March 31, 2017

Great expectations

The story

Just like you've spent most of residency waiting for graduation, researchers have spent the developmental lifetime of PCSK9 inhibitors waiting to see if the drugs reduce cardiovascular disease. A mammoth new clinical trial attempts to answer the question.

The background

Researchers found in 2005 that loss-of-function gene mutations to proprotein convertase subtilisin–kexin type 9 (PCSK9) dramatically lowered LDL cholesterol levels without apparent side effects, and since then the race has been on in the pharmaceutical industry to get PCSK9-inhibiting antibodies to market. Studies to date have proven that PCSK9 inhibitors lower LDL cholesterol beyond levels achieved with statin therapy, but the field has been waiting for the big shoe to drop in the form of RCTs powered to detect differences in outcomes.

The study

Drugmaker Amgen's $1 billion FOURIER trial examined the effect of PCSK9 inhibitor evolocumab (Repatha) in 27,000 patients at high risk for cardiovascular disease. Evolocumab combined with statins reduced a composite outcome of cardiovascular events by 15% relative to statins and placebo (9.8% vs. 11.3%, respectively) after a median follow-up of 2 years. The drug was well-tolerated and reduced cholesterol by 60% after 48 weeks. Reductions in cardiovascular risk were seen after only 1 year of treatment.

The reaction

Many were impressed that evolocumab improved outcomes in such a short time period, but given tremenous drug expectations, some expected a larger magnitude of benefit. Evolocumab is priced at $14,000 per patient per year, and at a number needed to treat of 70, insurance companies would have to pay roughly $1 million to prevent one event in high-risk patients.

The takeaway

With only mild known adverse effects, you'd prefer to have your high-risk patients on evolocumab. But costs remain prohibitive, and whether insurance companies and international guidelines embrace PCSK9 inhibitors remains to be determined.

Say it on rounds

When you've just shut your eyes, and your new admission rolls in at 5 AM

Mind power takes on all kind of new meaning these days. In a proof-of-concept study, a quadriplegic man used a brain-computer interface to reach and grasp with his arms. The device, labeled a neuro-prosthesis, linked the motor cortex of the man's brain with his arm via electrodes. The man completed multi-joint tasks with 80 - 100% accuracy after two years of working with the implant. Videos show him using the device to feed himself and drink coffee.

When you nap without setting an alarm

Indefinite sleep has never meshed well with residency, but indefinite anticoagulation may be on the horizon for unprovoked DVT. An RCT of almost 4,000 patients with DVT found that extending anticoagulation beyond 6 or 12 months with reduced dose rivaroxaban reduced the risk of recurrent DVT by 75% compared to aspirin therapy. Bleeding rates were similar between the aspirin and reduced dose rivaroxaban groups, but were increased in a third group of patients on treatment dose rivaroxaban.

When you're unfazed by the smells of the hospital

Trust us: the nose evolves quickly. A study of nose traits and their relationships to climate found that nostril width correlated with temperature and humidity. Some of the study's strongest associations were found between Northern Europeans and narrow nostril width, a trait which may have helped the ethnic group adapt to cold, dry climates. Skin pigmentation also correlated with climate, while nose height and protrusion did not.
PLoS Genetics

Brush up


Help define psoriatic arthritis (PA) by what it’s not. Unlike rheumatoid arthritis and its proximal, symmetric joint involvement, PA affects distal joints, often in a ray pattern in which all of the joints of a single digit are involved while other digits are spared. Spinal involvement is common in both PA and ankylosing spondylitis, but PA typically presents around the fourth decade of life rather than the second. Nail disease like pitting and onycholysis help separate PA from osteoarthritis.

What's the evidence

For interleukin inhibition in PA? Inflammatory cytokines interleukin-23 and interleukin-17 help drive psoriasis and psoriatic arthritis. The monoclonal antibody ustekinumab, directed in part against interleukin-23, improved disease activity in patients with PA at 24 weeks in a 2013 phase III RCT of 600 patients with active disease. Blockade of interleukin-17 with ixekizumab reduced progression of structural joint damage compared to placebo at 24 weeks in a 100-person phase III RCT from 2017.

What your research friends are talking about

Mary-Claire King's early NIH funding led to the identification of the BRCA1 gene. Now she worries that proposed cuts to the NIH budget will lose a generation of scientists. President Trump's 'America First' budget offers the largest cuts in the institute's history, and many worry that young, risk-taking scientists will be the first to feel the squeeze.

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