Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial.

BACKGROUND: Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR. METHODS: At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT®) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: ≥ 12% + ≥ 200 mL above baseline (criterion A), ≥ 15% above baseline (criterion B); and ≥ 10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups. RESULTS: 5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 ± 0.44 L (47.6 ± 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used. CONCLUSIONS: A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.

Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.

BACKGROUND: Gender differences may occur in many chronic diseases. We have examined the influence of gender in chronic obstructive pulmonary disease (COPD) on long-term responses to tiotropium. METHODS: Subgroup analysis of data from the Understanding the Potential Long-term Impact of Tiotropium (UPLIFT) trial (4-year, randomized, double-blind, placebo-controlled trial of tiotropium in patients with COPD). RESULTS: Of 5992 patients, 75% were men and 25% women. Mean age was 65 and 63 years, respectively. Baseline post-bronchodilator forced expiratory volume in 1s (FEV(1))=47% predicted(men) and 49% predicted(women). St George's Respiratory Questionnaire (SGRQ) total score was 44.9 and 48.7units, respectively. At 48 months, improvement in trough FEV(1) over control was 92mL(men) and 77mL(women) (p<0.001 for both), with no differences in the rate of decline (trial primary endpoint). Hazard ratio (HR) (95% confidence interval [CI]) for first exacerbation (tiotropium/placebo) was 0.87(0.81, 0.93)(men) and 0.83(0.74, 0.94)(women). Number of exacerbations (per patient-year) was reduced with tiotropium in men (from 0.82 to 0.71) and women (from 0.92 to 0.77) (p<0.005 for both). HR (95% CI) for a hospitalized exacerbation was 0.89(0.79, 0.99) and 0.77(0.62, 0.94), respectively. HR (95% CI) for mortality during treatment was 0.85(0.72, 0.99)(men) and 0.85(0.62, 1.18)(women). Improvements in SGRQ total score (tiotropium-control) at 1, 2, 3 and 4 years were: -2.8, -2.3, -3.6, -2.4(men) and -2.7, -2.6, -2.6, -2.1(women) (p<0.05 for all). CONCLUSION: Long-term treatment of COPD with tiotropium improves lung function, exacerbations and health status in men and women, with similar magnitudes of benefit. Boehringer Ingelheim trial 205.235; ClinicalTrials.gov: NCT00144339.

Effects of bariatric surgery on mortality in Swedish obese subjects.

BACKGROUND: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality. METHODS: The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%). RESULTS: The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). CONCLUSIONS: Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.

Porcine transfer study: virtual reality simulator training compared with porcine training in endovascular novices.

PURPOSE: To compare the learning of endovascular interventional skills by training on pig models versus virtual reality simulators. METHODS: Twelve endovascular novices participated in a study consisting of a pig laboratory (P-Lab) and a virtual reality laboratory (VR-Lab). Subjects were stratified by experience and randomized into four training groups. Following 1 hr of didactic instruction, all attempted an iliac artery stenosis (IAS) revascularization in both laboratories. Onsite proctors evaluated performances using task-specific checklists and global rating scales, yielding a Total Score. Participants completed two training sessions of 3 hr each, using their group's assigned method (P-Lab x 2, P-Lab + VR-Lab, VR-Lab + P-Lab, or VR-Lab x 2) and were re-evaluated in both laboratories. A panel of two highly experienced interventional radiologists performed assessments from video recordings. ANCOVA analysis of Total Score against years of surgical, interventional radiology (IR) experience and cumulative number of P-Lab or VR-Lab sessions was conducted. Inter-rater reliability (IRR) was determined by comparing proctored scores with the video assessors in only the VR-Lab. RESULTS: VR-Lab sessions improved the VR-Lab Total Score (beta = 3.029, p = 0.0015) and P-Lab Total Score (beta = 1.814, p = 0.0452). P-Lab sessions increased the P-Lab Total Score (beta = 4.074, p < 0.0001) but had no effect on the VR-Lab Total Score. In the general statistical model, both P-Lab sessions (beta = 2.552, p = 0.0010) and VR-Lab sessions (beta = 2.435, p = 0.0032) significantly improved Total Score. Neither previous surgical experience nor IR experience predicted Total Score. VR-Lab scores were consistently higher than the P-Lab scores (Delta = 6.659, p < 0.0001). VR-Lab IRR was substantial (r = 0.649, p < 0.0008). CONCLUSIONS: Endovascular skills learned in the virtual environment may be transferable to the real catheterization laboratory as modeled in the P-Lab.

Assessment of a virtual interventional simulator trainer.

PURPOSE: To assess the construct validity of the Procedicus Virtual Interventional Simulator Trainer (Procedicus-VIST) and its use as a training tool. METHODS: Two groups comprised of 8 interventional radiologists (experts) and 8 medical students (novices) performed 6 renal artery procedures on the Procedicus-VIST. All participants received a 45-minute standardized didactic introduction before starting the simulations. The first 2-hour session was used for familiarization, whereas the second session constituted the testing period. During each procedure, objective performance data including procedure time, fluoroscopic time, contrast, cine loops, lesion coverage, tool:lesion ratio, placement accuracy, and residual stenosis were recorded by the Procedicus-VIST software. Exit surveys were completed to document demographic and subjective data. A visual analogue scale (VAS) from 0 to 100 was used to rate total, guidewire, catheter, balloon, stent, fluoroscopic, and joystick realism, as well as the simulator's pedagogic value. RESULTS: There were no significant differences in performances between the 2 groups in residual stenosis, placement accuracy, procedure time, number of cine loops, lesion coverage, or tool:lesion ratio. The total fluoroscopic use was greater for the novice group (p < 0.01). Experts rated 6 of the 8 subjective parameters favorably, whereas the novice group approved of 7. CONCLUSIONS: Using this study design, the quantitative metrics recorded by the Procedicus-VIST software failed to stratify performances based upon experience level, with the exception of fluoroscopic use. Investigation comparing standard training to virtual reality training should be performed to assess any differences in actual performance in the catheterization laboratory.