Richard Lehman’s journal review—29 July 2013

Richard LehmanJAMA  24-31 July 2013  Vol 310
It’s possible that you want to read about US physicians’ views on their role in cost containment, and about rates of breast cancer survival in white and black US women (there is little difference) and even about raccoon rabies virus variant transmission through solid organ transplantation, and you may wish to know that kidney stones are slightly associated with cardiovascular risk in women but not men.

All this can be found in this week’s JAMA. But as it would be impertinent for me to talk about my US colleagues, or indeed about raccoons, I shall move straight on to a piece about complicated grief, which takes the form of a moderated discussion.

416    Grief shapes all our lives as we encounter it, and “the death of a loved one is one of life’s greatest, universal stressors to which most bereaved individuals successfully adapt without clinical intervention.” I quote from the opening of this article, because it ushers us straight into the kind of discourse—“stressors,” “adapt,” “clinical intervention,”—which doctors can hide behind when approached by a grieving person. As the discussion progresses, we get ever more deeply mired in protective pseudo-science. Complicated grief is grief that “lasts more than one year,” and it has a “prevalence of 7%.” But because grief is not a disease as such, we have to look for ways to fit it into other disease categories. The article concludes that “Individuals with complicated grief have greater risk of adverse health outcomes, should be diagnosed and assessed for suicide risk and comorbid conditions such as depression and posttraumatic stress disorder, and should be considered for treatment.” I hope that grief-stricken people are genuinely helped by these “shoulds” and this search for “comorbidity,” and I confess that I have sometimes myself given SSRIs to bereaved people, but I hope I have also helped them in other ways, as far as I could. Yet that ability is limited by something we all have to take account of, which is the economy of our own souls. Grief may be too much for any one person to bear, or to share alone. The greatest works of art created are an invitation to share grief together, as in the Story of Gilgamesh, or the tragedies of Ancient Greece, or Lear, or the Pietà, or the Taj Mahal, or some portraits by Rembrandt, or the work of Bach which begins with a slow dance, “Kommt ihr Töchter, hilft mir klagen.”

NEJM  25 July 2013  Vol 369
307    Medicine needs more boring research. Here is a terrific example: a double-blinded comparative effectiveness trial of two common alternative approaches to rheumatoid arthritis which was not settling with methotrexate. Half of them got etanercept and the other half got hydroxochloroquine and sulfasalazine: they all carried on with methotrexate. If they were not responding at 24 weeks, they were switched over. When the blinding was lifted at 48 weeks, there was no significant difference between the two treatments, whether or not they were switched. And they measured all sorts of patient-relevant end-points, such as harm of treatment, health-related quality of life, and pain: hurray! This trial will clarify the options for thousands of people with a nasty, disabling condition; it will save money for health systems; and the patients will have gone off taking the treatment which worked best for them. But rheumatology conferences and journals will continue to be stuffed with presentations about genomics, new inflammatory pathways and new drugs to try out on them. Medicine would get much further by taking pause to find out more about what it is already doing to people.

319   But there are still some life-shortening conditions where there are so few therapeutic options that everybody with them should be invited to take part in randomized trials of new interventions. One such is chronic thromboembolic pulmonary hypertension. Progression leads to reduced walking distance and ultimately to death, and is accompanied by an inexorable rise in B-type natriuretic peptide. So when a drug comes along that leads to an improvement in walking distance and a decrease in BNP over 16 weeks, it could mark a potential breakthrough, though we cannot be certain without longer trials. The drug is riociguat, a member of a new class of compounds, the soluble guanylate cyclase stimulators. The two trials reported here and here are very similar and encouraging. Yet the accompanying editorial contains a pretty explicit warning:
“Another caveat, which is not unique to PATENT-1 and CHEST-1, is the relationship to the sponsoring company. The study was supported by Bayer HealthCare, and although the manuscript was drafted by the first author, editorial assistance was provided by a company supported by the sponsor (Adelphi Communications). In addition, although the authors had access to the complete database, the statistician was employed by Bayer HealthCare. Riociguat is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue for the sponsor. In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients.” So where does the buck stop—with the NEJM which printed these studies, and will presumably get reprint income from Bayer, or with the FDA? Which impartial body is going to conduct the necessary replication studies and long-term mortality studies? Do we get to see the full data set?

362   This week’s NEJM review article is about hypoglycaemia—something that we all need to take more account of when piling on treatments for diabetes. This paper deals with the detail of autonomic regulation of hypoglycaemia awareness, and why awareness tends to diminish with each hypoglycaemic episode. The wider clinical relevance of hypoglycaemia is the subject of a brilliant article by Kasia Lipska and Victor Montori in this week’s JAMA Internal Medicine.

Lancet  27 July 2013  Vol 382
311   Central venous lines are now seen quite commonly in the community as well as in hospital, though like most GPs, I haven’t actually inserted one since I left the wards some decades ago. Insertion through an arm vein is now frequent practice, though it can sometimes lead to deep vein clots in the arm. This meta-analysis shows that this is a fairly significant risk compared with direct central placement, and not surprisingly it depends on the site of the arm vein and its diameter, plus the time the cannula remains in situ and the cancer status of the patient. Oddly enough though, it seems that these arm thromboses never cause significant pulmonary embolism.

326   To wipe or to suck? This lowly question gets Lancet space, and quite rightly: the practices of obstetrics concern every new member of the human race. Although my first memories go back a long way, I cannot remember whether they sucked out my nose and mouth when I entered the world, or just used a hanky. This randomized trial from Birmingham, Alabama, shows that the hanky does perfectly well for neonates born at 35 weeks onwards.

331   Few stories in science are stranger than the visit of Sir Humphry Davy to Paris in 1813, at a time when Great Britain and France were at war. He was received with great acclaim, received a medal from Napoleon, and was challenged by Gay-Lussac to identify a new substance which had the form of purplish brown crystals. Davy took out his travelling chemistry set and identified it as a new element, thereafter called iodine. Another 80 years would pass before the role of iodine in the human body was discovered, and we are still finding out about it. In this study, urinary iodine levels were examined in stored specimens from 1040 first-trimester pregnant women, with adjustment made for creatinine, and these levels were then compared with the IQ of offspring measured at 8 years of age. “After adjustment for confounders, children of women with an iodine-to-creatinine ratio of less than 150 μg/g were more likely to have scores in the lowest quartile for verbal IQ (odds ratio 1•58, 95% CI 1•09—2•30; p=0•02), reading accuracy (1•69, 1•15—2•49; p=0•007), and reading comprehension (1•54, 1•06—2•23; p=0•02) than were those of mothers with ratios of 150 μg/g or more.” This really is quite impressive, and it would be nice to get further information from other cohort studies—this one came from the Avon Longitudinal Study of Parents and Children. As the authors say, “Iodine deficiency in pregnant women in the UK should be treated as an important public health issue that needs attention.”

BMJ  27 July 2013  Vol 347
It’s the end of July and there is sleepiness in the air; even people who aren’t on holiday feel as if they should be; e-mails go unanswered, and jobs get postponed. Perhaps this accounts for the lack-lustre contents of the journals at this time of year too. This week’s BMJ research section begins with two “does A lead to B?” type articles, neither of huge interest. Whole-population Danish registers were interrogated to find out if assisted conception was associated with adolescent mental disorders and found a small and nonsensical association with ovulation induction/intrauterine insemination, but not with in vitro fertilisation/intracytoplasmic sperm injection.

And a Canadian register was trawled for evidence that renal outcomes after acute coronary syndrome might be influenced by invasive versus conservative management: they found that early invasive management of acute coronary syndrome is associated with a small increase in risk of acute kidney injury, but not dialysis or long term progression to end stage renal disease.

Of much greater general interest is the question of whether pertussis vaccination confers useful protection to adolescents and adults. For several years, I was able to diagnose pertussis frequently in grown-ups with persistent paroxysmal coughing, thus sparing them further futile investigation and treatment. Then we were stopped from ordering either saliva or blood testing for pertussis IgG and we’re back to guessing, trying antibiotics, beclometasone, and so forth. Here is a study from Kaiser Permanente in California which detected pertussis by PCR test and compared subjects who had or had not received a reduced acellular pertussis (Tdap) vaccine at any time previously. Using two different control populations, they concluded that pertussis vaccine confers 50-60% protection.

Not content with denying us access to diagnostic tests for pertussis, the Oxfordshire NHS Death Panel also told us years ago that we should not refer varicose veins for surgery, and we duly obeyed. But this is set to change with a new NICE guideline. Here is a ringing declaration of rebellion: “Traditionally, conservative care (compression and advice) has been considered a low cost intervention for people with symptoms such as aching or pain from varicose veins. It has thus been routinely offered before interventional treatment. However, the evidence identified in this guideline challenges this practice, showing that interventional treatment is more clinically effective and cost effective than conservative care for people with symptomatic varicose veins. In some regions of the UK, endothermal ablation is not currently available. The guideline provides solid evidence that this is the first choice of treatment on both clinical and cost effectiveness grounds, and should be made available throughout the UK.” Take that, you GP-led death panels: British veins deserve the best that British surgeons can offer.

JAMA Intern Med  22 July 2013  Vol 173
1300   The more you look at what we are incentivized to do with elderly diabetic patients, the scarier it gets. Are we reducing beta-cell decline, or accelerating it? Are we reducing cardiovascular risk, or increasing it? When we tighten control, are we preventing cognitive decline or inducing it? For every treatment beyond metformin, we simply don’t know. But there is increasing evidence that by inducing hypoglycaemia, commonly with sulfonylurea drugs or insulin, we are in danger of damaging the elderly brain, and elderly people with dementia then become more prone to hypoglycaemia. It’s a bidirectional disaster area, as this study shows. In an elderly diabetic cohort followed for 12 years, “those who experienced a hypoglycaemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycaemic event… Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycaemic event compared with participants who did not develop dementia.”

1318   Statins are great. And the initial randomized trials showed no increase in muscle aches in the treated group. Now that is really strange, because every GP has encountered many patients who are desperate to continue taking a statin but cannot because of muscle pains which recur whenever they do. Nor do we quite know the full range of muscle effects which statins can produce: this retrospective cohort study with propensity score matching concludes that “musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers.” But let’s not get carried away: the odds ratios in the study were pretty small (1.07-1.1).

Plants of the Week: Nasturtiums

The nasturtiums we loved as children and grow for colour and salad-making at this time of year are really hybrids of Tropaeolum species: the true Nasturtium is water-cress.

As we went from one showy, loveless compartment to another in a famous local garden today, the only plants that lifted our spirits were pot-grown nasturtiums of darkest crimson or palest yellow. In our own little garden we just grow vulgar orange ones, mottled or otherwise, which quickly sprawl over everything.

We seldom eat our nasturtiums but I did once make a serious attempt to grow the Andean perennial nasturtium Tropaeolum tuberosum as a food crop. It is frost-hardy and produces crops of 30 tons per hectare at a height of 3,000 metres (9,800 ft) above sea level, and features in pre-Inca Peruvian drawings. Needless to say, my one plant of the cultivar “Ken Aslet” disappeared forever the year after planting.