Research Spotlight

Posted June 15th 2017

A leadless pacemaker in the real-world setting: The Micra Transcatheter Pacing System Post-Approval Registry.

Robert C. Kowal M.D.

Robert C. Kowal M.D.

Roberts, P. R., N. Clementy, F. Al Samadi, C. Garweg, J. L. Martinez-Sande, S. Iacopino, J. B. Johansen, X. V. Prat, R. Kowal, D. Klug, L. Mont, J. Steffel, S. Li, D. Van Osch and M. F. El-Chami (2017). “A leadless pacemaker in the real-world setting: The micra transcatheter pacing system post-approval registry.” Heart Rhythm: 2017 May [Epub ahead of print].

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BACKGROUND: First-in-man studies of leadless pacemakers have demonstrated high rates of implant success, and safety and efficacy objectives were achieved. Outside of the investigational setting, there are concerns, particularly over cardiac effusion and perforation, device dislodgement, infection, telemetry, and battery issues. OBJECTIVE: The acute performance of the Micra transcatheter pacemaker from a worldwide postapproval registry is reported. METHODS: The registry is an ongoing prospective single-arm observational study designed to assess the safety and effectiveness of Micra in the postapproval setting. The safety end point was system- or procedure-related major complications at 30 days post implant. We compared the major complication rate with that of the 726 patients from the investigational study. Electrical performance was also characterized. RESULTS: The device was successfully implanted in 792 of 795 registry patients (99.6%) by 149 implanters at 96 centers in 20 countries. Through 30 days post implant, a total of 13 major complications occurred in 12 patients, for a major complication rate of 1.51% (95% confidence interval, 0.78%-2.62%). Major complications included cardiac effusion/perforation (1, 0.13%), device dislodgement (1, 0.13%), and sepsis (1, 0.13%). After adjusting for baseline differences, the rate of major complications in the registry trended lower than the investigational trial (odds ratio, 0.59, 95% confidence interval, 0.27-1.27; P = .18). Early pacing capture thresholds were low and stable. CONCLUSION: Performance of the Micra transcatheter pacemaker in a real-world setting demonstrates a high rate (99.6%) of implant success and low rate (1.51%) of major complication through 30 days post implant. In particular, the rates of pericardial effusion, device dislodgement, and infection were low, reinforcing the positive results seen in the investigational study.


Posted June 15th 2017

Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the PROFILE Trial After 24 Years.

Milton Packer M.D.

Milton Packer M.D.

Packer, M., B. Pitt, J. L. Rouleau, K. Swedberg, D. L. DeMets and L. Fisher (2017). “Long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure: Primary results of the profile trial after 24 years.” JACC Heart Fail 5(6): 399-407.

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OBJECTIVES: The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND: Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use. METHODS: Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction


Posted June 15th 2017

Midterm Outcome of the Agility Total Ankle Arthroplasty.

Justin M. Kane M.D.

Justin M. Kane M.D.

Raikin, S. M., K. Sandrowski, J. M. Kane, D. Beck and B. S. Winters (2017). “Midterm outcome of the agility total ankle arthroplasty.” Foot Ankle Int 38(6): 662-670.

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BACKGROUND: Ankle arthritis is a debilitating condition that causes severe functional impairment. While arthrodesis has been the gold standard of surgical treatment for this condition, significant improvements in total ankle arthroplasty have made it a viable alternative. The purpose of this study was to look at the midterm follow-up of the Agility total ankle. METHODS: A retrospective review of prospectively collected data was conducted on 127 consecutive Agility total ankles implanted between 2002 and 2009. Charts were reviewed to collect patient demographics. In addition, coronal alignment, overall arc of motion, tibiotalar component motion, syndesmotic fusion, zones of osteolysis, and subsidence were determined. A Kaplan-Meier survival and linear regression analysis were used to predict implant failure. A multivariate regression analysis was used to assess whether radiographic measures were predictive of patient satisfaction. RESULTS: Ninety (78.2%) of 115 patients retained their primary implant, of which 105 were available for evaluation, with an average follow-up of 9.1 years. Twenty-five had their implant removed. The average score for the Foot and Ankle Ability Measure (FAAM) activities of daily living subscale was 82.4, FAAM sport subscale 55.3, postoperative visual analog scale (VAS) for pain 12.7, and Short Form-12 (SF-12) Health Survey physical component 45.8 and SF-12 mental component 56.1. Average arc of motion across the implant was 22.3 and 6.3 degrees in adjacent joints. Osteolysis most commonly occurred in zones 1 and 6. No statistical differences were found in the rate or location of subsidence. Linear regression analysis demonstrated that age at the time of surgery was predictive of failure ( P = .036). Inflammatory and atraumatic arthritis demonstrated higher likelihoods of revision. No correlation was detected between radiographic parameters and outcomes scores ( P > .05; rho >0.2). A significant reduction in mean VAS pain scores by 67.6% was maintained at an average of 8 years. DISCUSSION: Our results were improved over the nondesigner outcomes published in the current literature. Survivorship approached 80% at 9 years, with Kaplan-Meier 14-year survival calculated at 70.4%. Patients with their original implant were functioning with a high level of satisfaction based on statistically validated outcome scores, which was independent of the radiographic appearance of their implant. Age at the time of surgery and inflammatory/atraumatic arthritis were predictive of failure.


Posted June 15th 2017

Open-label, Phase II Study to Assess Efficacy and Safety of Canakinumab Treatment in Active Hyperimmunoglobulinemia D with Periodic Fever Syndrome.

Romain Banchereau, PhD

Romain Banchereau, PhD

Arostegui, J. I., J. Anton, I. Calvo, A. Robles, E. Iglesias, B. Lopez-Montesinos, R. Banchereau, S. Hong, Y. Joubert, G. Junge, V. Pascual and J. Yague (2017). “Open-label, phase ii study to assess efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia d with periodic fever syndrome.” Arthritis Rheumatol: 2017 May [Epub ahead of print].

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OBJECTIVE: To evaluate the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). METHODS: This was a 3-part, open-label study with a 6-month treatment period (P1; 300 mg or 4 mg/kg q6w), a 6-month withdrawal period (P2), and a 24-month treatment period (P3). The primary endpoint was reduction in frequency of attacks during treatment period compared with the historical period (HP; period in which patients did not receive drugs other than NSAIDs and/or steroids). RESULTS: All nine patients completed P1 and P2, whereas only eight completed P3. All patients achieved a complete response during P1, and only two required dose adjustments. The median number of attacks per patient decreased from 5 (3-12) during HP to 0 (0-2) during P1. During P2, seven out of nine patients flared with a median of 110 days (62-196) after the last canakinumab dose. Laboratory parameters were normalized at Day 15 and remained at normal levels throughout the study. The blood transcriptome assessed during P1 showed upregulated interferon and myeloid-related inflammatory responses in untreated patients compared to healthy controls, which rapidly decreased following canakinumab injection, reaching levels comparable to those of healthy controls. At least one adverse event (AE) was detected in all nine patients; most of them being mild in intensity, with infections being the most frequent AE. Serious AEs were reported in four patients. CONCLUSIONS: This study demonstrated the efficacy and safety of canakinumab treatment to control active HIDS and to suppress inflammatory transcriptional responses.


Posted June 15th 2017

A Phase 1, Open-Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS-102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil.

Carlos Becerra M.D.

Carlos Becerra M.D.

Becerra, C. R., K. Yoshida, H. Mizuguchi, M. Patel and D. Von Hoff (2017). “A phase 1, open-label, randomized, crossover study evaluating the bioavailability of tas-102 (trifluridine/tipiracil) tablets relative to an oral solution containing equivalent amounts of trifluridine and tipiracil.” J Clin Pharmacol 57(6): 751-759.

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TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 x 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-infinity and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors.