Always lots in a Prescriber to report. I do believe the time may have come to use some subheadings:
NSAIDs vs. Cox-2s
This was a report on the CONDOR trial, which I was pleased to see was aimed at answering the perennial question: Are COX-2 inhibitors actually any safer for the GI tract than old-style NSAIDs with PPI cover? According to this report, it seems they are, but don’t be too quick to rush for the celecoxib – it seems that a) this study contradicts previous evidence and b) the comparator was slow-release Diclofenac, which may put the gastric lining at higher risk than short-acting as it’s in contact with the gastric lining for longer. Whether there’s any hard evidence for this I don’t know, but it’s a useful point to be aware of on two grounds – firstly, of course, because it casts doubt on the validity of this study, and secondly because it’s a handy excuse for getting patients off expensive slow-release formulations of dubious extra benefit and onto the quicker short-acting ones. (I do try to be honest with patients where cost is a major factor in changing a drug, but it’s nice to have something in the way of patient benefit to throw in to sweeten the pill, if you will pardon the unintentional pun.)
Two other interesting points from this report. Firstly, the Diclofenac also increased the rate of lower GI events compared to the Celecoxib, and a PPI won’t help you there. Secondly, I’ve also wondered whether adding a PPI to a Cox-2 does anything further to reduce the risk in particularly susceptible patients, and it appears that a previous Cochrane review has concluded it does. So, in patients with a past history of PUD and intractable pain not responding to other measures, it does sound as though Celecoxib + Omeprazole might be a combination that could be considered.
Useful points from this one:
The reason why the lab always tells us to recheck borderline hypothyroid results in three months is, it appears, because ‘progression of thyroid destruction’ (how dramatic they make it sound) can take place over months or years, so it may be necessary to monitor TFTs every three to six months for a prolonged period of time until the rate of change is established or until it appears to have stabilised. When it’s stabilised, of course, we normally check yearly – but it seems it may be possible to leave the intervals up to three years. Not sure I’d do that in practice, but interesting to know about.
If getting a TSH level into the normal range doesn’t get your patient feeling quite right, try titrating further to bring it into the lower half of the reference range to see if that helps.
Not currently an issue for me as it would never have occurred to me to use combined liothyronine (T3) and thyroxine, but, in case anyone ever waves a printed-off Internet article under my nose assuring me that this is exactly the way to go about treating their thyroid problem, I can now feel assured that it isn’t. A meta-analysis has now, apparently, found no clear benefit from combined treatment. (Prescriber recommends that if the patient wishes to discuss combined treatment further then referral to an endocrinologist should be considered. Huh – yes, having considered that one, I can tell you that I haven’t the least intention of arranging an NHS referral just so that someone can get a second opinion that there’s no point doing something that has been shown to be ineffective.) By the way, in case you were wondering why we use T4 & not T3 for replacement, it’s because T4 has a longer half-life so the hormone levels are steadier.
Erratic levels, or a need for doses above 200 mcg/day to get the levels up to where they should be, may not mean non-compliance (although that is of course the most usual reason). Malabsorption may be the problem. Rule out coeliac disease and conditions that reduce acid secretion, autoimmune gastritis and H. pylori infection being the two examples given there. As for the compliance problem, it’s worth telling patients that it’s OK to take missed tablets at any time later on in the week, due to the long half-life.
Some useful pointers for managing hypothyroidism in pregnancy, pending referral to endocrinology: Check TSH before conception if you get the chance, and check TSH and T4 as soon as pregnancy is confirmed and at the beginning of the second and third trimesters, plus four to six weeks after the dose increase I’m about to mention. You’ll probably need to increase the levothyroxine dose by around 50%, so aim to increase it by 25 to 50 mcg/day as soon as the pregnancy is confirmed. (The article suggests that a simple way to do this is to advise taking two extra daily doses of levothyroxine per week. Personally, I think it’s a darned sight simpler to be on the same dose each day.) Remember that check 4 – 6 weeks later. You’re looking to keep the T4 levels in the upper part of the reference range. After delivery, the woman can go back to her previous dose – breastfeeding does not require a dose change.
Antithyroid drugs achieve cure in 40 – 50% of patients with Graves’ disease. The advantage of carbimazole over propylthiouracil is that it requires a more reasonable number of tablets per day (a decent propylthiouracil dose may require 9 – 12 tablets per day) and less frequent dosage. Prophylthiouracil, however, may be slightly better in pregnancy/breastfeeding as it is more protein-bound and thus less likely to cross the placenta or enter milk (it’s not proved that carbimazole does any harm in pregnancy, but there have been possible links with choanal atresia and fetal aplasia cutis and so some endocrinologists are happy to use it in pregnancy and some aren’t). However, on the whole, propylthiouracil is only used for people who have minor side-effects with the carbimazole.
Destructive thyroiditis can cause transient thyrotoxicosis due to the release of stored thyroid hormone. Antithyroid drugs won’t help (as they inhibit the manufacturing process rather than the hormone in the bloodstream), and the thyroiditis normally settles spontaneously within four weeks. For severe subacute thyroiditis, prednisolone 40 mg daily tapered off over 2 – 4 weeks may be helpful.
Getting back to the pregnancy/breastfeeding issues – in pregnancy in women with Graves’ disease, there is about a 1% risk of fetal thyrotoxicosis due to maternal antibodies crossing the placenta. This apparently is likely to resolve by about 1 – 3 months after birth, but the baby will usually require an antithyroid drug during this time. And breastfeeding is safe with antithyroid drugs, but use the lowest dose possible and check baby’s TFTs if mother is on 20 mg or more of Carbimazole daily.
Steroids in COPD
A report on a JAMA study. Have you ever wondered whether high-dose IV steroids would benefit your patient with a COPD exacerbation more than the steroid tablets you can give? Rest assured on that score – it seems they do not. Oral prednisolone (between 20 & 80 mg daily) was as effective as high doses of IV steroids in this study.
What you do about this depends on whether the problem is with breathlessness or frequent exacerbations. There appear to be some subtle differences between the batting order of LABA, LAMA, & ICS introduction, but frankly it didn’t look to me to make a huge amount of difference as both groups are supposed to end up on all three of them eventually anyway (there wasn’t any discussion of the ICS-in-COPD controversy, which I thought was a shame). The main differences are that in frequent exacerbations you can try carbocisteine or rescue antibiotics, and possibly prolonged antibiotics, whereas in general SOB you’d be looking more at pulmonary rehab and oral theophylline, plus possibly a raft of symptomatic measures.
However, before you get into any of that, consider: 1. Is it really COPD? (Apparently, around 50% of primary care patients diagnosed as having COPD on clinical grounds turn out not to have it when they actually have spirometry.) 2. Is it only COPD? Lots of COPD patients have co-morbidities that may be the actual cause of the breathlessness. 3. Are they actually using the therapy they’re meant to be on properly (correct technique and proper compliance)?
Some thoughts on other COPD therapies:
Theophylline: Doesn’t help all that much in stable COPD, but probably worth trying after you’ve gone as far as you can on the various combinations of inhalers and pulmonary rehabilitation. Start low, titrate up, and assess whether or not it’s doing anything.
Nebulisers: Apparently an overwhelming proportion of the COPD patients who try them feel they improve their breathlessness and well-being, although this is sometimes only the case in exacerbations. I don’t usually consider them, but maybe I should.
Mucolytics: may be less helpful than previously thought, as the meta-analysis showing them to reduce exacerbation and hospitalisation rates was based mainly on studies that didn’t use ICS – apparently, once ICS use was controlled for, any benefit was minimal. However, possibly of some use in patients with frequent exacerbations.
Roflumilast: a phosphodiesterase 4 inhibitor that can be used as maintenance therapy in patients with an FEV1 <50% of predicted. It may reduce exacerbation frequency and improve quality of life in some ways, but it can cause GI upset and significant weight loss and it’s debatable how much it adds to inhaler use.
Long-term prophylactic antibiotics – can reduce exacerbation rates, but risky in terms of drug resistance and possible SEs – did you know long-term macrolides can cause liver dysfunction? No, me neither. Scary.
Rescue packs: they recommend five days of antibiotics and seven days prednisolone, which is apparently what NICE guideline recommends. How this fits in with the advice to give steroids for fourteen days followed by a reducing course, I don’t know.
Regular low-dose prednisolone: possibly of help in end-of-life patients, but probably not otherwise.
Oxygen: SBOT, again, is really mainly for end-of-life patients. Others are better off either getting assessed for LTOT or having nothing.
Pulmonary rehabilitation: actually does work, though trusts will vary in their criteria for referral.
Cool air to the face: can help breathless, anxious patients feel better.
Short-acting anxiolytics: ditto.
Opiates: useful for symptomatic management of COPD in end-of-life care .
Nausea and vomiting in pregnancy
This is a summary of a Cochrane meta-analysis. I was pleased to see it, but unfortunately it was minimal help, as the bottom line is that we really don’t know a lot about the topic. About the only thing we seem to be clear on is that acupuncture isn’t helpful. Acupressure (P6 or ear), ginger, B6, and anti-emetic drugs all seem to fall under the ‘no clear overall evidence’ banner, for potential risks as well as for potential effectiveness. Oh, well – I guess I’ll keep doing what I’ve always been doing.
Bacterial infections in pregnancy/postnatally
Studies on rats suggest that some unpronounceable side chain contained by ‘many group 3 and group 4 cephalosporins’ (a list of the names would have killed the authors, apparently) may cause testicular damage to exposed fetuses, although no teratogenic effects have been reported in humans and it’s still recommended as the second-line antibiotic in UTIs in pregnancy.
Metronidazole appears OK in both pregnancy and breastfeeding, but it may make the milk taste off-puttingly unpleasant to the baby.
Ciprofloxacin may be safer than we think in pregnancy. Although it’s generally avoided due to concerns about cartilage damage, this is based on animal studies and a study of over 500 women exposed in the first trimester found no evidence of teratogenicity.
Clindamycin appears OK.
Pyuria post-partum may reflect inflammation secondary to trauma during labour, rather than being a UTI.
Nitrofurantoin could cause haemolysis in a fetus with glucose-6-phosphate dehydrogenase deficiency.
If a pregnant woman with a UTI has systemic symptoms, she should be admitted for IV antibiotics. Ditto for women with endometritis post-partum. Admission should also be arranged for a woman with a C-section wound that breaks down, for debridement and secondary closure.
Bacterial vaginosis isn’t the harmless irritant it’s often dismissed as – in pregnancy, it’s associated with late miscarriage, premature delivery or PROM, low birth weight, chorioamnionitis, and postpartum endometritis. Despite this, it’s debatable whether there’s any role for screening or treating asymptomatic women, though if a woman is symptomatic or if she’s previously had a late miscarriage or premature birth then she probably should be treated. If you do treat, oral clindamycin is an option.
Persistent pyrexia despite antibiotic therapy may be due to an unpleasant-sounding problem by the name of septic pelvic thrombophlebitis, which is probably due to damage to the ovarian venous endothelium. Refer for investigations (ultrasound, CT).