Research Spotlight

Weber, J., M. Mandala, M. Del Vecchio, H. J. Gogas, A. M. Arance, C. L. Cowey, S. Dalle, M. Schenker, V. Chiarion-Sileni, I. Marquez-Rodas, J. J. Grob, M. O. Butler, M. R. Middleton, M. Maio, V. Atkinson, P. Queirolo, R. Gonzalez, R. R. Kudchadkar, M. Smylie, N. Meyer, L. Mortier, M. B. Atkins, G. V. Long, S. Bhatia, C. Lebbe, P. Rutkowski, K. Yokota, N. Yamazaki, T. M. Kim, V. de Pril, J. Sabater, A. Qureshi, J. Larkin and P. A. Ascierto (2017). “Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma.” N Engl J Med 377(19): 1824-1835.

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BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (>/=15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

Thompson, J., N. Jones, A. Al-Khafaji, S. Malik, D. Reich, S. Munoz, R. MacNicholas, T. Hassanein, L. Teperman, L. Stein, A. Duarte-Rojo, R. Malik, T. Adhami, S. Asrani, N. Shah, P. Gaglio, A. Duddempudi, B. Borg, R. Jalan, R. Brown, H. Patton, R. Satoskar, S. Rossi, A. Parikh, A. ElSharkawy, P. Mantry, L. Sher, D. Wolf, M. Hart, C. Landis, A. Wigg, S. Habib, G. McCaughan, S. Colquhoun, A. Henry, P. Bedard, L. Landeen, M. Millis, R. Ashley, W. Frank, A. Henry, J. Stange and R. Subramanian (2017). “Extracorporeal cellular therapy (elad) in severe alcoholic hepatitis – a multinational, prospective, controlled, randomized trial.” Liver Transpl: 2017 Nov [Epub ahead of print].

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Severe Alcoholic Hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal liver treatment (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin >/=8 mg/dL, Maddrey’s Discriminant Function (DF) >/=32 and Model for End-Stage Liver Disease (MELD) score

Townsend, R. R., F. Mahfoud, D. E. Kandzari, K. Kario, S. Pocock, M. A. Weber, S. Ewen, K. Tsioufis, D. Tousoulis, A. S. P. Sharp, A. F. Watkinson, R. E. Schmieder, A. Schmid, J. W. Choi, C. East, A. Walton, I. Hopper, D. L. Cohen, R. Wilensky, D. P. Lee, A. Ma, C. M. Devireddy, J. P. Lea, P. C. Lurz, K. Fengler, J. Davies, N. Chapman, S. A. Cohen, V. DeBruin, M. Fahy, D. E. Jones, M. Rothman and M. Bohm (2017). “Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (spyral htn-off med): A randomised, sham-controlled, proof-of-concept trial.” Lancet 390(10108): 2160-2170.

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BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5.5 mm Hg (95% CI -9.1 to -2.0; p=0.0031), 24-h DBP -4.8 mm Hg (-7.0 to -2.6; p<0.0001), office SBP -10.0 mm Hg (-15.1 to -4.9; p=0.0004), and office DBP -5.3 mm Hg (-7.8 to -2.7; p=0.0002). No significant changes were seen in the sham-control group: 24-h SBP -0.5 mm Hg (95% CI -3.9 to 2.9; p=0.7644), 24-h DBP -0.4 mm Hg (-2.2 to 1.4; p=0.6448), office SBP -2.3 mm Hg (-6.1 to 1.6; p=0.2381), and office DBP -0.3 mm Hg (-2.9 to 2.2; p=0.8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5.0 mm Hg (95% CI -9.9 to -0.2; p=0.0414), 24-h DBP -4.4 mm Hg (-7.2 to -1.6; p=0.0024), office SBP -7.7 mm Hg (-14.0 to -1.5; p=0.0155), and office DBP -4.9 mm Hg (-8.5 to -1.4; p=0.0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.

Roberts, W. C., T. M. Becker and S. A. Hall (2017). “Usefulness of total 12-lead qrs voltage as a clue to diagnosis of patients with cardiac sarcoidosis severe enough to warrant orthotopic heart transplant.” JAMA Cardiol: 2017 Nov [Epub ahead of print].

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Importance: Severe heart failure caused by cardiac sarcoidosis is difficult to diagnosis without biopsy. Objective: To assess whether total electrocardiographic 12-lead QRS voltage may be a clue to diagnosis. Design, Setting, Participants: Case-series study with cases collected at Baylor University Medical Center at Dallas, Dallas, Texas, from January 13, 2005, to January 24, 2017. The clinical records of 16 patients with severe heart failure caused by cardiac sarcoidosis were studied. Examination of total 12-lead electrocardiographic QRS voltage (peak of the R wave to the nadir of either the Q or S wave, whichever was deeper) was performed prior to orthotopic heart transplant (OHT). Gross and microscopic pathologic specimens of the native hearts were studied. Main Outcomes and Measures: The primary outcome was to correlate the total 12-lead QRS voltage measurement with various morphologic features in the native diseased heart. Results: The 16-patient study group consisted of 8 men and 8 women; 12 (75%) were white and 4 (25%) were black. At the time of OHT, patient age ranged from 50 to 67 years (mean, 57 years). Cardiac sarcoidosis was diagnosed by pre-OHT biopsy results in 2 (13%) patients and by examination of the native heart after OHT in 14 (87%) patients. Total nonpaced 12-lead QRS voltage mean was 117 mm (range, 52-155 mm) for 8 patients and total paced 12-lead QRS voltage was 90 mm (range, 67-161 mm) for 12 patients. These low mean values were similar to those of patients with carcinoid heart disease (mean [SD], 105 [40] mm), cardiac amyloidosis (104 [35] mm), and severe cardiac adiposity (120 [31] mm) studied at necropsy or after OHT. In contrast, mean (SD) values were 323 (109) mm in patients with massive cardiomegaly, 257 mm in patients with severe aortic stenosis, 272 (86) mm in patients with severe pure aortic regurgitation, 220 (67) mm in patients with severe pure mitral regurgitation, 197 (64) mm in patients with hypertrophic cardiomyopathy, and 153 (40) mm in patients with idiopathic dilated cardiomyopathy. Conclusions and Relevance: Most patients diagnosed with cardiac sarcoidosis causing severe heart failure and warranting OHT had low total 12-lead QRS voltage measurements despite having native hearts of increased weight. This finding may provide a clue to the diagnosis of this disease.

Packer, M. (2017). “The imminent demise of cardiovascular drug development.” JAMA Cardiol: 2017 Nov [Epub ahead of print].

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The development of new cardiovascular drugs is at its deepest nadir in decades.¹ Major pharmaceutical companies have ended research activities in cardiology,² and applications to and approvals by the US Food and Drug Administration for new cardiovascular pharmaceuticals have declined dramatically even as innovations in other therapeutic areas have soared.