An opinionated take on NEJM highlights for April 2018


Are we nearing an asymptote with implantable cardiac pumps?

Severe heart failure is common, and spare hearts for transplant are rare, which has led to the development of implantable mechanical alternatives. In the last few decades, progress has been immense, and in the latest installment of a 3rd (4th?) generation pump, outcomes have reached a level where survival of several years is the rule. Still, at every iteration incremental improvement is less, and performance remains well behind what happens with transplant in terms of complications such as infection, stroke, or bleeding. One is left with the impression that perhaps, there are fundamental limits associated with the non-biological nature of the solution that cannot be overcome.  It may be that we will figure out how to grow biological replacement hearts before we fully optimize the bioengineering of mechanical pumps. Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure; A New Left Ventricular Assist Device — Better, but Still Not Ideal (subscriber access)


New twists in hypertension

Blood pressure (BP) is typically measured during physician encounters, and it has been a long running debate whether this is optimal – some patients may get stressed by the encounter and have a higher BP than in usual circumstances (white coat hypertension), and for some patients, these point measurements may miss elevated BP at other times of the day (masked hypertension). This has led to monitoring of ambulatory BP – but then the question becomes: what do you do with the results as all our evidence is based on office BP measurements? A large registry study of 66,000 Spanish patients answers some of these questions by telling us that (1) even isolated white coat hypertension confers CV risk and likely should be treated, (2) masked hypertension confers most CV risk and should definitely be treated. The implication is that it is not those patients with high BP in the office that deserve an ambulatory monitor, it is those with normal BP for whom a confirmatory test that they do not have masked hypertension is useful – another telehealth/IoT application in the offing. Even when hypertension is detected, it is often poorly treated – as a silent risk factor it is often difficult to convince patients of the benefit of therapy when there is no immediate impact – success requires a good sociocultural understanding of the patient context, and sometime it requires some creativity to get there as in a study describing a highly successful intervention leveraging black barbershops to reinforce awareness and adherence among their hypertensive patrons.  Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality; The Value in an Ambulatory Blood-Pressure Registry; A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops; Inventing a New Model of Hypertension Care for Black Men (subscriber access)


Gene therapy marches on

Thalassemia is a genetic disease in which the oxygen carrying molecule hemoglobin is defective. In its worst forms, regular transfusion is necessary for survival with significant associated risks. Since cure is achievable via a bone marrow transplant (which is not always possible and has its own problems) it is a small step to consider the possibility of re-engineering the patient’s own stem cells with a corrected hemoglobin gene. In a study of 22 transfusion-dependent thalassemia patients, Bluebird Bio was able to harvest each patient’s stem cells, modify them genetically, and reinfuse them with the result that many patients became transfusion independent and those who did not required 75% fewer transfusions than before. There remains a whole bunch of technical elements to be optimized – but it seems clear that reliable cures are within reach.  In addition, the comparative simplicity of this disease model makes it an ideal test bed to continue to learn how to make cell therapeutics reliable and predictable. Bluebird has to be on the radar of pretty much any pharma who might want to establish/solidify a presence in this space. Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia; Gene Therapy as a Curative Option for β-Thalassemia (subscriber access)


A historical first: the development of a medicine for development medicine

The ability to sweat is critical to body-temperature control, and this is why x-linked hypohidrotic ectodermal dysplasia (XLHED) is a life threatening genetic condition. It is driven by mutations of the EDA (ectodysplasin A) gene resulting in a lack of signaling to drive fetal formation of sweat glands and tooth germs (which can be detected by routine ultrasound during pregnancy). In a novel approach, a German group infused Fc-EDA (Edimer Pharmaceuticals, a fusion protein including the receptor binding domain of EDA) into the amniotic cavity at week 26 of gestation of three affected fetuses. It worked, with skin biopsies of the post-delivery infants showing significant sweat glands and functional sweat production. To my knowledge, this is the first ever use of a drug to intentionally modify fetal development in humans – it won’t be the last. Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia; In Utero Protein Therapy for an Inherited Developmental Disorder (free access)


I/O triumphant

PD-1/PD-L1 blockade agents pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, BMS, often used in combination with ipilimumab/Yervoy) continue to duke it out in various cancers often showing impressive activity. It is impossible to do justice to the firehose of clinical data from the dozens of on-going trials of those agents. In a nutshell though, pembro has scored a big win for the biggest prize of first line therapy for lung cancer. However nivo is also picking up some wins, most recently in advanced renal cancer. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer; Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden; Neoadjuvant PD-1 Blockade in Resectable Lung Cancer (free access); Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma; Immunotherapy in Advanced Renal Cancer — Is Cure Possible? (subscriber access)


Another unusual advertisement

I have been seeing more and more ads in the journal that are not about the benefit of particular therapeutics. The latest example is the back-cover of the April 5 issue, with an ad for Walgreens as a supplier of limited distribution drugs for oncology. Clearly targeted at oncology practices involved in the buy-and-bill process, it touts prior-authorization and patient support services. Interesting timing given the rumors flying around including a buy-out of AmerisourceBergen, Amazon’s potential interest in the space, and the tie-up between Aetna and the arch-rival CVS.


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.