Sense about Sepsis

Posted on 1 May 2015 by Keith Barrington

Recent guidelines regarding the evaluation and treatment of early onset sepsis, or the baby who has risk factors, have been widely criticized.

Especially by me! And by me!

The AAP for example recommends antibiotic treatment for all infants born after a maternal history of chorioamnionitis. The statement I wrote for the CPS a few years ago in contrast, did not. We recommended a CBC and close observation alone in infants who had a history of chorioamnionitis, but appeared well. This was based on an incidence among well-appearing infants after an obstetric diagnosis of chorioamnionitis of well below 2%. Of course it is not zero, as babies who look OK at birth might be in the early stages of infection and become sick later. Also there are big problems in the diagnosis of chorio, even in the papers that we cited to make our recommendation.

When we made our recommendations (2007), the difference of opinion with the AAP and the CDC was understandable, there were many unknowns based on the limitations of the data; the AAP/CDC approach was based on a fear of missing real cases, ours was based on a fear of massive over-treatment of relatively low-risk patients (although, of course both ‘sides’ were fearful of the other issue as well).

Now there is a lot more information, and a new publication from 2 of the authors of the most recent version of the AAP recommendation, along with James Wynn, makes some recommendations based on those new data. I think at last (and this is not surprising, given that the first author is the always excellent Bill Benitz) that these recommendations are sensible, reasonable, and likely to do the least harm to the largest number of babies.

They say the following (I have skipped a couple which were of less day to day value to working paediatricians) (EOS is early onset sepsis):

 2. Infants who exhibit persistent, progressive, or moderately severe to severe clinical signs consistent with EOS should receive empiric antibiotic therapy after cultures are obtained. Infants with mild-to-moderate respiratory findings (flaring, grunting, retractions, or tachypnea) immediately after birth may be monitored closely for resolution of transitional behaviors, without initiation of antibiotic treatment unless signs worsen or persist for more than 6 hours.

4. Preterm infants (<34 weeks’ gestation or <1500 g) are at significantly increased risk for EOS…, it is reasonable to continue to stratify risk based on those traditional risk factors. Because most preterm infants have clinical signs of illness, most will qualify for empiric treatment. Preterm infants who appear well and have minimal or no risk factors (eg, no chorioamnionitis, preterm premature rupture of membranes, or GBS colonization with inadequate intrapartum prophylaxis) may be candidates for close monitoring and serial laboratory evaluation.

5. Well-appearing late-preterm and term infants should be managed with close clinical observation, because of the low sensitivity of risk factors in ascertainment of EOS in this group. Efforts to improve ascertainment of EOS cases in this population are commendable, but should not obscure the limited utility of the strategies attempted to date.

6. Even with selective treatment strategies, most treated infants will not have bacterial infection. In treated infants, serial normal diagnostic tests, such as blood counts or C-reactive protein levels, are highly predictive of the absence of infection and should be relied upon (in addition to culture results) to minimize the duration antibiotic exposure. However, isolated abnormal hematological or acute-phase-reactant measurements should not justify continuation of empiric antibiotics for more than 48 hours in well-appearing infants with negative culture results.

I agree totally!

Which is unusual!

I should cut down on the exclamation marks!

The analysis of clinical signs, and that modest respiratory signs can be followed, is a welcome improvement, as are the recognition of the importance of persistently negative lab findings, and the lack of importance of positive lab findings.

UPDATE** after further reading, I have to change this to I agree ‘almost totally’. #4 implies, if I read it right, that preterm babies with serious respiratory illness should all get antibiotics, even if there are no risk factors. But for preterm babies born after c-section for maternal indications with intact membranes and no labour, the risk of sepsis is very close to zero, even if they have serious respiratory findings. This is a substantial minority of our preterm babies and they can safely be managed without blood culture or antibiotics.

I think we should now be able to go forward to an international consensus, based on good data, which will avoid over-treatment of low-risk patients but also ensure that almost all truly septic babies receive timely care.

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What’s new with Caffeine?

Posted on 27 April 2015 by Keith Barrington

Lodha A, et al. Association of Early Caffeine Administration and Neonatal Outcomes in Very Preterm Neonates. JAMA Pediatr. 2014. First, a study of which I was a co-author; we examined from the CNN whether infants that received caffeine starting in the first 2 days of life had different outcomes from those whose caffeine started later. The outcomes of interest were survival and bronchopulmonary dysplasia, as well as PDA and retinopathy, all things which have been reported as potentially being affected by caffeine; and the babies of interest were less than 31 weeks gestation. Of course the secondary analyses of the CAP trial showed that infants who received caffeine at 3 days of life or earlier had better short term respiratory outcomes, but that adjusted analysis showed no effect on BPD. In this new study the unadjusted analysis showed no effect on either mortality or BPD, the adjusted analysis (adjusted for gestational age, SGA, being intubated on day 2, where you were born, surfactant and SNAP score) did show an association with less BPD, but no effect on mortality. PDA was less frequent in both adjusted and unadjusted analyses. There were 5000 babies in the analysis, and nearly 4000 of them got caffeine in the first 2 days of life, which I think is evidence of a change in practice after the CAP trial, as 40% of the babies were still intubated on day 2 by which time they were getting caffeine. I was a bit surprised that only 40% of the babies in the ‘later’ caffeine group were on assisted ventilation on day 2, as that means that hundreds of babies less than 31 weeks gestation who were breathing spontaneously were not getting caffeine by day 2. I thought it had become routine to administer caffeine to babies in this gestational age group who were not intubated, or just before extubation in the first day or 2 of life. There was also less NEC stage 2 or more, less severe RoP, and less ‘severe neurological injury’ among infants with early compared to late caffeine, none of which were very convincing after adjusting the analyses, but all of which suggest there isn’t a safety issue. These data are clearly only observational, but tend to confirm the implications of the CAP trial, and that caffeine use is safe, even with very early use.

Alur P, et al. Serum caffeine concentrations and short-term outcomes in premature infants of 29 weeks of gestation. J Perinatol. 2014. These data were from a center that does weekly caffeine serum concentrations while infants are receiving the drug. Which is certainly not something I have ever done, and I think is not necessary, however it does give an opportunity to perform a retrospective study like this, which showed that the infants who had higher average caffeine concentrations had less BPD, they also got home earlier from the hospital and had no clear adverse effects. On the multivariate logistic regression analysis, higher caffeine concentration was associated with less BPD, but increased gestational age was not, which makes me wonder if there was some confounding, and if the lower levels were found in the least mature babies, but I don’t know why that would be. It might partly explain the statistical findings though.

Marcus CL, et al. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med. 2014;190(7):791-9. This very long term follow up of some babies from the CAP trial showed that children from both groups had more sleep apnea than expected for their age, but there were no differences between groups. Which is both reassuring (with regard to the effects of caffeine) and a little surprising (why do they have more obstructive apnea than the general population?)

Katheria AC, et al. A Pilot Randomized Controlled Trial of Early versus Routine Caffeine in Extremely Premature Infants. American journal of perinatology. 2015(EFirst). I would have called this a pilot trial comparing giving caffeine very very early versus very early! 21 infants who were not intubated in the DR were randomized within the first 2 hours of age to get caffeine immediately or wait until 12 hours. Of course the study is too small to say a lot, except that the cardiovascular and respiratory differences are all in the direction of better function in the very very early group. With regard specifically to the cardiovascular differences, echocardiograms performed during the interval where the treatments were different between groups showed higher SVC flow and Right Ventricular Output in the caffeine group, with difference in LVO. Blood pressure was also different until the ‘control’ group got caffeine, after which there was difference. Bill Meadow (Soloveychik V, et al. Acute hemodynamic effects of caffeine administration in premature infants. J Perinatol. 2009;29(3):205-8.) previously showed an effect of caffeine (not necessarily very early, or very very early) on both blood pressure and LVO in 31 preterm infants. In his study, only infants with a closed PDA were included, which probably accounts for the difference in echocardiographic effects.

These cardiovascular effects of caffeine deserve further study, and the use of very very early caffeine might well turn out to be valuable, especially as these infants will almost all be receiving caffeine at some point in their lives, giving it immediately after stabilization could possibly reduce cardiovascular dysfunction, as well as improving respiratory outcomes.

McPherson C, et al. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015. This study, in contrast, shows adverse effects (potentially) of caffeine therapy. 74 preterm infants, less than 31 weeks gestation were randomized to get caffeine citrate before 24 hours of age in either standard dose, (20 mg/kg) or a high loading dose (of 80 mg/kg). After the loading period, which took a total of 48 hours, patients in both groups received the same dose (10 mg/kg/day). The patients in the high dose group did worse. They had more cerebellar hemorrhages, there were more tone problems at term equivalent age, and more abnormal neurologic signs at that age. At 2 years there was no difference between the groups.

This study certainly should inhibit other studies of very high loading doses of caffeine. Keeping to 20 mg/kg looks like the right place to be at present. Starting very early could well be a good idea, but needs more study, to ensure efficacy and safety.

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Neonatal Updates

Posted on 26 April 2015 by Keith Barrington

There’s been a lot of good stuff published recently, so time for a couple of Neonatal Updates. First the most recent (May) issue of the Archives Fetal and Neonatal edition was packed with interesting publications.(including 2 I have already blogged about).

Salas AA, et al. A randomised trial of re-feeding gastric residuals in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(3):F224-F8. In this study 72 infants, between 23 and 29 weeks gestation, who were getting minimal enteral nutrition/trophic feeds during the first week of life were randomized to either have their residuals re-fed, or thrown away, whenever the residual was over 1/3 of the feed volume or over 2 mL. There were no substantial differences in outcomes between the groups, but a lot of babes in each group (around 40%) had an episode of interruption of their feeds for at least 12 hours.

Big question.. why evaluate gastric residuals at all? We stopped routinely aspirating prior to feeds a few years ago, and the only apparent effect has been a reduction in the number of babies who have an episode of feeding interruption. This study shows that if you do still measure them, at least you can give them back.

Coste F, et al. Ventilatory control and supplemental oxygen in premature infants with apparent chronic lung disease. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(3):F233-F7. This takes me back… when I was a fellow I started a study looking at the respiratory control effects of hypoxic, hyperoxic, and 2% CO2 challenges on infants with BPD. Enrollment was very slow and I finished fellowship with only 3 or 4 patients, leading to some data in a drawer, but no publication. One of the reasons for doing it was that some people had suggested that babies with BPD were like adults with COPD, reliant on hypoxic drive, and liable to become hypercarbic if you gave them too much oxygen. In fact, it was clear from reading the literature that that was not true for adults with COPD at all (even though it was still being taught to medical students, maybe it still is), in fact hypoxic drive is suppressed in adults with chronic hypoxia, and the minor increase in CO2 that occurs when you increase, or start, supplemental oxygen is due to effects on VQ matching (I think it was Michel Aubier who proved that). So I thought it was likely that hypoxic drive was impaired in babies with BPD, and that it was important to give them enough oxygen to maintain a good PO2 (this was started in the days before pulse oximeters). The little data I had, showed no increase in transcutaneous CO2 when I increased the oxygen administered, and an intact CO2 response.

This new paper enrolled babies undergoing the physiologic challenge at 36 weeks to see if they satisfied Michele Walsh’s physiologic definition of BPD. About 1/4 of the babies who were able to get down to 21% passed the test, the other 3/4 becoming too hypoxic to stay off oxygen. Infants developed unstable breathing when the oxygen was stopped with frequent appearance of periodic breathing. Interestingly this happened to the babies who passed the test, as well as to those who failed. So even if you pass the O2 discontinuation test, the fact that you were still receiving oxygen or resp support at 36 weeks was a sign that your respiratory control was still not optimal.

Kaandorp JJ, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(3):F216-F23. Over 200 women with signs of fetal hypoxia during labour were randomized to allopurinol or placebo prior to delivery. Despite all the prior evidence that inhibiting xanthine oxidase, thus reducing free radical production, is protective in animal studies. This multicenter RCT was not able to show benefit, either on the primary outcome, which was on a biomarker of brain injury, S100ß, or on any clinical outcomes. Of course, as we are so poor in predicting significant perinatal depression/encephalopathy from clinical indicators prior to birth, most of the babies were fine, with only a mild reduction in mean cord pH compared to the population (7.19). On posthoc analysis girls did have some reduction in the S100ß, but I can’t see if the interaction term was significant, so that tends to look at bit unreliable.

I don’t think this spells the end of allopurinol, the animal data, and the safety demonstrated by this trial suggests that it is worth pursuing. We just need ways to predict more accurately which babies might benefit.

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Paracetamol for the PDA?

Posted on 26 April 2015 by Keith Barrington

EL-Khuffash A, et al. Late medical therapy of patent ductus arteriosus using intravenous paracetamol. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(3):F253-F6. (CoI statement: The authors of this paper are friends, colleagues and collaborators of mine), the effects of intravenous paracetamol on closing the PDA in infants who were being considered for PDA ligation are reported.

The dose was 60 mg/kg/day in four divided doses. Echos were done after 3 days of treatment and the course continued for a further 3 days if the PDA remained open.

Some of the background includes the fact that the 2 hospitals in Dublin don’t give NSAID’s during the first week  of life, “due to the equivocal nature of the evidence regarding early PDA treatment” and don’t give them after 3 weeks “where ibuprofen is not known to be effective” which doesn’t give much time to use the ‘standard’ therapy. So of the 36 babies reported, 13 had never had ibuprofen as they were after 3 weeks, and 15 were said to have contra-indications (11 NEC, 3 IVH, and 1 thrombocytopenia, none of which I am sure are really contra-indications, but let’s let that pass for now) only 8 had received ibuprofen (presumably a single course).  The pre-paracetamol echo data show physically large PDAs, mean diameter of 3.3 mm, most babies had reverse diastolic flow in the abdominal aorta.

Nine of the babies had closure of their PDA after paracetamol, most of the others had a major constriction, and only 4 needed their PDA ligated in the end.

So if you have a very restricted use of ibuprofen, this is supportive data which shows that if you give IV paracetamol, many babies have closure of the PDA. Of course it doesn’t tell you what happens to them if you don’t give paracetamol, or if you give them ibuprofen. For that we, of course, need a prospective RCT.

As an aside, intravenous paracetamol is unfortunately unavailable in Canada, I’d really like to be able to give it… but as an analgesic!

 

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Timing of MRI after HIE

Posted on 17 April 2015 by Keith Barrington

Three recent articles have investigated whether we should wait until a week or so after birth to perform brain imaging in infants with encephalopathy, or whether earlier imaging might be just as predictive.

The three articles have consistent findings, which is remarkable in itself! All three note that infants at high risk, most of whom have undergone hypothermia treatment, when they have MRI at 2 to 4 days of age, the results are very similar to the findings if you wait until a week or so to do the study.

Agut T, et al. Early identification of brain injury in infants with hypoxic ischemic encephalopathy at high risk for severe impairments: accuracy of MRI performed in the first days of life. BMC Pediatrics. 2014;14(1):177.

Boudes E, et al. MRI obtained during versus after hypothermia in asphyxiated newborns. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(3):F238-F42.

Skranes JH, et al. Brain imaging in cooled encephalopatic neonates does not differ between four and 11 days after birth. Acta Paediatrica. 2015.

Now I think you could say the same about many of these type of studies as about the studies of brain imaging in very preterm babies. Which is, that if the reason that you want to do the study is to aid in medical decision making (which is explicitly stated in the first of the 3 articles) we need much better data of the positive predictive value of the findings for profoundly adverse outcomes.

The best data I think come from the analysis of the TOBY trial, Rutherford M, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. The Lancet Neurology. 2010;9(1):39-45. That study used a scoring system, created by the same group, and showed that the positive predictive value of moderate or severe lesions in the basal ganglia and thalami, severe white matter lesions, or an abnormal posterior limb of the internal capsule for death or severe disability at 18 months of age was 0·76 (95% CI 0·65–0·87).

Severe disability was defined as at least one of: mental development index (MDI) less than 70 (2 or more SD below the mean) on the Bayley infant scales (BSID II) at 2 years;  cerebral palsy with a GMFCS of 3–5 (unlikely to be ambulant) or bilateral cortical visual impairment with no useful vision.

There is some evidence that a 2 year Bayley is more predictive of limited longer term functioning after HIE than it is for former extreme preterm infants, for example this article from the follow up of the NRN trial, Pappas A, et al. Cognitive outcomes after neonatal encephalopathy. Pediatrics. 2015;135(3):e624-34. Of 30 babies with a Bayley 2 MDI less than 70, 27 of them had a full scale IQ less than 70 at 6 to 7 years of age. (Most of the infants with an MDI less than 70 were below 55, 24 of the 30; also 23 of the 31 babies with an IQ below 70 were below 55).

If we put all this together it seems that it might be possible to have a reasonably accurate prediction of severely abnormal outcome using MRI shortly after, or even during the final day of, therapeutic hypothermia.  I think before we rush to performing early MRI, and use them for decision making, we should have more, and more direct, evidence that a certain severity of abnormality on the early MRI, accurately predicts profound impairment, and that this is better than clinical examination, or other predictive indices.

 

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Bubble Up

Posted on 10 April 2015 by Keith Barrington

In recent years the introduction of Helping Babies Breathe in low-income countries has proven to be effective in reducing fresh stillbirth rates. Babies who would otherwise be considered to be fresh stillbirths are given a chance, helped to breathe and often survive without any complications. Vossius C, et al. Cost-Effectiveness of the “Helping Babies Breathe” Program in a Missionary Hospital in Rural Tanzania. PLoS ONE. 2014;9(7):e102080. This study for example showed a cost per life saved of just over 200 dollars, over the first year of the program. As the retraining is done without new equipment and during the hours of work, it costs next to nothing, so the costs per life saved should drop even further as the years go by.

Some babies do go on to need respiratory support, which is itself costly and in limited supply in middle resource countries.

A new paper from Nicaragua describes the results of introducing and promoting the use of bubble nasal CPAP in an NICU that was already providing assisted ventilation. (Rezzonico R, et al. Impact of the systematic introduction of low-cost bubble nasal CPAP in a NICU of a developing country: a prospective pre- and post-intervention study. BMC Pediatrics. 2015;15(1).) They showed that after the change in practice there were many more babies who only required CPAP, the proportion more than doubled to over 60%, and the mortality rate decreased despite an increase in admissions.

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Not Neonatology : Photos from the antipodes

Posted on 10 April 2015 by Keith Barrington

I have re-organized the photos on the photograph pages (click on the menu under the header banner), so each gallery now occupies a separate page. At the same time I have added and re-organized a page on Australian wildlife without wings, and a page on New Zealand birds, some of which have appeared before on other posts, and some are newly posted.

I hope you enjoy them.

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A Facebook Page

Posted on 9 April 2015 by Keith Barrington

Sainte Justine Neonatology now has a facebook page.

You can find it here : http://www.facebook.com/neonatologie

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Off-label NO: No… or Yes?

Posted on 8 April 2015 by Keith Barrington

Recent articles about off-label use of inhaled Nitric Oxide (iNO) in the preterm infant shows that such use is :

a. extremely variable from one center to another, (Truog WE, et al. Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation. J Perinatol. 2014.)

and b. increasing in some places.  Ellsworth MA, et al. Off-Label Use of Inhaled Nitric Oxide After Release of NIH Consensus Statement. Pediatrics. 2015;135(4):643-8.)

As you can tell from the title of the 2nd article, the authors wished to see what effect the release of the NIH consensus statement had. I was involved in the hearings that led to production of that statement, which concluded, as the authors of this article put it :

The resulting NIH statement and American Academy of Pediatrics clinical report indicated that available evidence did not support the routine use of iNO in preterm infants, though rare clinical situations and new management strategies did merit further study.

The first of these 2 references suggested that use might have been decreasing after the consensus statement, at least among the extremely low birth weight infants in the Neonatal Research Network generic database. The second article suggests the opposite, in the NICUs in the Pediatrix network. In those units iNO is used more often off-label than ‘on-label’, very nearly 50% of all the NO days are in babies less than 29 weeks gestation, and those babies average 7 days of treatment, compared to 5 days for the term babies.

If you recall, both the Cochrane Systematic Review (Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane database of systematic reviews (Online). 2010;12:CD000509), and the IPD meta-analysis that we published (Askie LM, et al. Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials. Pediatrics. 2011;128(4):729-39.) show no clear advantage of iNO in any subgroup of preterm babies. The possible benefit in babies with early evolving chronic lung injury, shown in the NOCLD trial, was not confirmed by the NewNO trial, presented at a Hot Topics, and not yet published, (As soon as it is published we will be updating the Cochrane Review).

So why is there still any use in the preterm? Are we all anti-evidence based medicine cooks?  I don’t think so, I think there are still unanswered questions in the preterm, and as a result situations where it is reasonable to consider the use of iNO.

The studies of early rescue use of iNO, which show no benefit (and a possible increase in intracranial hemorrhage) enrolled preterm infants with severe respiratory failure. But only a minority of those infants have severe pulmonary hypertension, in particular those who had oligohydramnios after PPROM. Some babies like that have a very limited response to surfactant, and after surfactant they have clear lungs on x-ray, and often have a big ductal saturation gradient, i.e. evidence of right to left shunting and supra-systemic PA pressures. When I have given iNO to such babies (and others have reported this also) they often have a dramatic response and go from being hypoxic to rapid weaning of their oxygen requirements.

When we did the IPD meta-analysis of iNO in the preterm we wanted to specifically address whether preterm infants with evidence of PPHN had a different response, and potentially a benefit from iNO. Unfortunately there were very few babies who had a record of either having, or not having, pulmonary hypertension. So although there were more survivals without BPD among preterm infants who had a diagnosis of PPHN it was not clear whether or not this might have been due to chance. Other case series, and one subgroup analysis of one of the RCTs, also suggest that there may be a benefit, but all we can say at present is that such babies often have a big improvement in oxygenation in the short term.

The other situation in which iNO is being used is during acute deteriorations in oxygenation in babies who are developing BPD. In those babies you can also get improvements in oxygenation, even among those who don’t have clear evidence of pulmonary hypertension, presumably because you improve VQ matching.

I think, therefore that there is room to perform more trials in those 2 groups of babies, to see whether the acute improvements in oxygenation lead to improved survival or reduced complications.

Randomizing very sick, hypoxic, preterm babies who have clear evidence of PPHN in the first few hours of life to iNO or placebo will be difficult, but not impossible. It could even be done with a rescue phase for babies who stay hypoxic after a period of placebo use. It is possible that the placebo babies would gradually improve without iNO, and that improving gradually, rather than suddenly, would lead to a smoother clinical course, and less intracranial hemorrhage.

The second group of babies would be easier to study, I think; babies who at a couple of weeks of age have signs of early lung injury, and very high oxygen requirements, this represents about half of the babies in the Ellsworth publication. In those babies, who often get iNO for very long periods if there is an initial response, I think there is a chance of benefit, but a real risk of very high costs without overall clinical benefit.

This is not the same group of babies as studied in NOCLD or the NewNO trial. The babies in those trials were typically on low oxygen and respiratory support, so it will require targeted trials to investigate the highest risk babies.

Now I know I’m on the right track when what I say agrees, largely, with what Neil Finer and Nick Evans write! (Finer NN, Evans N. Inhaled Nitric Oxide for the Preterm Infant: Evidence Versus Practice. Pediatrics. 2015;135(4):754-6).

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Bevacizumab or that other more expensive one?

Posted on 2 April 2015 by Keith Barrington

A very interesting and depressing group of articles in today’s BMJ. Retinopathy of prematurity is a small market compared to wet macular degeneration in the elderly, in whom VEGF inhibitors are proven to be extremely effective. Ranibizumab (I will call it RBZ) is far more expensive than BVZ for the effective dose, and the company responsible refuses to apply for a licence for BVZ for this indication, despite the 6 comparative trials which show equal efficacy, and a Cochrane review showing equal toxicity. The companies’ tactics are appalling:

The NHS spends £244m a year on ranibizumab, the second highest amount for any drug. However, research and development costs do not explain why ranibizumab is priced 10-20 times higher than bevacizumab, Philip Rosenfeld, professor of ophthalmology at the Bascom Palmer Eye Institute in Florida told The BMJ. He was involved in the early phase trials of ranibizumab and was one of those who pioneered the use of bevacizumab for wet AMD. He said bevacizumab is also more expensive to make than ranibizumab.

Ranibizumab is a monoclonal antibody fragment derived from the same parent monoclonal antibody as bevacizumab. Both drugs act by inhibiting vascular endothelial growth factor (VEGF), preventing blood vessel growth. Roche holds the intellectual property rights for both, although Novartis has the rights to market ranibizumab in Europe. Bevacizumab is licensed for use only in cancer conditions, and Roche has never applied for a marketing authorisation for ophthalmic conditions—despite repeated calls from politicians to do so. This means only the more expensive ranibizumab has such a licence, and prescriptions of bevacizumab— even in its repackaged form for ophthalmic use—are “off label,” …..

But eight years on, bevacizumab is scarcely used for AMD in the NHS, and the companies have not done the necessary trials. ……  Minutes from a NICE workshop show that Roche said decisions not to develop bevacizumab for ocular use have been “due to corporate considerations.”

The article goes on to say :

An accompanying article shows how the manufacturers didn’t want to do the trials themselves and when it was agreed that the public should fund both a comparative and a dosing trial, they did all they could to scupper them—even turning to the Royal National Institute of Blind People (RNIB) for help. Then once these trials were published, they embarked on a campaign to undermine and divert attention from the results, raising safety concerns themselves and via their key opinion leaders and charities.

That accompanying article describes the way Novartis has tried to wreck other trials.

The need to compare bevacizumab and ranibizumab for ophthalmic use was perceived to be a priority for the NHS. And so the “randomised controlled trial of alternative treatments to inhibit VEGF in age-related choroidal neovascularisation” (IVAN) trial was conceived, at a cost to the public of about £10m……

However, there was resistance to the trial from the outset. Barney Reeves, professorial research fellow in health services research at Bristol University and one of the IVAN trialists, told The BMJ that it was a difficult trial to do politically. “The drug manufacturers didn’t want it done,” he said, adding: “Novartis tried to prevent UK ophthalmologists joining the IVAN trial, with their sales representatives lobbying potential principal investigators against the trial and telling them that the IVAN protocol was seriously flawed.”

Emails obtained by The BMJ under a freedom of information request show that clinicians with ties to Novartis urged some primary care trusts to pull out of the trial. The emails show discussions between ophthalmologists close to Novartis about how “big centres” in the US pulled out of the CATT trial because they would lose industry funding for other trials. The emails said that this situation “could be applied to the UK”—that is, researchers would be put off IVAN for fear of losing industry studies.

Emails also show that Novartis approached ophthalmology centres to conduct trials into other eye conditions for them at the same time IVAN was progressing. Novartis helped the investigators in these industry funded trials to obtain supplies of ranibizumab, in stark contrast to its approach to the IVAN trialists.

A new trial, not included in those systematic reviews has just been published in the NEJM. It showed that in diabetic macular oedema, nine shots of BVZ ($50 per dose), RBZ ($1,200 per dose), and aflibercept ($1,950) produced an equivalent benefit.

It was accompanied by an editorial which ended thus:

“We believe that all financial incentives and logistic barriers to providing the least expensive drug, among drugs equivalent in safety and efficacy, should be eliminated so that patients may benefit fully from the results of this Diabetic Retinopathy Clinical Research Network trial as well as those from other comparative trials.”

Which sounds eminently sensible, but not likely to hold much sway with Novartis, whose main consideration appears to be their own benefit, and not the patients.

Extreme preterms are small fry of course, in many ways. A single treatment, in a small number of babies, is not going to make a huge amount of money for anyone, unless you can find a way to restrict the treatment choices to only the more expensive drug. So Novartis are sponsoring a trial of RBZ against laser (NCT02375971), when, if we need to study RBZ at all, what is needed is a trial of RBZ against BVZ. Unfortunately such a trial would be likely to show that they are equivalent, as they are in adults, so I don’t hold out much hope that Novartis will fund such a trial.

 

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