Dragi Weekly No. 278: COVID-19, LADA guidelines, vitamin D and asthma

Hello everyone! It is time for a new season of Dragi Webdo and time to go back to work for many. Here are the news that I have seen during the summer. To begin with, I can only recommend you to read the article about using placebo in chronic pain that was published in the BMJ and that shows that a placebo, even when telling it is a placebo, has a certain placebo effect and the importance of the patient-doctor relationship in the placebo effect. Have a good reading!

1/ Pharmacovigilance

The risk of lower limb amputation with canaglifozine was evaluated in the BMJ through a cohort study comparing canaglifozine to GLP-1 receptor agonist with propensity score match. The authors confirm the higher risk, but only for patients over 65 with a past medical history of cardiovascular disease. The number of patients to treat each year to cause an amputation (NNH) is 274.

The French Agency for Drug Safety informs about the risk of QT prolongation with levetiracetam, in order to prevent doctors associating it with other medications responsible for this cardiac abnormality.

2/ COVID-19

As we get closer to the end of school holidays (in the Northern hemisphere), the French association of community paediatricians and the French society of paediatrics have published guidelines building on the advice from the French Academy of medicine. They advise a reinforcement of immunization strategies: against influenza (according to the usual criteria, not for every child contrary to the USA) and against rotavirus (which is usually recommended in the USA). This last one is actually not recommended anymore in France since 2015 due to insufficient medical benefit, partly because of the risque of intussusecption. Limiting the prevalence of theses diseases may limit the burden of emergency rooms according to the authors. The press release of the Academy of medicine has only one reference, it's not much and the vaccine remains being not reimbursed. Regarding management of COVID-19 before 6 years old, the authors only recommend a screening test only for severe cases or persisting symptoms over 3 days or in case of contact with a COVID+ patient. For children over 6, all should be tested if symptomatic. The time off school should be at least 7 days and until symptoms disappear.

The BMJ has published an article regarding physical distancing, advising for 2 metres rather than 1 metre between people. They have also produced a table estimating the risk of transmission according to different situations:

An article in the JAMA has found out that, among patients hospitalized for COVID, 87% had a post-COVID syndrome, defined as symptoms persisting despite a normal PCR test. The patients had been followed for around 2 months and were presenting mostly with fatigue (53%), dyspnea (43%), joint pain (27%) and chest pain (22%).

3/ Respiratory medicine

I have already written several times about the possible benefit of vitamin D for childhood asthma (here and a bit there). In a study published in the JAMA, 200 children with vitamin D deficiency and an ICS-controlled asthma were randomized between a placebo group and a vitamin D 4,000 IU per day group. After 48 weeks, there had not been any improvement for the delay until the first severe exacerbation. One can regret that, in this article, there is not any information about the non-severe asthma attacks and the use of short-term relievers, but there was not any difference for ICS use. Overall, this study should be included in the next Cochrane meta-analysis on this topic.

In a NEJM study, the treatment with 3 days of amoxicillin was studied against placebo, for non severe pneumonias of children aged between 2 months and 5 years in Pakistan, in general practice. The reasoning was that, considering the pneumococcal vaccination, the amoxicillin was not useful anymore. As a matter of fact, with this vaccination, atypical pneumonia are the most frequent ones after 3 years old; macrolides do not have much use (see this Cochrane review). The failure rate at day 3 was significantly larger in the placebo group (NNT = 43; 4.8% vs 2.5%), no difference at day 14. So, we can draw 2 interesting findings: 3 days of amoxicillin seem to be enough, instead of 5; and even we miss a pneumonia, it seems to evolve favorably. 

4/ Diabetes

I wanted to finish with the guidelines regarding the Latent Autoimmune Diabetes in Adults (LADA), a diabetes mellitus intermediate between type 1 and type 2, affecting between 2 to 12% of the diabetic patients (quite a lot!). The diagnosis is usually made among patients over 30 years old with a low BMI and anti-GAD+ antibodies. These patients usually have a C-peptide that decreases much less faster than type 1 diabetes patients and therefore can be treated by non-insuline antidiabetic drugs. But few patients will have a low C-peptide and will require insulin. I won't discuss this further.

And that's all for the comeback ! Thanks for your loyalty. If not already done, do not hesitate to subscribe on Facebook, Twitter or to the newsletter by e-mail: you have to put your e-mail address in the top right field of this page and confirm the subscription in an e-mail entitled "FeedBurner Email Subscriptions" that will be sent to you and may land in your junk folder.

See you next week!

 

@Dr_Agibus (free translation by @carttom)

Dragi Webdo n° 270: COVID-19 (HCSP, SFP, hydroxychloroquine, PCR), NSAIDS and infections, knee OA, gynaecological exam

Welcome for this first Dragi Weekly post-lockdown! I hope that you and your patients have enough masks to protect yourselves. We have already written about it, but take care of yourself. The French High Health Authority has published "quick answers" on this topic: healthcare professionals distress: prevent, identify, guide (here in French). Happy reading !

1/ COVID-19

To begin with, I will share here the link (in French) of the atoute website from Dr. Dupagne, because it is very comprehensive and interesting.

Let us move on with hydroxychloroquine. In this NEJM paper, 1400 patients with a severe form of COVID received hyxdroxychloroquine or standard care, without randomization, in an American hospital. After inverse probability weighting according to the propensity score, no link was found between using hydroxychloroquine and the risk of death or orotracheal intubation. OK, but this is not randomized.

In an article from the BMJ, the outcome for hospitalized COVID patients with pneumonia receiving oxygen (but without criteria for ICU) was assessed in France. 84 patients received hydroxychloroquine out of 181 total patients, without randomization. At day 21, 76% of patients who received hydroxychloroquine were transferred to ICU (and 11% of deaths) versus 75% in the control group (and 9% of deaths). Once again, no statistical difference.

A retrospective study in the JAMA compared mortality of COVID patients who received azithromycin, hydroxychloroquine, both of them or neither of them. Once again, no difference in mortality between the different patient groups after adjusting on confounding factors.

So here comes a randomized controlled trial of 150 Chinese hospitalized patients with a moderate to mild COVID, receiving hydroxycholorquine + standard of care versus standard of care only. At day 28, no change to a more severe COVID form was found in around 80% of patients from both groups, whatever the treatment plan was, with no difference between the 2 groups. Adverse effects occur in 30% of patients with hydroxychloroquine versus 10% of patients without it. So, not only this medication is inefficient, even for low-severity patients, but it exposes them to adverse effects. This study was randomized so it is time now to try other molecules to fight COVID (and I send you back to this editorial by P. Glasziou about the "waste in COVID-19  research").

The French colleges of paediatricians (link in French here) have proposed an algorithm about the management of kids with a suspicion of COVID-19 and PCR indications (it applies from kindergartens to elementary schools, but it will prove to be some sports to do a swab to a child under 5). Globally, the PCR has to be done in case of symptoms if there is a COVID patient among close relatives or if there is no clear cause in case of no obvious contagion.

The French High Council of Public Health (in French here) has published guidelines for people with a suspicion of COVID as past medical history. If one of these people (patient A) is in contact with a COVID+ person (patient B), there are 2 possibilities:

- if patient A had a PCR positive once, no need for quarantine

- if patient A did not have a confirmed diagnosis by PCR, a serology is advised to establish the status regarding COVID. Quarantine is only advised if the serology does not show a previous infection.

Some data from BMJ about the lab tests for COVID: PCR has a sensibility between 70% and 98% in a study, but only 63% if we just look at the figure for nasopharyngeal swab. A table to compute the post-PCR test probability for a positive or negative result based on the clinical pre-test probability is given. Pre-test probability algorithm are seldom used in France (except for pulmonary embolism).

Pre-test probability	PCR negative Post-test probability	PCR positive Post-test probability
5%	1.6%	42%
15%	5%	71%
25%	10%	82%
50%	24%	93%
75%	49%	98%
90%	74%	99%

In the French study CORONADO including 1300 diabetic patients with COVID, the authors find out that only BMI was a risk factor for intubation or death within 7 days: but not the age, not the level of glycaemic control, not the ACEi/ARB drugs...

2/ Oncology

During lockdown, there has been a huge drop for cancer screening tests (bowel, breast and cervix). It will be important to see the consequences of this drop in the future, especially for mammograms...

3/ Infectious diseases

A multicentric retrospective study looked at the risk of infection from using NSAIDs for anterior sinusitis in children. The authors found out that taking NSAIDs was associated with an increase in intracranial and orbital complications for 30 patients who took NSAIDs versus 90 patients who did not (80% vs 44% of adverse effects). It is only retrospective but this is another argument against NSAIDs in infections.

4/ Rheumatology

A lot of things have already been tested in knee osteoarthritis. This article from Annals of Family medicine studied the efficacy of intra-articular injections of hypertonic dextrose, as part of prolotherapy (an alternative therapy method which aims to make musculo-skeletal structures proliferate). The authors randomized 76 patients to receive dextrose injections or saline solution. After 1 year, patients who had dextrose injections had a lower WOMAC pain score (-10 points on a scale of 50) as well as a lower WOMAC function score (same magnitude of difference). There were also better scores for quality of life (studied by EQ5D) and no adverse event was recorded. Overall, we need to wait for more studies before rushing on this miracle treatment.

5/ The qualitative study by @Petronille

This week's article is a French paper that studies the impact of the first pelvic exam for French women between 18 and 30 years old, recruited from the surgery of a general practitioner. For these women, this exam is viewed as a rite of passage towards the adult age (to be noted: a good mother-daughter relationship could have a positive impact on this experience). The pelvic exam should follow a discussion between the doctor and the patient, should be quick, gentle and painless and be followed by a phase of reinsurance - the moments for discussion being experienced as very important. For the included women, the patient-centered approach was more important than the exam by itself: compliance with the will of the patient, quality of the relationship, inclusion of each patient's individuality. The authors offer a guide to improve the management of this first exam, possibly limited by the premises, but that makes think about this exam (and the others) offered at the surgery. This guide includes the relationship aspect, put forward on the agenda by the patients' study, contrary to the very technical guidelines by the CNGOF (NFrench National College of Gynaecologists and Obstetricians, link here in French).

That's all for this week. Do not forget to subscribe on Facebook, Twitter or to the newsletter by e-mail if it is not already done. You have to put your e-mail address at the top right of the page and confirm the subscription thanks to an e-mail labelled "FeedBurner Email subscriptions", that will be sent to you and may end up in your junk folder. 

I wish you very good week, full of rest, full of courage, full of sprinkles and joy in your life! Thanks for reading me each week!

@Dr_Agibus - free translation by @carttom

Dragi Weekly No. 268 : COVID (thrombotic disease guidelines, ARB and ACE inhibitors), COPD (GOLD 2020), neuropathic pain, pain tolerability, pernicious anemia, Dreamscape

Hello! Holidays are a good time to rest and break the rhythm in these complicated times. I still hope you're doing well. Lots of things this week, enjoy the reading!

1/ COVID-19

The American College of Cardiology has issued guidelines regarding the thrombotic risk in COVID. For ambulatory patients, measures to prevent a sedentary should be carried out, but prophylactic anticoagulation should not be systematic. It can nevertheless be discussed in patients with risk factors for thrombosis and low risk of bleeding. For hospitalized patients (not in intensive care), prophylactic anticoagulation is recommended (not at intermediate or effective doses). Also no screening for DVT is recommended if D-dimer > 1500 and patient is asymptomatic.

Following the poor study in the NEJM, the Lancet publishes a randomized controlled trial evaluating remdesivir versus placebo in COVID: no clinical improvement at D28 in the whole cohort but may be a faster improvement in patients with symptoms less than 10 days old (and this is not significant...) But it would "work" in an unpublished study according to a communication from Gilead...

A retrospective study published in the NEJM investigated the risk of COVID associated with antihypertensive drugs. When matched on a propensity score, none of the antihypertensive classes, including ACE inhibitors and ARBs, were associated with a significant increase in the risk of COVID or severe COVID.

2/ Pain

Is a Numeric Rating Scale (NRS) a good tool for assessing pain tolerability in chronic pain? In this study, when the NRS was below 4, the pain was tolerable (ok, there it is) but when it was between 4 and 6, 19% of the patients "already" considered it not tolerable. It is from 8 and above that more than 50% of the patients consider it not tolerable, but even then between 30% and 50% of the patients consider it tolerable. So let's just ask patients how they feel rather than deciding what action to take based on a numerical value.

The BMJ  discusses treatments for chronic pain with a focus on pregabalin and gabapentin. They work well on neuropathic pain and are recommended for first-line use. The NNT of pregabalin>600mg/d is about 10 for a 50% reduction in pain with a similar NNH of discontinuation for similar side effects. For gabapentin >1200mg/d, the NNT is rather 6, and the NNH 30. So advantage to gabapentin. To limit premature discontinuation, the authors recommend starting at a low dose and stopping the increase at the onset of symptoms or even lowering the dose. Looking at tricyclics antidepressants have a NNT of 3.6 and serotonin-noradrenaline reuptake inhibitors of 6.4. So gabapentinoids would work less well in the end. Finally, these antiepileptics have proven efficacy in neuropathic pain but not in low back pain, sciatica and migraines

The Cochrane collab has published a review on the efficacy of epidural corticosteroid infiltration in radicular pain. The authors found an immediate benefit of -5 points (/100), and in the medium term (3 months) of -4 points. In short, it is statistically significant but not necessarily clinically relevant.

3/ Cardiovascular disease

A randomized controlled trial of NEJM including more than 1000 patients found non-inferiority of apixaban versus dalteparin in the management of cancer-associated venous thrombosis without increasing the risk of bleeding.

As a reminder, the recommended dual antiaggregation therapy for STE-ACS is aspirin+tigagrelor or prasugrel. In case of stable coronary artery disease with stent: aspirin+clopidogrel. This study compared aspirin + ticagrelor vs aspirin + clopidogrel in NSTE-ACS in patients over 70 years old: no difference on the net clinical benefit, but less bleeding with clopidogrel which seems to be preferable (In France we stayed a lot on clopidogrel, I believe).

4/ Respiratory diseases

The GOLD has updated the COPD guidelines for 2020. I will put below the 2 important figures: the one to determine the initial treatment, and the one to adapt according to the intensity of dyspnea or exacerbations. There is always a tendency to decrease inhaled corticosteroids (especially if repeated pneumonia, eosinophils < 100 or mycobacterial CDTI). The importance of smoking cessation, physical activity, and influenza and pneumococcal vaccination should be noted. It is also necessary to think about looking for co-morbidities (coronary artery disease, depression, GERD, osteoporosis...). In case of exacerbation, the authors recommend :

- B2 short-acting +/- short-acting anticholinergics,

- oral steroids: 40 milligrams for five days, "but should be limited to significant exacerbations."

- antibiotics (amox+ac.clavu or macrolides or tetracycline for 5 to 7 days if sputum is purulent (sensitivity 94%, but specificity 52% for a bacterial cause) associated with increased dyspnea or increased volume of sputum.

5/ Gastro-enterology

Le BMJ talks about  pernicious anemia (1/3 of patients have normocytic anemia with normal B12). It can be suspected in the presence of anaemia, but also in the presence of unexplained symptoms: fatigue, cognitive impairment or concentration disorders, paresthesias (but also alopecia, dyspnoea, palpitations, gastrointestinal disorders, depressive symptomes). Signs of severity are: paresthesia and hyporeflexia, ataxia and loss of muscle strength, dyspnea and peripheral edema, cognitive disorders and depression. The assessment therefore requires a serum B12 test and then serum intrinsic factor antibodies  (In fact, even if B12 is normal, it does not eliminate the diagnosis: holotranscobalamin, methylmalonic acid and homocysteine should be checked before looking for anti IF Ac). Treatment 1000µg of B12, 3 times a week for 2 weeks then once a month.

6/ The game of the month: "Dreamscape"

"Dreamscape" is a visually attractive strategy game that will take you to the world of dreams! Indeed, each player we will call "sleepers", draw cards of various difficulty representing a "dream landscape". You will then have to collect the elements that make it up (water, rock, earth tokens...) to recreate them on your personal board and score points! Also be careful not to take too many nightmare tokens which will disturb your sleep (and reduce your chances of victory...) The mechanics are original, interesting and accessible. In short, a game that I recommend!

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See you soon!

@Dr_Agibus

Dragi Weekly No. 264 : masks, NOACs, PCOS, thermometers, vericiguat, diabetes treatments, Bad bones

Hello! I hope you're well. This week's ticket will have a lot of cardiology because this week's American cardiology congress was an e-congress. Enjoy your reading!

1/ Infectiology

First of all, a publication found that in the case of coronaviruses (but not influenza or rhinoviruses), surgical masks are effective in filtering particles larger than 5µm but also those smaller than 5µm, and would therefore be useful to avoid airborne (aerosol) transmission.

The French Academy of Medicine has issued a statement recommending the wearing of masks for exits during containment and the widespread use of masks to prepare for exit from containment. In situations of mask supply shortage, clothes masks are recommendedfor the public . For this, I refer you to the site stop-postillons.fr. 

The BJGP compared methods of temperature measurement in children under 5 years, focusing on non-contact infrared thermometers, axillary (and tympanic) thermometers. The authors found a difference of 0.14°C between non-contact and axillary thermometers, which is quite good, but there were variations ranging from -1.57°C to +1.29°C, which is still a lot. The results for tympanic thermometers were similar. In short, the temperature measurements are always so variable depending on the instrument...

2/ Cardiovascular disease

Concerning the debate on ACE inhibitors and ARBs in patients suspected of having COVID, an editorial from the BMJ proposed an algorithm, which goes against the recommendations of the cardiology societies, since the benefit of preventive discontinuation in asymptomatic patients is not certain:

The COMPASS study in 2017 was reported in which the benefit of adding rivaroxaban to aspirin versus aspirin alone in post-infarction was moderate. This year, data from the study were analyzed by comparing diabetic patients to non-diabetic patients. I must admit that I do not really understand the interest of the paper, which repeats the same thing as the original publication, with results that are no longer significant on overall mortality in either diabetic or non-diabetic patients (whereas they were when all patients were analyzed). The authors calculated a "net" clinical benefit (cardiovascular mortality, infarction, stroke and major bleeding), and here this benefit is not significant.

Another article compared different non-vitamin K antagonist oral anticoagulants (NOACs) in a matched cohort study. The authors found no difference in efficacy between rivaroxaban, apixaban and dabigatran. However, rivaroxaban was responsible for more bleeding than dabiagatran (NNH=189) and apixaban (NNH=295). Compared to dabigatran, apixaban was responsible for more gastrointestinal bleeding (NNH=95). With all this and since the time it has been said, the risks of rivaroxaban are clearly superior to other NOACs for identical benefits . (see here and there, again here and there. At some point, it is necessary to stop the lobbying...). 

A new treatment for heart failure has been developed. It is vericiguat, a oral soluble guanylate cyclase stimulator tested versus placebo in symptomatic patients with LVEF < 45% mostly treated with beta-blockers, ACE inhibitors and aldosterone antagonist. Treatment with vericiguat significantly improved the cardiovascular composite endpoint (NNT=24 patients per year) but without benefit on cardiovascular mortality or overall mortality. This is always worrying in a study that found more side effects in the placebo group compared to the treatment group. In short, a benefit that is not very important and a strategic position is hard to find given the benefit of neprilysine inhibitors compared to this treatment. 

Finally, the ISCHEMIA study that I mentioned here has finally been officially published in the NEJM.

3/ Gynecology

One article talks about polycystic ovary syndrome (PCOS) in adolescents. The diagnostic criteria are refined:
- irregular menstrual cycles: cycles > 90 days (if menarche > 1 year), cycles less than 21 days or more than 45 days (if menarche between 1 and 3 years), cycles less than 21 days or more than 35 days (if menarche > 3 years) or primary amenorrhea (if age > 15 years or > 3 years post-tearche). Cycle irregularities are normal in the 1st year.
- hyperandrogenism: hirsutism (hair on areas usually hairless in women), severe acne or biological hyperandrogenism (free testosterone, SDHEA, LH, FSH, 17-OH progesterone to be performed 3 months after stopping all hormonal contraception). No dosage of AMH.
- Pelvic ultrasound: not to be done in young women before the 8th year after menarche because the ovaries are normally multifollicular at that time (avoid over-diagnosis).
Treatment includes menstrual hygiene and oestro-progestative contraception. The benefit of metformin is to be discussed on a case-by-case basis (but it doesn't work a lot, I had mentioned it here), and spironolactone can be used to counter hirsutism. (My other post on the PCOS and British guidelines: here)

4/ Diabetology

A study in diabetes care studied second-line treatments in type 2 diabetes from a cohort study. The metformin + sulfonamide combination was at higher risk of cardiovascular events, mortality and hypoglycemia than the other combinations. The most effective treatments with a lower risk of hypoglycemia were metformin + GLP-1 analogue or + SGLT2 inhibitor. It is also clear that metformin+DPP4 inhibitor or + basal insulin is less effective than metformin+GLP-1a or +SGLT2i combinations.

5/ The game of the week "Bad Bones"

For this month, I'm talking about "Bad Bones"!  In this game, you play as a brave hero who must defend the village (below) against skeletal attacks. The skeletons move at each turn towards the famous village and you will have to counter them with the help of your hero, or by using defenses such as walls (to make them bounce and direct them away from the village), or catapults (to send them on the other players). The game is simple, fairly fast, and provides a good dose of stress with the number of skeletons growing over the turns! 

 That's the end for this week, good luck to all of you and see you next week!

 @Dr_Agibus