did. (Note: this difference in antibiotic use between delayed prescriptions and no prescriptions was not statistically significant)
Patient Satisfaction
With regards to patient satisfaction: 80% of patients were very satisfied with the consult if they didn’t get a script at all. So the fear that patients always want antibiotics and will not be satisfied if they don’t get them is not indicated in this study. Or perhaps the doctors where very good at explaining why they didn’t need antibiotics. The highest level of patient satisfaction was 89% and this was in the patient led delayed script group- where they were given a script and told only to fill it if things didn’t get better.
Other Evidence on Delayed Antibiotic Prescribing
A Cochrane Systematic Review was done in 2013 (before this study was published), and it found 10 trials making a total of 3157 patients comparing delayed prescribing for respiratory tract infections.
Just like in the BMJ study, if given an immediate script for antibiotics 93.3% will use antibiotics.
Again, just like our study, when given a delayed script only 32% will use antibiotics. Looking at the forrest plot, all the studies in this Cochrane review showed this same result with regards to this massive reduction in antibiotic use with delayed prescriptions.
Of those who were denied antibiotics, 14% still used antibiotics according to this Cochrane review. This is a little bit lower than the 27% in the BMJ who used antibiotics even though they were refused them initially.
Again, this review found no difference in the clinical outcomes whether you got immediate antibiotics, delayed antibiotics or no antibiotics.
So the results are very consistent. Offering a script and asking the patient to only use it if things don’t get better in a few days, will reduce antibiotic use by 60% and that’s the absolute reduction. Thats huge.
Bottom Line
Offering a delayed antibiotic prescription for a respiratory tract infection – where you give the patient a script and tell them only to use if things don’t get better in a few days – will reduce antibiotic use by 60%. Completely refusing to give a script for antibiotics will only marginally decrease antibiotic use compared to a delayed prescription. There is no difference in clinical outcomes when giving an immediate script, a delayed script or no script.
Discussion
Firstly, no other tool that has been studied is as effective at reducing antibiotic use as this. Delayed prescribing achieves a 60% absolute reduction in antibiotic use. The trials that look at patient education and doctor education do not come anywhere near this in terms of reducing antibiotic use.
Secondly, the qualitative evidence on why doctor prescribe antibiotics for respiratory tract infections seem to indicate four main reasons:
The first is the fear that patient will develop a bad complication from their illness – and you can understand this because if you’re a GP who has been working for several decades, it’s almost inevitable that you’ll send someone home with a mild infection that will then end up getting really sick. And that might scare the bageebes out of you and change the way you deal with these respiratory tract infections.
The second reason is that we think the patient wanted the antibiotic – and it turns out that we’re usually off target with this one, patients often don’t want them at all. They just want an explanation. In my own experience, I’ve had patients who I could have sworn were just coming because they wanted antibiotics and after I explained why I didn’t think it was necessary, to my shock they’re like: “oh few….I was so scared you were going to tell me to take antibiotics…I really hate taking them”.
The third reason antibiotics are prescribed when they probably shouldn’t be is because of diagnostic uncertainty. So here the doctor is not sure whether its viral or bacterial, so to er on the side of caution they give antibiotics.
Finally, the fourth reason is to do with time. Doctors fear that spending the time to explain why a patient doesn’t need antibiotics will take much more time than just printing a script and giving it to the patient. And will make them run late for the rest of the day.
Delayed prescriptions are brilliant because they tackle all four of these reasons. If a doctor fears the patient will develop a nasty complication from not getting antibiotics, they still have a script should things get worse. If the doctor fears the they will lose the patient by not giving them a script because they think the patient really wants one – well in delayed prescribing the patient still gets a script. And if the doctor is worried about time, it’s just as quick and easy to give a script and say use these in a couple of days if things don’t get better.
Lastly, all four methods of delayed prescribing led to the same amount of antibiotic use, so it makes sense to use the method that’s easiest for the patient – which is to give them the script and let them drive their decision take it or not, rather than make them call me or leave it with reception.
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. In other words, what is the added benefit of ezetmibe over statins?
Guess that acronym
Let’s play….guess that acronym…
So IMPROVE-IT stands for: IMProved Reduction of Outcomes -Vytorin Efficacy International Trial. So they took the I the M and the P from IMProved ….well played vytorin…well played.
And double points because it nicely played on the title of the PROVE-IT trial which was a trial comparing high dose statin to medium dose statin.
Study Design
They took the highest risk patients you can possibly study. Men and women over the age of 50 who had just had a heart attack (within the last 10 days). They had to have an LDL cholesterol of over 1.3mmol/L (50mg/dL). They excluded those with kidney and liver disease. While they originally recruited 5000 patients, this number seemed to increase to 18,144 for reasons which will be discussed later. They also extended this trial…twice. So the follow up ended up being 7 years on average.
They randomised these 18,000 patients to one of two group. One group got simvastatin at 40mg and the other group got simvastatin 40mg plus ezetimibe 10mg.
The primary outcome they were assessing was a composite of: Death from cardiovascular disease, myocardial infarction, unstable angina requiring hospital admission, revascularisation and stroke. A pretty controversial composite outcome because some argue that unstable angina and revascularisation which is just stents and things, should not be grouped together with heart attacks and strokes. They call them “softer” outcomes. But as we’ll see later from the breakdown of each of these outcomes, revascularisation and angina didn’t contribute much to the results of this composite.
Baseline characteristics of the patients in the study
All of the patients in the study had just had a heard attack within the last 10 days. But 20% of them had had a heart attack on another occasion as well as this one, so this was their second or third heart attack. The average age was 64. A quarter of them were women and a quarter had diabetes. The average LDL cholesterol was 2.4mmol/L (93.8mg/dL)
Results
LDL cholesterol decreased from 1.8mmol/L in the statin only group to 1.4mmol/L in the statin/ezetimibe group. So about a 20% reduction in LDL which is what we’ve seen in other trials with ezetimibe.
With regards to the primary outcome, the composite of heart attacks, strokes, angina and revascularisation – it went from 34.7% in the statin only group to 32.7% in the ezetimibe-statin group.
So there was a 2% reduction in cardiovascular disease when adding ezetimibe to a statin for these extremely high risk patients when given for 7 years. To put it another way: 98% of people who have just had a heart attack and take this drug for 7 years will not derive any benefit from it.
To put these numbers in perspective: 35% developed cardiovascular disease over 7 years in this trial. A statin would reduce a 35% risk to about 26% if it was low dose and to about 23% if it was high dose. Ezetimibe reduced it from 35% to 33%.
While this trial required 18000 patients and 7 years of follow up to show a 2% reduction in CVD, a different trial that gave statins immediately after a heart attack only needed 3000 patients and 16 weeks to show 2% reduction in CVD. This was the MIRACL trial.
The relative decrease in cardiovascular disease was about 6% with ezetmibe (range from 1%-11%). Compare this to statins which give about a 25% relative risk reduction. Going from low dose to high dose statin even gives you more bang for your buck than ezetimibe – it offers about a 10%-15% further reduction in cardiovascular disease on top of that already given by the low dose statin
Now lets break down that composite outcome. The good thing, is that the bulk of the 2% reduction came from hard outcomes. They mostly came from heart attacks and strokes. There was a 1.7% reduction in non-fatal heart attacks and a 0.6% reduction in strokes.
But! there was no difference in cardiovascular mortality. Or in overall mortality. Compare this to statins which consistently show a reduction in mortality – at least for secondary prevention by about 10%. But alas, ezetimibe could not show a difference in mortality even in this very high risk population
In terms of harms, they did a good job of looking very thoroughly at all sorts of side effects, and there was really no difference in harms between the two groups. Importantly, no difference in cancer rates, because previous studies had signalled an increased risk of cancer with ezetimibe.
Discussion
Firstly, 42% of patients stopped therapy in each group. Now that is a very high drop out rate. So make of that what you will.
Secondly, there were 5 amendments to the protocol during the study! One being to increase the sample size. Was this because they didn’t like the results they were seeing? They reported in their methods that they were looking for a certain number of events 5,200 to be exact. But was that the plan from the beginning? Or did that become the plan while the study was going on? There was a lot riding on this trial. 3 billion dollar a year in sales, they really couldn’t afford not to show a benefit. Even at the expense of sound methodological quality perhaps?
When they ran the statistics before the study, they calculated that they needed 5000 people to detect a 9% relative risk difference in cardiovascular outcomes, but they ended up with 18,144! So my question is: where was that interim analysis for 5000 people? They must have done one to then decide to increase the number to 18,000…where is that report?
This drug is being heavily marketed for use in primary prevention. But, there is no evidence that it works at all in primary prevention. You could argue it barely works for secondary prevention. But let’s assume that this 6% relative reduction carries true even in primary prevention, what benefits might patient who haven’t had heart attacks be getting from this drug? In Australia, guidelines recommend initiating cholesterol therapy once the 5 year risk reaches 15%. A statin would reduce that risk to about 10% over that five years. Whereas ezetimibe would reduce it to 14.1%. So a 0.9% reduction in cardiovascular disease if taken every day for 5 years. In America and the UK their guidelines are recommend starting therapy at a 10 year risk of 10%. So if a patient with this risk took ezetimibe every single day for 10 years, only 0.6% of them would get any sort of benefit from this drug.
Another criticism of this trial that has been published is that standard of care after a myocardial infarction is high dose statins at a dose of 80mg of simvastatin. While the majority of the cardiovascular benefit comes from the first 10mg, there is evidence that 80mg provides a small but significant benefit on top of this. This study only used 40mg, which is below the recommended post MI dose of statin. So would we still see a benefit for ezetemibe on top of the recommended 80mg simvastatin? That is anyones guess.
This is the second drug that lowers cholesterol and also lowers cardiovascular disease. So I guess it adds to the argument for the lipid hypothesis. But its important to not get carried away and use drugs that lower cholesterol but don’t have evidence on cardiovascular outcomes There have been several drugs like: fibrates, torcetrapib and niacin that improve the lipid profile but have shown no improvement in cardiovascular outcomes – some even showing harms. So while the authors, in their conclusion make a very bold statement that “this study clearly proves the lipid hypothesis” I am still cautious.
Bottom Line
For patients who have just had a heart attack, adding ezetimibe to statin therapy will at best (given other studies showing no benefit) reduce cardiovascular disease with a 6% relative reduction. Compare this to statins and blood pressure medications which offer a relative risk reduction of around 30%. Ezetimibe will not reduce death, compared to statins which consistently show reductions in death in secondary prevention. There is no evidence that ezetimibe has any benefit in primary prevention.
References:
IMPROVE-IT: http://www.nejm.org/doi/full/10.1056/NEJMoa1410489
ENHANCE trial: http://www.nejm.org/doi/full/10.1056/NEJMoa0800742#t=abstract
SEAS trial: http://www.nejm.org/doi/pdf/10.1056/NEJMoa0804602
SHARP trial: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60739-3/abstract
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 their gait speed
Bottom line: There was no difference in the number of people who had clinically important improvements in their physical function.
Sexual Function
To be included in the sexual function trial, participants had to have low libido as per a low score on a libido scale called the DISF-M-II scale. They also had to have a partner willing to have sexual intercourse with them at least twice per month. 459 patients qualified for this study. The primary outcome was the improvement on a sexual function scale called the PDQ-Q4 scale (Psychosexual Daily Questionnaire – Question 4). This score asks people about their sexual encounters. For example: Did you experience any of the following today: sexual daydreams, sexual intercourse, flirting, ejaculation. There are 12 of these in total, each with a “yes” or “no” making a total possible score of 12.
The average baseline score was 1.4 in both groups. In the placebo group, it went to an average of 1.3. In the testosterone group went to 1.9. Making a 0.6 point increase in this 12 point scale over placebo with testosterone therapy.
They assessed erectile dysfunction as a secondary outcome using a score called the IIEF erectile function score. This increase by 2.6 points with testosterone over placebo. Compare this to phosphodiesterase type-5 inhibitors (Viagra, etc.) which in meta-analyses of elderly men has shown to increase this score by 5.7 points.
Bottom Line: Treating men with low testosterone and low libido with testosterone therapy will given them about half an extra flirt, or half an extra spontaneous erection, or half an extra sexual daydream per day. Though direct comparisons have not been done, testosterone appears to be inferior to phosphodiesterase type-5 inhibitors.
The Cardiovascular Trial
By way of background, there are trials which point to an increased risk of cardiovascular disease with testosterone therapy. One randomised controlled trial of 209 elderly men in 2010 found that those in the testosterone trial were 6 times more likely to develop a cardiovascular adverse event than those in the placebo group. Because the Testosterone Trials had men with low cardiovascular risk, it was not powered to pick up a difference in cardiovascular events. So instead they used the surrogate marker of non-calcified coronary artery plaque volume and coronary artery calcification score. 170 men were enrolled in this part of the trial and they put them into a CT coronary angiogram machine at the start of the study and at the end of the study to see who had more atherosclerotic plaque built up in their coronary arteries. There was more atherosclerosis and a higher coronary artery calcification score in those receiving testosterone
Bottom line: Testosterone therapy will increase the amount of atherosclerotic plaque in the coronary arteries as well as the coronary artery calcification score. While this study was not powered to detect a difference in patient oriented outcomes of cardiovascular disease, previous studies have signalled an increase in CVD with testosterone therapy
The Cognition Trial
493 of the 790 men met criteria for Age Associated Memory Impairment and there was no improvement in cognitive functions or memory with testosterone
Bottom Line: testosterone therapy does not improve cognition in men with age associated memory impairment
The anaemia Trial
126 patients out of the cohort of 790 were anaemic, half of which had no known cause. The primary outcome was how many people achieved a rise in haemoglobin by 1g/dL. 54% of men did this when given testosterone versus 15% who were given placebo.
Bottom Line: Treating low testosterone with testosterone therapy in anaemic patients will improve anaemia with a number needed to treat of 3
The Bone trial
Here they took 211 patients and checked whether their Volumetric Bone Mineral Density changed using quantitative CT scanning. They also checked BMD with DEXA scanning. And there was a slight increase in bone mineral density with testosterone therapy. What we really care about is fractures though, because after all, this is why we care about BMD. They checked for fractures at regular intervals in all the 790 participants. During the 12 months of the study – 6 got a fracture in the testosterone group and 6 got a fracture in the placebo group.
Bottom Line: Testosterone therapy increases bone mineral density but there is no evidence that it reduces fractures
Adverse Events
There was no difference in adverse events between the two groups
Patient Global Impression of Change
In the above summary for each of the trials, only the primary outcomes have been listed. These T-trials had a lot of secondary outcomes and some of them were statistically significant while others were’t. But one of the secondary outcomes deserves mention.
It great when trials actually ask the patient…”did you feel better on this drug?” And this trial did that. They did each of the 790 participants these questions: “Since the beginning of the trial, has your sexual desire been better, not changed or worse?”, “Has your walking ability been better, unchanged or worse?” and “has your energy been better, unchanged or worse.?
With regards to physical functioning, around 11% of those who got placebo said that their walking ability got much better compared to 18% of those who got testosterone. So an absolute difference of 7% in the patients impression of their improvement in physical functioning. Making a number needed to treat of 15.
For vitality, around 10% of those in the placebo group said their energy levels were much better, compared to about 21% in the testosterone group. Making a number needed to treat of around 10 for patient impression of improvement in vitality. With regards to sexual function, 5% of those getting placebo said that their sexual desire was much better, compared to 20% of those who got testosterone. The NNT is 7, So for every 7 patients with low testosterone and low libido who are treated with testosterone therapy, 1 will report an improvement sexual function.
Final Bottom Line:
For elderly men who have low testosterone levels that is not due to pathology of the reproductive system, restoring their levels with testosterone therapy to that of a young man, will not improve objective measures of vitality or physical functioning but will result in a slight improvement in objective measures of sexual functioning which is of marginal clinical significance and is likely inferior to phosphodiesterase type-5 inhibitors. But, there will be a subjective improvement in sexual function, vitality and physical function in about 10% of patients. Testosterone will not improve cognition in those with age related memory impairment. It will improve anaemia with a NNT of 3 in those with anaemia. It will improve Bone Mineral Density but not reduce fractures. Concerningly, while this study was not powered to detect a change in cardiovascular disease, it did find an increase in the amount of atherosclerotic plaque in the coronary arteries as well as the coronary artery calcification score with testosterone therapy. This is on a background of previous studies which have showed increased cardiovascular disease with Testosterone therapy.
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.
What would you do if you had a kidney stone base on all this evidence? I think we can agree that there is no benefit for nifedipine but would you take tamsulosin? Say, if you had a stone greater than 5mm?
Currently, the guidelines in Europe (European Association of Urologists) and America (American Urological Association) both recommend medical expulsion therapy if the stone is less than 10mm and provided there is no indication for urgent stone removal.
The scary thing is that this is not the only example of where a meta analysis was “proved wrong” by a large, well designed randomised controlled trial. A study has found that large, definitive randomised controlled trials differ in the results of the meta-analysis that preceded it about 35% of the time.
References:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008509.pub2/full
http://www.nejm.org/doi/full/10.1056/NEJM199708213370806#t=abstract
Music Polyrhythmics – El Fuego
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-section
Birth trauma went from 1.4% to 0.6% with planned C-Section and this was mainly because of decreased bone fractures and brachial plexus injuries
Hypotonia which lasted greater than 2 hours went from 1.8% to 0.2%
There was a decrease in Low Apgar score at 5 minutes, it went from 0.9% to 0.1% with planned C-section
Rates of intubation and ventilation also decrease – from 1.3% to 0.3%
And neonatal ICU admission decreased from 3% to 1.5%
In terms of maternal outcomes – there was really no difference here. No difference in postpartum bleeding, mortality, genital tract injury, wound issues or infection. Having said that…they didn’t look at pain and return to normal function which I think we know would have been better in the planned vaginal delivery group.
Interestingly, they re-analysed the data, to see if there was a difference in baby outcomes depending on how well trained the obstetrician was in doing vaginal breech deliveries. And it did seem to make a difference: instead of that 5% risk of the primary outcome with planned vaginal delivery – If the only looked at obstetricians was super trained – with more than 20 years experience in delivering breech babies, this primary outcome went down to 3.2%. Which is still greater than C-section which if you remember was 1.6% but still, better than the vaginal breech delivery average.
This study quickly had a tremendous impact on practice almost immediately after publication:
For breech delivery in the Netherlands for example, the caesarian section rate went from 50% to 80% within 2 months of this study being published.
The American College of Obstetrics and Gynaecology changed their guidelines within a few months from the publication of this study to now recommend a planned caesarian section for all term singleton breech presentations.
In Australia, by 2005, only 3.7% of babies in breech presentation were delivered vaginally. And the number of obstetricians confident In performing a vaginal breech delivery is diminishing across the world.
In 2006 a survey was done on Australian obstetrics and gynaecology trainee’s who were in their final year of training, and only 11% of them said they would OFFER a vaginal delivery to their women in breech. I imagine this would me much less if done today.
The term breech trial researchers published another paper 2 years later where they followed up a selection of the original babies in the term breech trial to see if there was any difference in outcomes after a couple of years. Only 85 of the 121 birthing centres were pre-selected to be involved in this 2 year follow up. So out of the 2088 women in the actual term breech trial, 1159 were to be included in this 2 year follow up study. As the child reached 2 years of age, the investigators sent out questionares to these 1159 women about their Childs development. Questions about communication, gross motor skills, fine motor skills, problem-solving skills, and person-social skills. The plan was to see whether there was any difference in child death rates outside of the initial neonatal or perinatal period OR if thee was any neurodevelopment delay. They only managed to get data from 920 and they found no difference in death or neurodevelopemental delay between the planned C-section and the planned vaginal delivery from breech babies at 2 years follow up.
So whats the bottom line? Well I’ll leave the lead author of the study to answer that in a quote from a response to a commentary she published in the BMJ:
“for those women preferring a vaginal breech birth, they should be reassured that although planned caesarean section reduced the risk of perinatal or neonatal mortality or serious neonatal morbidity, compared to planned vaginal birth, in the Term Breech Trial, 95% of babies in the planned vaginal birth arm did well. Also, although our statistical power was limited, we did not find planned caesarean to be associated with better outcomes for the children at 2 years of age”
Reference:
Term Breech Trial: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02840-3/abstract
2 year follow up trial: https://www.ncbi.nlm.nih.gov/pubmed/15467565
music by Polyphonics song El Fuego