Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Cost-effectiveness of mass screening for dipstick hematuria in Japan.

BACKGROUND: Dipstick urine tests are a simple and inexpensive method for detecting kidney and urological diseases, such as IgA nephropathy and bladder cancer. The nationwide mass screening program, Specific Health Checkup (SHC), started in Japan in 2008 and targeted all adults between 40 and 74 years of age. Dipstick urine tests for proteinuria and glucosuria are mandatory as part of the SHC, but dipstick urine tests for hematuria are not. However, the dipstick hematuria test is often administered simultaneously with these mandatory tests by some health insurers. Hematuria is common in Japanese general screening participants, particularly elderly women, and the necessity of mass screening using the dipstick hematuria test has been discussed. This study aimed to evaluate the cost-effectiveness of mass screening for dipstick hematuria tests in addition to the SHC. METHODS: Using a decision tree and Markov modeling, we conducted a cost-effectiveness analysis from a Japanese societal perspective. RESULTS: Compared with the current SHC, mass screening for dipstick hematuria tests, in addition to the SHC, costs less and gains more, which means cost-saving. Similar findings were observed in the sex-specific analysis. CONCLUSION: Our results suggest that mandating the dipstick hematuria test could be justifiable as an efficient use of finite healthcare resources. The results have implications for mass screening programs not only in Japan but worldwide.

Possible burden of hyperuricaemia on mortality in a community-based population: a large-scale cohort study.

Hyperuricaemia is a risk for premature death. This study evaluated the burden of hyperuricaemia (serum urate > 7 mg/dL) for all-cause and cardiovascular mortality in 515,979 health checkup participants using an index of population attributable fraction (PAF). Prevalence of hyperuricaemia at baseline was 10.8% in total subjects (21.8% for men and 2.5% for women). During 9-year follow-up, 5952 deaths were noted, including 1164 cardiovascular deaths. In the Cox proportional hazard analysis adjusted for confounding factors, hyperuricaemia was independently associated with all-cause and cardiovascular mortality (adjusted hazard ratios [95% confidence interval]; 1.36 [1.25-1.49] and 1.69 [1.41-2.01], respectively). Adjusted PAFs of hyperuricaemia for all-cause and cardiovascular deaths were 2.9% and 4.4% (approximately 1 in 34 all-cause deaths and 1 in 23 cardiovascular deaths), respectively. In the subgroup analysis, the association between hyperuricaemia and death was stronger in men, smokers, and subjects with renal insufficiency. Adjusted PAFs for all-cause and cardiovascular deaths were 5.3% and 8.1% in men; 5.8% and 7.5% in smokers; and 5.5% and 7.3% in subjects with renal insufficiency. These results disclosed that a substantial number of all-cause and cardiovascular deaths were statistically relevant to hyperuricaemia in the community-based population, especially men, smokers, and subjects with renal insufficiency.

The Population-Attributable Fraction for Premature Mortality Due to Cardiovascular Disease Associated With Stage 1 and 2 Hypertension Among Japanese.

BACKGROUND: Our aim was to assess how the population-attributable fraction (PAF) for premature mortality due to cardiovascular disease (CVD) associated with hypertension changes if blood pressure (BP) thresholds for hypertension were lowered from systolic/diastolic BP ≥140/90 mm Hg to ≥130/80 mm Hg, as defined using the 2017 American College of Cardiology/American Heart Association blood pressure guideline. METHODS: Analyses were conducted using a database of participants who underwent a national health checkup examination started in 2008 in Japan (n = 510,238; mean age, 59.6 ± 8.1 years; 42% men). Each participant was categorized as having normal or elevated BP, or stage 1 or 2 hypertension according to the guideline. Data on premature mortality due to CVD occurring before age 70 years were available through March 2015. RESULTS: Over a median follow-up of 3.4 years, 739 deaths from CVD occurred. After multivariable adjustment, hazard ratios for premature CVD mortality for elevated BP, stage 1 hypertension, and stage 2 hypertension vs. normal BP were 1.02 (95% confidence interval, 0.72, 1.44), 1.33 (1.02, 1.75), and 2.41 (1.90, 3.05), respectively. The PAF associated with stage 1 and 2 hypertension was 4.4% and 39.4%, respectively. CONCLUSIONS: In the current nationwide study of Japanese adults, stage 1 and 2 hypertension were associated with an increased risk for premature CVD mortality. The PAF for premature CVD mortality associated with hypertension increased by 4.4% if BP thresholds for hypertension were lowered from systolic/diastolic BP ≥140/90 to ≥130/80 mm Hg.

Budget impact analysis of chronic kidney disease mass screening test in Japan.

BACKGROUND: Our recently published cost-effectiveness study on chronic kidney disease mass screening test in Japan evaluated the use of dipstick test, serum creatinine (Cr) assay or both in specific health checkup (SHC). Mandating the use of serum Cr assay additionally, or the continuation of current policy mandating dipstick test only was found cost-effective. This study aims to examine the affordability of previously suggested reforms. METHODS: Budget impact analysis was conducted assuming the economic model would be good for 15 years and applying a population projection. Costs expended by social insurers without discounting were counted as budgets. RESULTS: Annual budget impacts of mass screening compared with do-nothing scenario were calculated as ¥79-¥-1,067 million for dipstick test only, ¥2,505-¥9,235 million for serum Cr assay only and ¥2,517-¥9,251 million for the use of both during a 15-year period. Annual budget impacts associated with the reforms were calculated as ¥975-¥4,129 million for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥963-¥4,113 million for mandating serum Cr assay only and abandoning dipstick test. CONCLUSIONS: Estimated values associated with the reform from ¥963-¥4,129 million per year over 15 years are considerable amounts of money under limited resources. The most impressive finding of this study is the decreasing additional expenditures in dipstick test only scenario. This suggests that current policy which mandates dipstick test only would contain medical care expenditure.

Electrocardiographic assessment of incident atrial fibrillation in hemodialysis patients.

The prevalence and incidence of atrial fibrillation in hemodialysis patients have recently increased, but there are few evident predictors of incident atrial fibrillation in hemodialysis patients. The purpose of this study was to determine whether electrocardiographic findings can predict the development of atrial fibrillation in hemodialysis patients. A cohort of 299 patients (age, 63.1 ± 14.0 years; men, 59.2%; duration of hemodialysis, 80.3 ± 77.7 months) on hemodialysis therapy in December 2004 was included. To determine the incidence of atrial fibrillation, electrocardiographic findings were checked regularly every 1-3 months through December 2009. To detect paroxysmal atrial fibrillation, we examined electrocardiograms any time a patient had cardiac symptoms. Cox proportional hazard analysis was used to determine independent variables for the onset of atrial fibrillation. At the time of enrollment, 37 patients had pre-existing atrial fibrillation, for a prevalence rate of 12.4%. On the other hand, newly developed atrial fibrillation during the 5-year follow-up was determined in 45 patients, for an incidence rate of 4.37/100 patient-years. In multivariate analysis, age (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07) and the presence of a P-terminal force >0.04 mm/s as an electrocardiographic finding (hazard ratio, 4.89; 95% confidence interval, 2.54 to 9.90) were independently associated with new-onset atrial fibrillation. The prevalence and incidence rates of atrial fibrillation are high in maintenance hemodialysis patients. Age and the presence of a P-terminal force >0.04 mm/s as an electrocardiographic finding may predict new-onset atrial fibrillation in these patients.