Research Spotlight

Ben-Yehuda, O., Shahim, B., Chen, S., Liu, M., Redfors, B., Hahn, R.T., Asch, F.M., Weissman, N.J., Medvedofsky, D., Puri, R., Kapadia, S., Sannino, A., Grayburn, P., Kar, S., Lim, S., Lindenfeld, J., Abraham, W.T., Mack, M.J. and Stone, G.W. (2020). “Pulmonary Hypertension in Transcatheter Mitral Valve Repair for Secondary Mitral Regurgitation: The COAPT Trial.” J Am Coll Cardiol 76(22): 2595-2606.

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BACKGROUND: Pulmonary hypertension worsens prognosis in patients with heart failure (HF) and secondary mitral regurgitation (SMR). OBJECTIVES: This study sought to determine whether baseline pulmonary hypertension influences outcomes of transcatheter mitral valve repair (TMVr) in patients with HF with SMR. METHODS: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, 614 patients with HF with moderate-to-severe or severe SMR were randomized to TMVr with the MitraClip plus guideline-directed medical therapy (GDMT) (n = 302) versus GDMT alone (n = 312). Baseline pulmonary artery systolic pressure (PASP) estimated from echocardiography was categorized as substantially increased (≥50 mm Hg) versus not substantially increased (<50 mm Hg). RESULTS: Among 528 patients, 184 (82 TMVr, 102 GDMT) had PASP of ≥50 mm Hg (mean: 59.1 ± 8.8 mm Hg) and 344 (171 TMVr, 173 GDMT) had PASP of <50 mm Hg (mean: 36.3 ± 8.1 mm Hg). Patients with PASP of ≥50 mm Hg had higher 2-year rates of death or HF hospitalization (HFH) compared to those with PASP of <50 mm Hg (68.8% vs. 49.1%; adjusted hazard ratio: 1.52; 95% confidence interval: 1.17 to 1.97; p = 0.002). Rates of death or HFH were reduced by TMVr versus GDMT alone, irrespective of baseline PASP (p(interaction) = 0.45). TMVr reduced PASP from baseline to 30 days to a greater than GDMT alone (adjusted least squares mean: -4.0 vs. -0.9 mm Hg; p = 0.006), a change that was associated with reduced risk of death or HFH between 30 days and 2 years (adjusted hazard ratio: 0.91 per -5 mm Hg PASP; 95% confidence interval: 0.86 to 0.96; p = 0.0009). CONCLUSIONS: Elevated PASP is associated with a worse prognosis in patients with HF with severe SMR. TMVr with the MitraClip reduced 30-day PASP and 2-year rates of death or HFH compared with GDMT alone, irrespective of PASP.

Spigel, D., Jotte, R., Nemunaitis, J., Shum, M., Schneider, J., Goldschmidt, J., Eisenstein, J., Berz, D., Seneviratne, L., Socoteanu, M., Bhanderi, V., Konduri, K., Xia, M., Wang, H., Hozak, R.R., Gueorguieva, I., Ferry, D., Gandhi, L., Chao, B.H. and Rybkin, I. (2020). “Brief Report: Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination with Pegilodecakin in Patients with Metastatic Non-Small-Cell Lung Cancer (CYPRESS-1 and CYPRESS-2).” J Thorac Oncol.

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INTRODUCTION: Checkpoint inhibitors (CPI) have been approved to treat metastatic NSCLC. Pegilodecakin+CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS-1 and CYPRESS-2. METHODS: CYPRESS-1 (N=101) and CYPRESS-2 (N=52) included ECOG 0-1, 1L/2L metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS-1) or nivolumab (CYPRESS-2); experimental arms received pegilodecakin+CPI. Patients had PD-L1 tumor proportion score (TPS) ≥50% (CYPRESS-1) or 0-49% (CYPRESS-2). Primary endpoint was ORR per investigator. Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included immune activation biomarkers. RESULTS: Median follow-up for CYPRESS-1 and CYPRESS-2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin+pembrolizumab versus pembrolizumab were: ORR per investigator 47%vs.44% (Odds ratio:1.1;95%CI[0.5,2.5]); mPFS 6.3vs.6.1 months (HR:0.937;95%CI[0.541,1.625]); and mOS 16.3 months vs.not reached (HR:1.507;95%CI[0.708,3.209]). Results per blinded independent central review (BICR) were consistent. Treatment discontinuation rate due to AEs doubled in the experimental arm (32%vs.15%). Gr≥3 treatment related adverse events (TRAEs)(62%vs.19%) included anemia(20%vs.0%) and thrombocytopenia(12%vs.2%). Results for pegilodecakin+nivolumab versus nivolumab were:ORR per investigator 15%vs.12% (Odds ratio:1.2;95%CI[0.3,5.9]); mPFS 1.9vs.1.9 months (HR:1.006;95%CI[0.519,1.951]); and mOS 6.7vs.10.7 months (HR:1.871;95%CI[0.772,4.532]). Gr≥3 TRAEs (70.4%vs.16.7%) included anemia(40.7%vs.0%), fatigue(18%vs.0%), and thrombocytopenia(14.8%vs.0%). Biomarker data suggested activation of immunostimulatory signals of IL-10R pathway in pegilodecakin-containing arms. CONCLUSION: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in 1L/2L NSCLC. Pegilodecakin+CPI demonstrated overall higher toxicity compared to CPI alone, leading to doubling of treatment discontinuation rate due to AEs.

Kogutt, B.K. and Szymanski, L.M. (2020). “Diabesity and Pregnancy: How Do We Get Our Patients Moving?” Clin Obstet Gynecol Dec 4. [Epub ahead of print.].

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Obesity and diabetes are 2 commonly encountered complications in pregnancy that adversely affect pregnancy outcomes, maternal health, and the health of the offspring, both short-term and long-term. It is well established that physical activity provides numerous health benefits, both during and outside of pregnancy. By participating in physical activity, many of the negative consequences of both obesity and diabetes may be mitigated. Physical activity guidelines recommend that all adults, including pregnant women, perform at least 150 minutes of moderate-intensity exercise weekly in order to obtain health benefits. More physical activity may be needed to achieve weight management goals.

Lakin, J.R., Desai, M., Engelman, K., O’Connor, N., Teuteberg, W.G., Coackley, A., Kilpatrick, L.B., Gawande, A. and Fromme, E.K. (2020). “Earlier identification of seriously ill patients: an implementation case series.” BMJ Support Palliat Care 10(4): e31.

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OBJECTIVE: To describe the strategies used by a collection of healthcare systems to apply different methods of identifying seriously ill patients for a targeted palliative care intervention to improve communication around goals and values. METHODS: We present an implementation case series describing the experiences, challenges and best practices in applying patient selection strategies across multiple healthcare systems implementing the Serious Illness Care Program (SICP). RESULTS: Five sites across the USA and England described their individual experiences implementing patient selection as part of the SICP. They employed a combination of clinician screens (such as the ‘Surprise Question’), disease-specific criteria, existing registries or algorithms as a starting point. Notably, each describes adaptation and evolution of their patient selection methodology over time, with several sites moving towards using more advanced machine learning-based analytical approaches. CONCLUSIONS: Involving clinical and programme staff to choose a simple initial method for patient identification is the ideal starting place for selecting patients for palliative care interventions. However, improving and refining methods over time is important and we need ongoing research into better patient selection methodologies that move beyond mortality prediction and instead focus on identifying seriously ill patients-those with poor quality of life, worsening functional status and medical care that is negatively impacting their families.

Dutcher, E.G., Green, E.P. and Kaplan, B. (2020). “Using Behavioral Economics to Increase Transplantation Through Commitments to Donate.” Transplantation 104(12): 2467-2468.

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Like many countries, Japan is facing a shortage of deceased kidney donations. In Japan, this is exacerbated by certain cultural and religious objections to the use of deceased donors. Despite efforts to mitigate these objections and increase deceased donor utilization, only 111 deceased donors were performed in Japan in 2017 (while 14 002 patients remained on the waiting list). To increase the number of donors, Hirai et al 1 leverage behavioral economics and test 5 interventions and their impact on commitments to donate in Japan. Using these simple and inexpensive interventions, the authors are able to increase the commitment to donation, which will potentially lead to saving more lives through transplantation. In this commentary, we explore the economic principles that explain the behavior observed in their study and provide further considerations for using behavioral economics to increase deceased kidney donations in light of their findings. [No abstract; excerpt from article.].