Primecuts – This Week in the Journals

July 12, 2019


By Jonathan Rosenthal, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature.  This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee [1]

Nerve growth factor (NGF) is thought to play a role in the development of chronic pain conditions like osteoarthritis (OA). This study examined the NGF inhibitor tanezumab among patients with moderate to severe OA who did not respond to standard therapy.

About 700 patients were enrolled in a randomized, double-blinded, placebo-controlled study. Researchers compared two subcutaneous dosing regimens: 2.5 mg of tanezumab 8 weeks apart vs. 2.5 mg on day 1 and 5 mg at week 8. These were also compared against placebo. At 16 weeks, the primary endpoints were change from baseline in pain, physical function, and patient global assessment of OA.

Mean pain scores at week 16 were significantly lower in the 2.5 mg group, with a least squares mean decrease of 3.5 on a 10-point scale (p = 0.01), as well as in the 2.5/5mg group (mean change -3.7; p=0.002), when compared to placebo (mean change -2.9). Physical function scores improved in the 2.5 mg group (p = 0.007) and 2.5/5 mg group (p < 0.001), as did patient global assessment when compared to placebo. Adverse events including total joint replacements, fractures, nasopharyngitis, hyperalgesia, and paresthesia were more frequent in the treatment groups, but overall adverse events were similar between groups.

Longer follow-up beyond 16 weeks will be needed to better understand these adverse events. The study’s relevance is also limited by its exclusion criteria. It did not include patients with other rheumatologic and neurologic conditions, making management of OA with other comorbidities less clear.

Effects of antiplatelet therapy after stroke due to intracerebral hemorrhage (RESTART): a randomised, open-label trial [2]

Antiplatelet therapy is always a fine balance, but especially after intracerebral hemorrhage (ICH). This cleverly named study sought to weigh the risk of recurrent ICH against the risk of myocardial infarction (MI) and ischemic stroke, after ICH patients resumed antiplatelet therapy.

The authors conducted a multi-center, randomized study enrolling 537 patients who were taking either an antiplatelet or an anticoagulant at the time of their ICH. It excluded those with hemorrhagic conversion of ischemic stroke or trauma. The primary outcome was recurrent symptomatic ICH, while the secondary outcomes were a composite of all major hemorrhagic events and a composite of all major vaso-occlusive events.

Among the treatment group, 4% had recurrent ICH, compared with 9% of the control (no therapy) group (p = 0.06). There was no evidence that the patient’s age, antiplatelet drug used, or time from ICH to restarting antiplatelet affected outcomes. With regard to the secondary outcomes, 7% of the treatment group experienced major hemorrhagic events compared with 9% of the control group (p = 0.27), and 15% of the treatment group had major vaso-occlusive events compared with 14% of the control group (p = 0.92).

Whereas previous observational studies hinted that antiplatelet therapy after ICH would be tolerated, this randomized study provides some of the strongest evidence yet. Clinicians can be reassured by these data that, if anything, antiplatelet therapy after ICH may actually improve outcomes. Be wary of some limitations: The population was 92% Caucasian, limiting generalizability, and the authors did not study dual antiplatelet therapy. Lastly, the study had a difficult recruitment process and failed to meet its enrollment goals, which makes the study under-powered, but also raises concern for bias as 11 out of 12 eligible patients did not join.

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial [3]

GLP-1 receptor agonists are currently only available in subcutaneous formulations, making patient adherence a challenge when escalating diabetes therapy. The goal here: to compare a novel oral version of semaglutide with widely used and well studied subcutaneous liraglutide –and placebo – among patients with type 2 diabetes mellitus (T2DM).

This multi-center, randomized, double-blinded phase 3a trial included 711 patients with T2DM on metformin +/- SGLT2 inhibitors. The primary endpoint was change from baseline to week 26 in hemoglobin A1c (HbA1c), and the secondary endpoint was change from baseline to week 26 in body weight. Further analysis looked at HbA1c and body weight at week 52.

Semaglutide was superior to placebo (p < 0.0001) and non-inferior to liraglutide (p < 0.0001) with regard to change in HbA1c. In fact, semaglutide showed greater decreases in HbA1c (-1.2% vs. -1.1%, p = 0.0056) and weight (-4.4 kg vs. -3.1 kg, p = 0.0003) than liraglutide. At week 52, similar results were found. Adverse events were more frequent with semaglutide (80%) than liraglutide (74%), and mostly included nausea and diarrhea.

For clinicians, this could soon mean one more diabetic medication will be needle-free. Limitations include the exclusion criteria: those with renal disease, ocular disease, or pancreatitis, which limits our understanding of possible adverse effects on common comorbidities.

Negative Risk Markers for Cardiovascular Events in the Elderly [4]

Cardiovascular disease risk increases with age, and some guidelines can lead to near-universal recommendation of statin therapy at a certain age, even without other significant risk factors. Are there markers that could serve as negative risk factors to increase the specificity of statin therapy?

This study analyzed prior data from a multi-center, prospective study of 5,805 patients, used to look for positive risk factors for cardiovascular outcomes. Instead, negative risk factors were now investigated, including non-invasive imaging and serum markers. The primary outcome was coronary heart disease (CHD), which was a summation of MI, unstable angina, and coronary revascularization. The secondary outcome was cardiovascular disease (CVD), which included the previous, as well as ischemic stroke and cardiovascular death.

Among the risk factors tested, event rates were lowest for individuals with coronary artery calcium (CAC) scores of 0 (0.9 for CHD and 3.2 for CVD per 1,000 person-years), CAC ≤ 10 (0.9 and 2.8 per 1,000 person-years), and absence of carotid plaque (1.7 and 4.4 per 1,000 person-years). These same findings were demonstrated on multivariate-adjusted analyses

The conclusions from this study support the 2018 ACC/AHA guidelines that a CAC of 0 is associated with low enough risk to consider holding statins. This study is limited, however, in its number of follow-up years (median 2.7), giving some pause as patients affected by these results could be as young as 66, with many years ahead of them. Further, the study’s inversion of its original purpose from positive to negative risk factors raises some questions about its validity.

Minicuts

Meta-Analysis of Randomized Controlled Trials of Red Meat Consumption in Comparison With Various Comparison Diets on Cardiovascular Risk Factors [5]

Nutrition science is always tricky because results depend on the comparison diet; comparing snickerdoodles to lard makes the snickerdoodles look good. This meta-analysis of 36 randomized controlled trials, with 1803 subjects, stratified studies based on their comparison diets, trying to clear up some of the mixed signals in the literature. Ultimately, high-quality plant-based diets were superior to red meat-based diets for total cholesterol (weighted mean difference -10.2 mg/dL; 95% CI -14.8 to -5.5; p < 0.001) and LDL (weighted mean difference -7.7 mg/dL; 95% CI -12.8 to -2.5; p < 0.001). [6]

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy [7]

Cylcosporine, a calcineurin inhibitor, is a central therapy for membranous nephropathy but comes with significant toxicity, including, ironically, nephrotoxicity. 130 patients with active proteinuria were randomized to either rituximab or cyclosporine for 24 months. Rituximab was both non-inferior and superior to cyclosporine, with 60% of patients in the rituximab group achieving partial or complete remission of proteinuria compared to 20% in the cyclosporine group (p < 0.001 for both non-inferiority and superiority).

Assessment of Self-reported Prognostic Expectations of People Undergoing Dialysis [8]

This study aimed to compare patients’ expectations of their prognosis with average survival data in the US dialysis population. While more than 88% of the 996 patients expected to live more than 5 years (or were unsure of their prognosis), actuarial data showed 60% succumbed to illness within this time frame. Patients with expectations to live more than 10 years had more limited advanced care planning. They were less likely to have selected a surrogate decision maker (adjusted odds ratio 0.6; 95% CI, 0.4-0.9) and more likely to opt for cardiopulmonary resuscitation (aOR 5.3; 95% CI 3.2-8.7). This underscores the importance of patient-centered prognosis and goals of care discussions.

References

[1] Schnitzer, Thomas J., et al. Effect of tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee: a randomized clinical trial. JAMA 322.1 (2019): 37-48. https://jamanetwork.com/journals/jama/article-abstract/2737173

[2] Baigent, Colin, et al. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. The Lancet 394.10192 (2019): 39-50. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30840-2/fulltext

[3] Pratley, Richard, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. The Lancet 393.10191 (2019): 2613-2623. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31271-1/fulltext

[4] Mortensen, Martin Bødtker, et al. Negative Risk Markers for Cardiovascular Events in the Elderly. Journal of the American College of Cardiology 74.1 (2019): 1-11. http://www.onlinejacc.org/content/74/1/1

[5] Guasch-Ferré, Marta, et al. Meta-analysis of randomized controlled trials of red meat consumption in comparison with various comparison diets on cardiovascular risk factors. Circulation 139.15 (2019): 1828-1845. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035225

[6] Koperska, M. Cholesterol Unit Converter. OmniCalculator. https://www.omnicalculator.com/health/cholesterol-units. Accessed July 12, 2019.

[7] Fervenza, Fernando C., et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine 381.1 (2019): 36-46. https://www.nejm.org/doi/full/10.1056/NEJMoa1814427

[8] O’Hare AM et al. Assessment of Self-reported Prognostic Expectations of People Undergoing Dialysis: United States Renal Data System Study of Treatment Preferences (USTATE). JAMA Intern Med. Published online July 08, 2019. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737752

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