BY RIPAL GANDHI, MD, FSIR, AND SUVRANU GANGULI, MD, FSIR FALL 2020
This column alerts SIR members to abstracts that may have an impact on their practice and how they converse with referring clinicians. If you would like to suggest abstracts you feel should be included, email us at email@example.com or firstname.lastname@example.org.
Mortality and paclitaxel-coated devices: An individual patient data meta-analysis.
Circulation. 2020 Jun 9;141(23):1859-1869. doi: 10.1161/CIRCULATIONAHA.119.044697. Epub 2020 May 6.
Krishna J Rocha-Singh, Sue Duval, Michael R Jaff, Peter A Schneider, Gary M Ansel, Sean P Lyden, Christopher M Mullin, John P A Ioannidis, Sanjay Misra, Abraham R Tzafriri, Elazer R Edelman, Juan F Granada, Christopher J White, Joshua A Beckman, VIVA Physicians, Inc.
Background: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality.
Methods: Manufacturers of U.S. Food and Drug Administration-approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality and drug dose mortality were assessed.
Results: A total of 2,185 subjects and 386 deaths from eight PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6%–80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%–58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose–mortality association was identified.
Conclusions: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.
Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
Richard S Finn, Shukui Qin, Masafumi Ikeda, Peter R Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, Valeriy Breder, Philippe Merle, Ahmed O Kaseb, Daneng Li, Wendy Verret, Derek-Zhen Xu, Sairy Hernandez, Juan Liu, Chen Huang, Sohail Mulla, Yulei Wang, Ho Yeong Lim, Andrew X Zhu, Ann-Lii Cheng, IMbrave150 Investigators
Background: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The co-primary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (Aug. 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42–0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3–73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2–64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7–8.3) and 4.3 months (95% CI, 4.0–5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47–0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.
Conclusions: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.)
Intravascular ultrasound pulmonary artery denervation to treat pulmonary arterial hypertension (TROPHY1): Multicenter, early feasibility study
JACC Cardiovasc Interv. 2020 Apr 27;13(8):989-999. doi: 10.1016/j.jcin.2019.12.027.
Alexander M K Rothman, Jean-Luc Vachiery, Luke S Howard, Ghada W Mikhail, Irene M Lang, Michael Jonas, David G Kiely, Dalit Shav, Or Shabtay, Avital Avriel, Gregory D Lewis, Erika B Rosenzweig, Ajay J Kirtane, Nick H Kim, Ehtisham Mahmud, Vallerie V McLaughlain, Stanley Chetcuti, Martin B Leon, Ori Ben-Yehuda, Lewis J Rubin
Objectives: The aim of this study was to investigate whether therapeutic intravascular ultrasound pulmonary artery denervation (PDN) is safe and reduces pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) on a minimum of dual oral therapy.
Background: Early studies have suggested that PDN can reduce PVR in patients with PAH.
Methods: TROPHY1 (Treatment of Pulmonary Hypertension 1) was a multicenter, international, open-label trial undertaken at eight specialist centers. Patients 18–75 years of age with PAH were eligible if taking dual oral or triple nonparenteral therapy and not responsive to acute vasodilator testing. Eligible patients underwent PDN (TIVUS System). The primary safety endpoint was procedure-related adverse events at 30 days. Secondary endpoints included procedure-related adverse events, disease worsening and death to 12 months, and efficacy endpoints that included change in pulmonary hemodynamic status, 6-min walk distance, and quality of life from baseline to 4 or 6 months. Patients were to remain on disease-specific medication for the duration of the study.
Results: Twenty-three patients underwent PDN, with no procedure-related serious adverse events reported. The reduction in PVR at 4- or 6-month follow-up was 94 ± 151 dyn·s·cm-5 (p = 0.001) or 17.8%, which was associated with a 42 ± 63 m (p = 0.02) increase in 6-min walk distance and a 671 ± 1,555 step (p = 0.04) increase in daily activity.
Conclusions: In this multicenter early feasibility study, PDN with an intravascular ultrasound catheter was performed without procedure-related adverse events and was associated with a reduction in PVR and increases in 6-min walk distance and daily activity in patients with PAH on background dual or triple therapy.
Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): A multicentre, randomised, sham-controlled trial
Lancet. 2020 May 2;395(10234):1444-1451. doi: 10.1016/S0140-6736(20)30554-7. Epub 2020 Mar 29.
Michael Böhm, Kazuomi Kario, David E Kandzari, Felix Mahfoud, Michael A Weber, Roland E Schmieder, Konstantinos Tsioufis, Stuart Pocock, Dimitris Konstantinidis, James W Choi, Cara East, David P Lee, Adrian Ma, Sebastian Ewen, Debbie L Cohen, Robert Wilensky, Chandan M Devireddy, Janice Lea, Axel Schmid, Joachim Weil, Tolga Agdirlioglu, Denise Reedus, Brian K Jefferson, David Reyes, Richard D'Souza, Andrew S P Sharp, Faisal Sharif, Martin Fahy, Vanessa DeBruin, Sidney A Cohen, Sandeep Brar, Raymond R Townsend, SPYRAL HTN-OFF MED Pivotal Investigators
Background: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications.
Methods: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the U.K. and the United States, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749.
Findings: From June 25, 2015, to Oct. 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months.
Interpretation: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications.