A retrospective longitudinal cohort study of the clinical burden in myasthenia gravis.

BACKGROUND: Patients with generalized myasthenia gravis (MG) often experience debilitating exacerbations, with the possibility of life-threatening respiratory crises requiring hospitalization. Long-term longitudinal studies are needed to understand the burden of MG, including in patients whose disease is refractory to conventional treatment. METHODS: A retrospective, longitudinal, cohort study was conducted of patients in England aged ≥ 18 years with treatment-refractory or non-refractory MG, using data recorded during 1997-2016 in the Clinical Practice Research Datalink and the Hospital Episode Statistics databases. A control cohort of patients without MG, matched to the patients in the treatment-refractory MG cohort, was also identified. Outcome measures included myasthenic crises, MG exacerbations, MG-related hospitalizations, comorbidities, and all-cause mortality. Descriptive statistics were calculated for the overall MG population. For continuous variables, between-cohort comparisons were made using t tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data. For categorical data, the comparisons were made by chi-squared tests. Differences in clinical outcomes between cohorts were modeled using negative binomial regression. RESULTS: A total of 1149 patients with MG were included. Overall, 18.4% of patients experienced myasthenic crises, 24.6% experienced exacerbations, and 38.6% underwent MG-related hospitalizations. Most of these events occurred within 2-3 years of diagnosis. Patients with MG refractory to conventional treatment (n = 66) experienced more exacerbations and MG-related hospitalizations than patients with non-refractory disease (n = 1083). Patients with refractory MG experienced a higher frequency of renal disease and hypertension compared with patients with non-refractory MG, and with matched patients without MG. They were also more likely to have diabetes and congestive heart failure than the matched controls. Rates of all-cause mortality during the follow-up period did not differ between patients with refractory MG and non-refractory MG. CONCLUSIONS: These results show that conventional treatments for MG are not adequately managing patients' symptoms and that patients with refractory MG are more likely to experience certain comorbidities than those with non-refractory MG or matched controls without MG. Future research should focus on the impact of newer targeted therapies on long-term clinical outcomes and comorbid conditions.

Impact of Cardio-Renal-Metabolic Comorbidities on Cardiovascular Outcomes and Mortality in Type 2 Diabetes Mellitus.

BACKGROUND: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. METHODS: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. RESULTS: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. CONCLUSION: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

Prodromal symptoms of multiple sclerosis in primary care.

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Epidemiology and health outcomes associated with hyperkalemia in a primary care setting in England.

BACKGROUND: Real-world incidence, clinical consequences, and healthcare resource utilization (HRU) of hyperkalemia (HK) remain poorly characterized, particularly in patients with specific comorbidities. METHODS: Data from the Clinical Practice Research Datalink and Hospital Episode Statistics databases were analyzed to determine incidence of an index HK event, subsequent clinical outcomes, and HRU in the English population. Factors associated with index HK in a primary care setting were also identified for those with an index HK event during the study period (2009-2013) and matched controls. RESULTS: The overall incidence rate of an index HK event was 2.9 per 100 person-years. Use of renin-angiotensin-aldosterone system inhibitors was strongly associated with HK (odds ratio, 13.6-15.9). Few patients (5.8%) had serum potassium (K+) retested ≤ 14 days following the index event; among those retested, 32% had HK. Following an index HK event, all-cause hospitalization, HK recurrence, and kidney function decline were the most common outcomes (incidence rates per 100 person-years: 14.1, 8.1, and 6.7, respectively), with higher rates in those with comorbidities or K+ > 6.0 mmol/L. Mortality and arrhythmia rates were higher among those with K+ > 6.0 mmol/L. Older age, comorbid diabetes mellitus, and mineralocorticoid receptor antagonist use were associated with HK recurrence. Relatively few patients received testing or prescriptions to treat HK following an event. CONCLUSIONS: Severe index HK events were associated with adverse outcomes, including arrhythmia and mortality. Despite this, retesting following an index event was uncommon, and incidence of recurrence was much higher than that of the index event.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Incidence of urinary tract infection following initiation of intermittent catheterization among patients with recent spinal cord injury in Germany and the Netherlands.

Objective: To assess incidence of urinary tract infection (UTI) among patients with recent spinal cord injury (SCI) who initiated intermittent catheterization (IC).Design: Retrospective chart review.Setting: Two European SCI rehabilitation centers.Participants: Seventy-three consecutive patients with recent SCI who initiated IC.Outcome measures: Incidence of UTI, using six different definitions, each based on microbiology ± symptomatology ± mention of UTI . Rates were expressed in terms of numbers of UTIs per 100 patient-months (PMs). Attention was focused on first-noted UTI during the three-month follow-up, as assessed with each of the six definitions.Results: Fifty-eight percent of patients (n = 33) met ≥1 definitions for UTI during follow-up (rate: 31.5 UTIs per 100 PMs), ranging from 14% (5.3 per 100 PMs; definition requiring bacteriuria, pyuria, and presence of symptoms) to 45% (22.7 per 100 PMs; definition requiring "mention of UTI"). Ten cases were identified using the definition that required bacteriuria, pyuria, and symptoms, whereas definitions that required bacteriuria and either pyuria or symptoms resulted in the identification of 20-25 cases. Median time to UTI ranged from 42 days ("mention of UTI") to 81 days (definition requiring bacteriuria and ≥100 leukocytes/mm3).Conclusion: Depending on definition, 14% to 45% of patients with recent SCI experience UTI within three months of initiating IC. Definitions requiring bacteriuria and either pyuria or symptoms consistently identified about twice as many cases as those that required all three conditions. Standardizing definitions may help improve detection, treatment, and prevention of UTI within this vulnerable population.

Increasing cancer risk over calendar year in people with multiple sclerosis: a case-control study.

BACKGROUND: Data on cancer prevalence and incidence in multiple sclerosis (MS) patients are controversial. This study is aimed at estimating cancer risk in MS patients. METHODS: Nested case-control study using data collected between 01/01/1987 and 28/02/2016 from the United Kingdom Clinical Practice Research Datalink. Cancer diagnoses after first MS code (index date) was counted in 10,204 MS patients and 39,448 controls matched by sex, age, general practitioner, and registration year. Cancer rates were compared using multivariable Cox regression models. Ethics approval was not required. RESULTS: Cancer was reported in 433 (4.41%) MS patients and 2014 (5.31%) controls after index date. Cancer risk was associated with gender (HR for female = 0.88, 95% CI = 0.81-0.96, p = 0.004), age at index date (HR = 1.06, 95% CI = 1.06-1.07, p < 0.001), and index year (HR = 1.01, 95% CI = 1.00-1.02, p = 0.016), but not with MS status (HR = 0.95, 95% CI = 0.86-1.05, p = 0.323). A significant interaction between MS status and index year was found (HR = 1.02, 95% CI = 1.00-1.04, p = 0.022). Cancer risk was positively associated with index year among MS patients (HR = 1.03, 95% CI = 1.01-1.05; p = 0.010), but not controls (HR = 1.01, 95% CI = 0.99-1.02; p = 0.144). MS patients compared to controls had no increased risk for any specific cancer type. CONCLUSIONS: Overall cancer risk was similar in multiple sclerosis patients and matched controls. The frequency of cancer diagnoses has increased over time among MS patients but not in controls.

Oral Corticosteroid Treatment Patterns of Patients in the United States with Persistent Asthma.

BACKGROUND: Patients with poor asthma control may receive oral corticosteroid (OCS) therapy despite the risk for adverse effects. OBJECTIVE: We assessed OCS use frequency and treatment patterns in patients with persistent asthma in the United States (US). METHODS: We used the IBM MarketScan Commercial Claims and Encounters, Medicare Supplemental, and Medicaid Multistate Claims research databases to identify patients from January 1, 2012, to December 31, 2017, who were ≥12 years old, met the 2-year Healthcare Effectiveness Data and Information Set criteria for persistent asthma, and were continuously enrolled ≥6 months before (baseline) and ≥24 months after (follow-up) the persistent asthma index date. Patients were classified as high OCS use (defined as ≥450 mg of OCS prescribed within a 90-day period during follow-up), low use (use OCS but not meeting high use criteria), or no OCS use. RESULTS: We identified 435,675 patients, of whom 65% used OCS and 19% were classified as high OCS users at some point during follow-up. The annual prevalence of high OCS use ranged from 5.3% in 2013 to 7.6% in 2017. During the entire follow-up, high and low OCS users filled an average of 2.2 and 0.8 OCS prescriptions and received an average daily dosage of 2.2 and 0.3 mg, respectively. Once the patients became high OCS users, the average daily OCS dosage was relatively stable (5.1-7.1 mg) over 3 years. CONCLUSIONS: Patients with persistent asthma in the US have substantial exposure to OCS. OCS therapy should be considered carefully to avoid associated adverse effects.

Healthcare resource utilization by patients with treatment-refractory myasthenia gravis in England.

Aims: To examine healthcare resource utilization associated with refractory myasthenia gravis (MG) in England. Materials and methods: This was a retrospective cohort study of linked data from the Clinical Practice Research Datalink and the Hospital Episode Statistics database collected between 1997 and 2016. Included patients were ≥18 years of age at the index MG diagnosis. Patients with refractory MG were identified using an algorithm based on treatments received. Healthcare resource utilization since the index date was compared between refractory and non-refractory cohorts. Results: The study included 1149 patients with MG, of whom 66 (5.7%) were refractory. Sex and age at diagnosis did not significantly differ between the refractory and non-refractory cohorts. Rates of healthcare resource utilization per person-year were significantly higher (p < .05) for patients with refractory compared to non-refractory MG for GP visits, visits to other healthcare professionals, outpatient visits and inpatient hospitalization. Patients in the refractory cohort spent more total days hospitalized since the index visit than patients in the non-refractory cohort (median, 33 vs. 16 days [p < .0001]). Limitations: The algorithm for identifying refractory patients did not include clinical criteria. Also, treatments administered in hospitals or by specialists were not available in the databases. Conclusions: Patients in England with refractory MG more often visit healthcare providers, are hospitalized and visit an emergency room than patients with non-refractory MG.

A retrospective study to assess resource utilization and costs in patients with post-stroke spasticity in the United Kingdom.

OBJECTIVE: Post-stroke spasticity (PSS) is a common complication following stroke. This study describes the differences in healthcare resource utilization between patients who do and do not develop PSS in the UK. METHODS: Adults registered in The Health Improvement Network database with a recorded stroke between 2007 and 2011 were included. PSS was identified through Read codes; machine learning was used to retrospectively identify unrecorded PSS events. Patients with diagnosed or predicted PSS in the 12 months after stroke were matched to those with no PSS on age, sex, number of strokes, socioeconomic status, and comorbidities using the nearest neighbor algorithm. Utilization and costs associated with general practitioner visits, nurse visits, hospitalizations, referrals to specialists, laboratory tests, and medications in the 12 months after stroke were compared. RESULTS: Overall, 2,951 PSS cases were matched to 37,753 controls. During the first year, more PSS cases visited a physiotherapist (19% vs 7%) and occupational therapist (12% vs 5%) compared to controls. A greater proportion of cases were also referred to specialists (76% vs 64%) and hospitalized (33% vs 9%) compared to controls. Medication for spasticity was, on average, 14.68 prescriptions for cases and 5.64 for controls. Total mean costs per patient were £1,270 (standard deviation [SD] = 772) and £635 (SD = 273) for cases and controls, respectively. CONCLUSION: Costs after stroke for patients developing PSS are twice as high compared to patients who do not develop it, with the major driver being the number of hospital admissions. This highlights the need for better recording and closer management of PSS.

COPD exacerbations by disease severity in England.

OBJECTIVES: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated disease progression and are important drivers of health care resource utilization. The study aimed to quantify the rates of COPD exacerbations in England and assess health care resource utilization by severity categories according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. METHODS: Data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics were used to identify patients with a COPD diagnosis aged ≥40 years. Those with complete spirometric, modified Medical Research Council Dyspnea Scale information, and exacerbation history 12 months prior to January 1, 2011 (index date) were classified into GOLD severity groups. Study outcomes over follow-up (up to December 31, 2013) were exacerbation rates and resource utilization (general practitioner visits, hospital admissions). RESULTS: From the 44,201 patients in the study cohort, 83.5% were classified into severity levels GOLD A: 33.8%, GOLD B: 21.0%, GOLD C: 18.1%, and GOLD D: 27.0%. Mean age at diagnosis was 66 years and 52.0% were male. Annual exacerbation rates per person-year increased with severity, from 0.83 (95% confidence interval [CI]: 0.81-0.85) for GOLD A to 2.51 (95% CI: 2.47-2.55) for GOLD D. General practitioner visit rates per person-year also increased with severity, from 4.82 (95% CI: 4.74-4.93) for GOLD A to 7.44 (95% CI: 7.31-7.61) for GOLD D. COPD-related hospitalization rates per person-year increased from less symptoms (GOLD A: 0.28, GOLD C: 0.39) to more symptoms (GOLD B: 0.52, GOLD D: 0.84). CONCLUSION: Patients in the most severe category (GOLD D) experienced nearly three times the number of exacerbations and COPD-related hospitalizations as those in the least severe category (GOLD A), in addition to increased general practitioner visits. Better patient management to stabilize the disease progression could allow for an improvement in exacerbation frequency and a reduction in health care resource utilization.

Basal-bolus Therapy in Patients with Type 2 Diabetes Mellitus in the UK: Patient Characteristics, Treatment Patterns and the Effect of Switching to Premixed Insulin.

INTRODUCTION: Increasing emphasis is being placed on insulin use among patients with type 2 diabetes mellitus (T2DM). Basal-bolus (BB) therapy is regarded as the gold standard, but a high frequency of injections and the general complexity of this therapy are seen as barriers in real-world practice. Here we describe the characteristics and treatment patterns of patients with T2DM receiving BB in the UK, with specific focus on those switching to a simplified regimen of premixed insulin. METHODS: Patients with T2DM receiving BB from 1 January 2005 were identified from the Clinical Practice Research Datalink. Characteristics were described at treatment initiation or on 1 January 2005, and treatment patterns were assessed at 12 months of follow-up. Clinical factors were compared in two groups of patients who while receiving BB had one haemoglobin A1c (HbA1c) measurement of ≥53 mmol/mol (7.0%) and remained either on BB or switched to a premixed insulin regimen. RESULTS: Study criteria were met by 12,060 subjects (mean age 59 years; duration diabetes 12.4 years). The mean HbA1c concentration was 76 mmol/mol (9.1% of patients), and 84.0% of patients were overweight. At 12 months of follow-up, 74.5% of the patients who had started BB remained on it. While on BB, 8835 patients had a HbA1c measurement of ≥53 mmol/mol (7.0% of all patients); of these, 95.9% remained on BB and 4.1% switched to premixed insulin. Mean HbA1c levels were consistently higher for patients who switched to premixed insulin than for those who remained on BB, but the levels remained relatively unchanged over time. CONCLUSION: A large proportion of patients receiving insulin did not achieve good glycaemic control in clinical practice. A small subset with higher comorbidities and HbA1c levels switched to a simplified regimen. Little evidence was found that type of insulin therapy was associated with meaningful changes in key clinical factors over time. FUNDING: Eli Lilly and company.

Epidemiology, severity, and treatment of chronic obstructive pulmonary disease in the United Kingdom by GOLD 2013.

OBJECTIVES: In 2013, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) updated the management strategy on COPD based on severity using a combined assessment of symptoms, degree of airflow limitation, and number of exacerbations. This study quantified prevalence and incidence of COPD in the United Kingdom and estimated disease severity by GOLD 2013 categories A/B (low risk) and C/D (high risk). METHODS: The Clinical Practice Research Datalink was used to identify COPD patients ≥40 years. Patient characteristics were described, and prevalence was calculated on December 31, 2013. Five-year incidence (2009-2013) was estimated, with rates standardized using 2011 UK population age and sex. To classify patients by GOLD categories, spirometry results, the modified British Medical Research Council grade, and history of exacerbations were used. RESULTS: The prevalent cohort comprised 49,286 patients with COPD with mean age 70 years; 51.0% were male. Overall prevalence was 33.3 per 1,000 persons (95% confidence interval [CI]: 33.1-33.6); 66.4% were classified as GOLD A/B and 33.6% as C/D. The standardized prevalence of GOLD A/B was 21.9 per 1,000 persons (95% CI: 21.7-22.1) and of C/D was 11.1 (95% CI: 10.9-11.2). A total of 27,224 newly diagnosed COPD patients were identified with mean age 67 years at diagnosis; 53.0% were male. Incidence was 2.2 per 1,000 person-years (95% CI: 2.2-2.3); 68.7% were classified in categories A/B and 31.3% in C/D, of which 17.2% did not receive COPD maintenance medication. CONCLUSION: A third of COPD patients in the UK are considered high risk (GOLD 2013 categories C/D), and a third of patients are diagnosed for the first time at these severe stages. Given the progressive nature of the disease, results suggest that closer attention to respiratory symptoms for early detection, diagnosis, and appropriate treatment of COPD in the UK is warranted.