Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

The generalizability of observational data to elderly patients was dependent on the research question in a systematic review.

BACKGROUND AND OBJECTIVE: Despite the increasing use of data derived from randomized controlled trials (RCTs) to perform observational studies, little is known about the validity of this approach. We compared inferences from studies that were performed using Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) RCT data with those derived from studies using data from the population-based Cooperative Cardiovascular Project (CCP). METHODS: We performed a systematic review. Articles were included if similar study questions were addressed by at least one manuscript that used GUSTO data and one that used CCP data. RESULTS: GUSTO findings were disparate from CCP data regarding absolute rates of specific process or outcome measures, such as thrombolysis-associated intracranial hemorrhage (ICH) (0.65% versus 1.43%, respectively), atrial fibrillation (10% versus 21%, respectively), or use of beta-blockers (58% versus 37%, respectively). However, many important relations noted in GUSTO were corroborated by studies using CCP data. Both data sets identified similar predictors of ICH and presentation delay. The degree of variability in beta-blocker use (across geographic region) and angiography use (between genders) was remarkably similar when studied using CCP or GUSTO data. CONCLUSION: Inferences derived from GUSTO about treatment variations and risk factors for outcomes were generalizable to community patients.

Are critical pathways effective for reducing postoperative length of stay?

BACKGROUND: Many hospitals use critical pathways to attempt to reduce postoperative length of stay (PLOS) for diverse conditions and procedures. OBJECTIVE: To evaluate whether critical pathways were associated with reductions in postoperative PLOS after accounting for prepathway trends in PLOS. RESEARCH DESIGN: Retrospective cohort study, from 1988 to 1998. SETTING: Academic medical center department of surgery. SUBJECTS: A total of 10,960 admissions eligible for 1 of 26 critical pathways implemented from 1990 to 1996, from 2 years before to 2 years after each pathway implementation date. Coding definitions were developed and validated to identify admissions eligible for each pathway, and data were abstracted from the hospital's discharge database. MEASURE: A pathway was considered effective if, after its implementation, there was a statistically significant decrease in the prepathway trend for PLOS. RESULTS: Median number of annual eligible admissions per pathway was 59 (range, 18-706). Median PLOS for the prepathway periods was 8 days (interquartile range, 5-10 days). For 16 (62%) pathways, PLOS was already declining in the prepathway period. After adjusting for demographics, comorbidity, admission characteristics, and prepathway time trends in PLOS, 7 (27%) pathways were associated with a significant postimplementation decrease in the rate of change in PLOS (range among the 7 pathways, 5-45% decrease) and none with a significant increase from the prepathway trend for PLOS. CONCLUSION: Critical pathways may decrease postoperative stay for some, but not all, surgeries. Trends toward decreasing length of stay over time may reduce the impact of critical pathways on this outcome.

Understanding individual and small area variation in the underuse of coronary angiography following acute myocardial infarction.

BACKGROUND: Underuse of coronary angiography is common among patients with acute myocardial infarction (AMI) and the magnitude of underuse varies across geographic areas. OBJECTIVES: To examine the influence of patient demographic, clinical and hospital characteristics on underuse of coronary angiography, and the contribution of these factors to variation in underuse across geographic regions. RESEARCH DESIGN: Cohort study using data from the Cooperative Cardiovascular Project. SUBJECTS: Nine thousand four hundred fifty-eight patients in 95 hospital referral regions (HRRs) hospitalized for AMI in 1994 to 1995 and for whom angiography was rated necessary. MEASURES: Odds ratios (95% confidence intervals) associated with underuse of angiography according to patient and hospital characteristics. The difference between low and high rates of underuse of angiography across regions after controlling for regional differences in patient and hospital characteristics. RESULTS: Of those for whom angiography was rated necessary, 42% did not undergo the procedure. Underuse of angiography was associated with several patient demographic and hospital attributes (eg, female gender, black race, treatment in a hospital without angiography, treatment by a general practitioner) as well as with prevalent clinical characteristics, such as renal insufficiency, congestive heart failure, prior coronary artery bypass surgery, and chronic obstructive pulmonary disease. Across HRRs, variation in underuse ranged from 24.0% to 58.3%. The difference between low and high rates did not decline significantly after controlling for regional differences in patient or hospital characteristics. CONCLUSIONS: At the patient-level, rates of necessary angiography may be improved if we address disparities in care related to sociodemographic characteristics and to the technological capabilities of hospitals. In addition, practice guidelines should be updated to reflect clinical concerns about the risks and benefits of angiography and subsequent revascularization in certain patient sub-groups, both to provide appropriate guidance to physicians and to facilitate better estimates of underuse. The causes of regional variation in underuse do not appear to be related to regional differences in patient or hospital characteristics, and therefore, require further study.

Impact of gender on access to the renal transplant waiting list for pediatric and adult patients.

While the public and policy-makers place a priority on equity in the organ allocation process, several studies suggest that women may be less likely than men to receive a renal transplant. However, the cause of this disparity and whether it exists among children with end-stage renal disease (ESRD) are unknown. To address these issues, two nationally representative cohorts of incident patients were examined: (1) 7594 adults with ESRD onset between 1986 and 1993 for whom detailed data were available from the medical record on health status; and (2) 3217 patients <20 yr old who developed ESRD between 1988 and 1993. Patients were followed from initiation of dialysis for up to 10 yr until first activation on the United Network of Organ Sharing renal transplant waiting list. Access to the list for female and male patients with ESRD was compared using Cox proportional hazards models with adjustment for demographic, socioeconomic, and clinical factors. Crude rates of wait-listing per 100 person-years of ESRD were lower for female patients than male patients in both the pediatric (28.89 versus 34.18) and adult (3.94 versus 6.54) populations. Despite adjustment for numerous confounding factors, this gender-based disparity persisted in multivariate analysis. Among children with ESRD, female patients were 14% less likely to be listed than male patients (relative hazard [RH] 0.86; 95% confidence interval [CI], 0.78 to 0.93), and in the adult group, women were 18% less likely to be activated for transplant than men (RH 0.82; 95% CI, 0.72 to 0.93). These findings suggest that female patients of all ages with ESRD face barriers in being activated for cadaveric renal transplantation. Greater attention to this issue is necessary to improve equity in the organ allocation system and potentially improve the outcomes of female patients with ESRD.