Management and outcome of 500 multiple myeloma patients treated for first relapse outside clinical studies.

Treatment options for multiple myeloma (MM) at 1st relapse are expanding. The current study compared common 2nd line regimens administered in a real-world setting. MM patients registered in Maccabi health care services and treated with second line therapy during 2014-2020 were evaluated, analyzing factors affecting time to third line therapy (TT3T). The study included 500 MM patients, previously treated with proteasome inhibitor (PI)-based induction. Median age at second line treatment was 68.5 years (IQR: 61.6-76.4). Most patients received a triplet based induction composed of PI (n = 471, 94.2%), with (n = 71) or without IMID (n = 400), followed by second line treatment composed of lenalidomide-dexamethasone (RD) (n = 225, 45%) or lenalidomide-dexamethasone-daratumumab (RD-Dara (n = 104, 20.8%)). Multivariable analysis confirmed treatment type (RD-Dara vs. IMID) to be associated with a lower risk to progress to third line therapy; (HR = 0.5, 95% CI 0.3-0.86, p = 0.012). Within a median follow-up period of 22.5 months (intraquartile range 11.1-39.4 m), median TT3T was not reached in patients receiving RD-Dara vs. 32.4 months (95% CI 18.0-46.8 m) with IMID, 18 months (95% CI 10.4-25.6 m) with IMID-PI and 12.1 months (95% CI 5.6-18.7 m) with PI-based regimen. In contrast, PI vs. IMID-based therapy and increased body weight were associated with a higher likelihood of progression (HR = 2.56 (95% CI 1.49-4.42); HR = 1.43, (95% CI 0.96-2.14), p = 0.08). To conclude, second line therapy with RD-Dara was associated with a significantly longer TT3T compared with IMID-based regimen, longer than obtained with PI-IMID and PI-based regimens, in patients treated outside clinical studies and previously exposed to bortezomib.

The epidemiology and burden of gastroparesis: Real-world data from a large healthcare provider in Israel.

BACKGROUND: Gastroparesis is a gastrointestinal motility dysfunction characterized by delayed gastric emptying in the absence of gastric mechanical obstruction. Data on the epidemiology of gastroparesis are sparse even though the condition substantially impairs patients' quality of life. The aim of this study was to describe the epidemiology and estimate the short-term healthcare resource use burden of gastroparesis in a large population. METHODS: This cross-sectional study utilized computerized data from Maccabi Healthcare Services, a 2.5-million member state-mandated health organization in Israel. Data were collected between 2003 and 2018 to assess the prevalence of gastroparesis. Definite gastroparesis was defined by gastroparesis diagnosis and gastric emptying test. Probable gastroparesis was defined by gastroparesis diagnosis only. To compare the healthcare resource utilization (HCRU), data were also collected on controls that were individually matched (1:2) for age, sex, and comorbidities. KEY RESULTS: A total of 522 patients with gastroparesis were identified (21.1 per 100,000 WHO age-standardized), including 204 with definite gastroparesis (8.6 per 100,000 WHO). Male to female ratio was 1:2 and mean ± SD age of 54.7 ± 17.1 years. Diabetes accounted for 25.9% of gastroparesis cases and the rest were idiopathic. Gastroparesis patients were more likely to have cardiovascular diseases (10% vs. 6.9% for controls, p = 0.034) and lower prevalence of obesity (17% vs. 24.4%, p < 0.001). HCRU within the 2 years after index date were higher with more hospitalizations than controls (26.4% vs. 15.4%, p < 0.001), and more emergency room visits (31.6% vs. 24.1%, p = 0.002). CONCLUSIONS & INFERENCES: Gastroparesis is uncommon or under-documented in community care settings. Gastroparesis in general is associated with cardiovascular morbidities, lower BMI, and elevated utilization of healthcare services.

Resistant hypertension is associated with an increased cardiovascular risk compared to patients controlled on a similar multi-drug regimen.

The long-term risk associated with resistant hypertension compared to other phenotypes of hypertension is still unclear. We aimed to assess cardiovascular and renal outcomes over 10 years of follow-up of patients with uncontrolled resistant hypertension (uRH) compared to a similarly treated (≥ 3 medication classes including a diuretic) and adherent group whose blood pressure is under control. This retrospective cohort study utilized the computerized database of Maccabi Healthcare Services, a state-mandated health provider covering 25% of the Israeli population. Clinical outcomes were assessed using Cox regression multivariable analyses. A total of 1487 patients (50% males, mean age at baseline = 68.3 ± 10.4 years) were included in the uRH cohort and 1343 patients (50% males, 66.2 ± 10.6 years) in the controlled hypertension reference group (Controlled hypertension on multi drug regimen- CH-MDR). After adjusting for age, sex, BMI and patients' comorbidities, uRH was associated with a Hazard Ratio of 1.35 (95% CI: 1.08-1.69) for incidence of ischemic heart disease, 1.51 (1.06-2.16) for secondary cardiovascular events, and 1.36 (1.00-1.86) for risk of stroke or transient ischemic attack compared to the reference group. Patients with uRH were found to have more hospitalization days (mean, 4.2 vs. 3 days per year, p < 0.001), and more emergency room visits (83.3% vs. 77%, p < 0.001). Overall, uRH was associated with a 19% (95% CI 11% to 29%) increase in direct healthcare expenditures during the first year of follow-up. uRH is associated with a substantial increased risk of both cardiovascular and cerebrovascular events, when compared to similarly treated hypertensive patients whose blood pressure is under control.

Lifetime risk, life expectancy, and years of life lost to type 2 diabetes in 23 high-income jurisdictions: a multinational, population-based study.

BACKGROUND: Diabetes is a major public health issue. Because lifetime risk, life expectancy, and years of life lost are meaningful metrics for clinical decision making, we aimed to estimate these measures for type 2 diabetes in the high-income setting. METHODS: For this multinational, population-based study, we sourced data from 24 databases for 23 jurisdictions (either whole countries or regions of a country): Australia; Austria; Canada; Denmark; Finland; France; Germany; Hong Kong; Hungary; Israel; Italy; Japan; Latvia; Lithuania; the Netherlands; Norway; Scotland; Singapore; South Korea; Spain; Taiwan; the UK; and the USA. Our main outcomes were lifetime risk of type 2 diabetes, life expectancy in people with and without type 2 diabetes, and years of life lost to type 2 diabetes. We modelled the incidence and mortality of type 2 diabetes in people with and without type 2 diabetes in sex-stratified, age-adjusted, and calendar year-adjusted Poisson models for each jurisdiction. Using incidence and mortality, we constructed life tables for people of both sexes aged 20-100 years for each jurisdiction and at two timepoints 5 years apart in the period 2005-19 where possible. Life expectancy from a given age was computed as the area under the survival curves and lifetime lost was calculated as the difference between the expected lifetime of people with versus without type 2 diabetes at a given age. Lifetime risk was calculated as the proportion of each cohort who developed type 2 diabetes between the ages of 20 years and 100 years. We estimated 95% CIs using parametric bootstrapping. FINDINGS: Across all study cohorts from the 23 jurisdictions (total person-years 1 577 234 194), there were 5 119 585 incident cases of type 2 diabetes, 4 007 064 deaths in those with type 2 diabetes, and 11 854 043 deaths in those without type 2 diabetes. The lifetime risk of type 2 diabetes ranged from 16·3% (95% CI 15·6-17·0) for Scottish women to 59·6% (58·5-60·8) for Singaporean men. Lifetime risk declined with time in 11 of the 15 jurisdictions for which two timepoints were studied. Among people with type 2 diabetes, the highest life expectancies were found for both sexes in Japan in 2017-18, where life expectancy at age 20 years was 59·2 years (95% CI 59·2-59·3) for men and 64·1 years (64·0-64·2) for women. The lowest life expectancy at age 20 years with type 2 diabetes was observed in 2013-14 in Lithuania (43·7 years [42·7-44·6]) for men and in 2010-11 in Latvia (54·2 years [53·4-54·9]) for women. Life expectancy in people with type 2 diabetes increased with time for both sexes in all jurisdictions, except for Spain and Scotland. The life expectancy gap between those with and without type 2 diabetes declined substantially in Latvia from 2010-11 to 2015-16 and in the USA from 2009-10 to 2014-15. Years of life lost to type 2 diabetes ranged from 2·5 years (Latvia; 2015-16) to 12·9 years (Israel Clalit Health Services; 2015-16) for 20-year-old men and from 3·1 years (Finland; 2011-12) to 11·2 years (Israel Clalit Health Services; 2010-11 and 2015-16) for 20-year-old women. With time, the expected number of years of life lost to type 2 diabetes decreased in some jurisdictions and increased in others. The greatest decrease in years of life lost to type 2 diabetes occurred in the USA between 2009-10 and 2014-15 for 20-year-old men (a decrease of 2·7 years). INTERPRETATION: Despite declining lifetime risk and improvements in life expectancy for those with type 2 diabetes in many high-income jurisdictions, the burden of type 2 diabetes remains substantial. Public health strategies might benefit from tailored approaches to continue to improve health outcomes for people with diabetes. FUNDING: US Centers for Disease Control and Prevention and Diabetes Australia.

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Diabetes, but not pre-diabetes, is associated with shorter time to second-line therapy and worse outcomes in patients with multiple myeloma.

About 20% of MM patients have T2DM. We assessed the impact of T2DM/pre-T2DM on MM progression and OS. We collected retrospective data of newly diagnosed MM patients in Maccabi health services, Israel, between 2012 and 2016. The study included 503 MM patients, median age 67.2 years (IQR: 33.5-91.2). Median follow-up was 32 months (IQR 19.4-47). T2DM and pre-T2DM were recorded in 24.1% and 51% patients, respectively. Median TT2T and OS in the cohort were 17.5 months (95% confidence interval (CI) 15-20) and unreached, respectively. T2DM patients had shorter TT2T (HR = 1.31, 95%CI 1.0-1.72, p=.047), particularly transplanted patients; 20.2 vs. 40 months (HR = 2.09, 95%CI 1.18-3.71, p=.012). In a multivariable model, T2DM had a borderline significant risk of all-cause mortality, adjusted HR 1.38 (p=.09). Pre-diabetes had no impact on TT2T or OS. T2DM predicted a shorter TT2T, particularly in transplanted patients, and tended to be associated with shorter survival.

Respiratory morbidity in very low birth weight infants through childhood and adolescence.

OBJECTIVE: To describe the long-term (up to 18 years of age) respiratory outcomes of children and adolescents born at very low birth weight (VLBW; ≤1500 g) in comparison with that of children born >1500 g. METHODS: An observational, longitudinal, retrospective study comparing VLBW infants with matched controls, registered at a large health maintenance organization in Israel. Pulmonary outcomes collected anonymously from the electronic medical files included respiratory illness diagnoses, purchased medications for respiratory problems, office visits with either a pediatric pulmonologist or cardiologist and composite respiratory morbidity combining all these parameters. RESULTS: Our study included 5793 VLBW infants and 11,590 matched controls born between 1998 and 2012. The majority (99%) of VLBW infants were premature (born < 37 weeks' gestation), while 93% of controls were born at term. The composite respiratory morbidity was significantly higher in VLBW infants compared with controls in all age groups (relative risk [95% confidence interval]: 1 year: 1.22 [1.19-1.26], <2 years: 1.30 [1.27-1.34], 2-6 years: 1.29 [1.27-1.32], 6-12 years: 1.53 [1.47-1.59], 12-18 years: 1.46 [1.35-1.56]; respectively). Both VLBW infants and controls demonstrated a steady decline in the composite respiratory morbidity with aging. In VLBW infants, lower gestational age was associated with higher respiratory morbidity only until 2 years of age and the morbidity declined in each gestational age group until adolescence. CONCLUSION: Our study confirmed a strong association between VLBW and pulmonary morbidity. The higher prevalence of respiratory composite morbidity in VLBW infants persists over the years until adolescence. The respiratory morbidity is most evident in the first year of life and declines afterward.

Trends in the incidence of diagnosed diabetes: a multicountry analysis of aggregate data from 22 million diagnoses in high-income and middle-income settings.

BACKGROUND: Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. METHODS: In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995-2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. FINDINGS: Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from -1·1% to -10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. INTERPRETATION: The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Long-Term Follow-Up of Denosumab Discontinuers with Multiple Vertebral Fractures in the Real-World: A Case Series.

Denosumab discontinuation is associated with rapid reversal of bone turnover suppression and with a considerable increase in fracture risk, including a risk for multiple vertebral fractures (MVF). Long-term follow-up of patients who sustained MVF after denosumab discontinuation has not been reported. This case-series was aimed to provide a long-term follow-up on the management and outcome of denosumab discontinuers who initially presented with multiple vertebral fractures. Denosumab discontinuers were identified from a computerized database of a large healthcare provider. Baseline and follow-up clinical, laboratory, and imaging data were obtained from the computerized database and electronic medical records. The post-denosumab discontinuers MVF patients consisted of 12 women aged 71±12. Osteoporotic fractures were prevalent before denosumab discontinuation in 6 of the patients. The majority received bisphosphonates before denosumab. MVF occurred 134±76 days after denosumab discontinuation. The patients were followed for a median of 36.5 (IQR 28.2, 42.5) months after MVF. Two patients passed-away. Two patients suffered recurrent vertebral fractures. Following MVF, patients were treated inconsistently with denosumab, teriparatide, oral, and intravenous bisphosphonates, in various sequences. Two patients underwent vertebroplasty/kyphoplasty. This long-term follow-up of real-world patients with MVF following denosumab discontinuation reveals that management is inconsistent, and recurrent fractures are not uncommon. It calls for clear management guidelines for patients with MVF after denosumab discontinuation and for special attention to this high-risk group.

The effects of continuous glucose monitoring system on patient outcomes and associated costs in a real-world setting.

AIMS: Continuous glucose monitoring system (CGMS) technologies may alert unaware hypoglycaemia or near hypoglycaemia events. However, costs are a significant concern in general CGMS use. This study describes the real-world effects of both clinical outcomes and associated costs in a major Health Maintenance Organization, 1 year following preauthorization of CGMS for each patient. METHODS: Cohort study. Type 1 diabetes patients who were preauthorized CGMS were identified, and their medical records during the year before preauthorization were compared to the following year. Data were collected for glucose control, medical services utilization and related costs. RESULTS: We identified 524 eligible patients, 57% males. Adherence to CGMS use was improved by age. The proportion of patients reaching HbA1c  < 7.5% (58 mmol/mol) increased in the high-adherence group and decreased in the low-adherence group. There were no significant changes in outpatient medical services utilization. However, there was a decrease in emergency room visit rates (30%-19%, p < 0.01) and hospitalization rates (22%-12%, p < 0.01) with the highest decrease among the high-adherence group. Hospitalization duration also decreased. However, the total costs per patient were higher as CGMS adherence increased. CONCLUSION: Continuous glucose monitoring system technologies have the potential of both improving blood glucose control and reducing inpatient utilization. However, CGMS technologies costs may put a significant burden on healthcare systems.