Expert Insights from a Delphi-driven Neurologists' Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy.

Background: Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented. Objective: Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic. Methods: A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice. Results: The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic. Conclusions: Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.

Cost-effectiveness of fluocinolone acetonide implant (ILUVIEN®) in UK patients with chronic diabetic macular oedema considered insufficiently responsive to available therapies.

BACKGROUND: Diabetic macular oedema (DMO) may lead to visual loss and blindness. Several pharmacological treatments are available on the National Health Service (NHS) to United Kingdom patients affected by this condition, including intravitreal vascular endothelial growth factor inhibitors (anti-VEGFs) and two types of intravitreal steroid implants, releasing dexamethasone or fluocinolone acetonide (FAc). This study aimed to assess the value for money (cost-effectiveness) of the FAc 0.2 µg/day implant (ILUVIEN®) in patients with chronic DMO considered insufficiently responsive to other therapies. METHODS: We developed a Markov model with a 15-year time horizon to estimate the impact of changes in best-corrected visual acuity in DMO patients on costs and quality-adjusted life years. The model considered both eyes, designated as the "study eye", defined at model entry as phakic with an ongoing cataract formation or pseudophakic, and the "fellow eye". The model compared the FAc 0.2 µg/day implant with a 700 µg dexamethasone implant (pseudophakic patients only) or with usual care, defined as a mixture of laser photocoagulation and anti-VEGFs (phakic and pseudophakic patients). Costs were estimated from the perspective of the NHS and Personal Social Services; full NHS prices were used for drugs. RESULTS: In patients who were pseudophakic at baseline, at 36 months, the FAc implant provided an additional gain of 4.01 and 3.64 Early Treatment Diabetic Retinopathy Study (ETDRS) letters compared with usual care and the dexamethasone implant, respectively. Over the 15-year time horizon, this translated into 0.185 additional quality-adjusted life years (QALYs) at an extra cost of £3066 compared with usual care, and 0.126 additional QALYs at an extra cost of £1777 compared with dexamethasone. Thus, incremental cost-effectiveness ratios (ICERs) were £16,609 and £14,070 per QALY gained vs. usual care and dexamethasone, respectively. In patients who were phakic at baseline, the FAc 0.2 µg/day implant provided an additional gain of 2.96 ETDRS letters at 36 months compared with usual care, which, over 15 years, corresponded to 0.11 additional QALYs at an extra cost of £3170, resulting in an ICER of £28,751 per QALY gained. CONCLUSION: The FAc 0.2 µg/day implant provided good value for money compared with other established treatments, especially in pseudophakic patients.

Comparison of data characterizing the clinical effectiveness of the fluocinolone intravitreal implant (ILUVIEN) in patients with diabetic macular edema from the real world, non-interventional ICE-UK study and the FAME randomized controlled trials.

Objective: To compare the effectiveness and safety of the fluocinolone acetonide (FAc) intravitreal implant between the observational Iluvien Clinical Evidence study in the United Kingdom (ICE-UK) and the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) randomized controlled trials (RCTs) in people with diabetic macular edema (DME). Clinical Trials Registration: NCT00344968. Methods: This study selected patients randomized to receive 0.2 µg/day FAc insert (FAc treated eyes) or sham injection (control eyes) from the FAME RCTs, and patients' first FAc treated eye and non-FAc treated fellow (control) eye from the ICE-UK study. Outcomes included change in visual acuity (VA), central foveal thickness (CFT), and intraocular pressure (IOP). Results: After 12 months follow-up, mean change in VA was 5.0 letters improvement (p < .001) and 1.6 letters improvement (p = .003) in FAME FAc treated and control eyes, and 3.8 letters (p = .012) and -2.1 letters (p = .056) in ICE-UK FAc treated and control eyes, respectively. Mean change in CFT was -144 µm (p < .001) vs -72 µm (p < .001) in FAME FAc treated and control eyes and -113 µm (p < .001) vs -13 µm (p < .001) in ICE-UK FAc treated and control eyes. For eyes with a follow-up of 12 months, 77 (22.3%) and 15 (8.6%) FAME FAc treated and control eyes and 25 (18.7%) and six (4.3%) ICE-UK FAc treated and control eyes required emergent IOP-lowering therapy. Conclusions: Statistically significant improvements in VA 12 months after FAc implantation were observed in both the real-world study and in the RCTs. The improvement in VA and CFT in the RCTs was marginally greater than in the real-world study; however, recruits in the real-world study had more severe visual morbidity at baseline. Whilst there were many changes in the care of people with DME over this time, these data all support the value of treatment with FAc intravitreal implant.

Cardiovascular outcomes in women with advanced breast cancer exposed to chemotherapy.

PURPOSE: To quantify incidence of cardiovascular outcomes in patients with advanced breast cancer receiving cardiotoxic and non-cardiotoxic chemotherapy. METHODS: This study identified all women at a Midwestern health system with initial diagnosis of American Joint Commission on Cancer Stage III/IV breast cancer (1995-2003) and random sample of 50 women initially diagnosed with Stage I/II who progressed to Stage III/IV. The rate of new cardiovascular outcomes (heart failure, dysrhythmia, and ischemia events) for cardiotoxic (anthracycline or trastuzumab) and non-cardiotoxic agents was calculated. RESULTS: Of 315 patients, 90.5% (n = 285) received systemic cancer therapy; 67.7% (n = 193) received cardiotoxic drugs. Older patients were less likely to receive cardiotoxic agents (86.4%, ≤59 years vs. 31.9%, 70+ years). Adjusting for age, race, stage, surgery/radiation, estrogen receptor/progesterone receptor status, and diagnosis year, rate of new cardiac events was higher in patients exposed to cardiotoxic drugs compared with those exposed to non-cardiotoxic drugs (adjusted hazard ratio = 2.5, 95%CI = 0.9-7.2). Patients with cardiac event history (relative risk = 3.2, 95%CI = 2.0-5.1) and those with heart failure history (relative risk = 5.9, 95%CI = 2.4-14.6) were more likely to receive non-cardiotoxic treatment. Heart failure events occurred steadily over time; after 3 years of follow-up, 16% exposed to cardiotoxic drugs experienced an event, and 8% of those exposed to non-cardiotoxic drugs experienced an event. CONCLUSIONS: Patients with cardiac comorbidity are less likely to receive cardiotoxic agents. Use of cardiotoxic agents is common; treatment is related to patient and tumor characteristics and is associated with substantial risk of cardiotoxicity that persists during patients' remaining lifespan.

The incidence of interstitial lung disease 1995-2005: a Danish nationwide population-based study.

BACKGROUND: Current data on incidence of interstitial lung diseases (ILDs) are sparse and concerns about an increasing trend have been raised. We examined incidence rates (IRs) of ILDs and changes in IRs between 1995 and 2005. METHODS: All persons with a first-time hospital discharge or outpatient diagnosis of ILD were identified through the Danish National Registry of Patients, which covers all Danish hospitals. Crude and age-standardised IRs were computed for ILD overall, as well as stratified by ILD subcategories. RESULTS: A total of 21,765 patients with ILD were identified. Between 1995 and 1998 the overall standardised IR of ILD decreased from 27.14 (95% CI 25.82-28.46) per 100,000 person-years to 19.36 (95% CI 18.26-20.46) per 100,000 person-years. After 1998 the IR increased considerably, peaking at 34.34 (95% CI 32.84-35.85) per 100,000 person-years in 2002. Subsequently there was a slight decrease. The highest IR was observed in the non-specific category "Respiratory disorders in diseases classified elsewhere". By ILD subcategory, the greatest average increase during the study period was observed in "Respiratory disorders in diseases classified elsewhere". CONCLUSION: The incidence rate of ILD in Denmark increased during the study period, most pronounced for ILDs associated with systemic diseases.

Incidence of cardiovascular events in breast cancer patients receiving chemotherapy in clinical practice.

PURPOSE: To assess the incidence of cardiovascular events among breast cancer patients after chemotherapy. METHODS: Women > or =18 years with a breast tumour who received chemotherapy in 1992-2003 were selected from the PHARMO RLS. Chemotherapy with anthracyclines, a combination of anthracyclines and taxanes or second line treatment with trastuzumab was classified as cardiotoxic. Cardiovascular events were determined based on drug use and hospital admissions. Incidence rates of cardiovascular events and hazard ratios (HR) for the cardiotoxic versus non-cardiotoxic chemotherapy group were assessed during the first year and total follow-up. RESULTS: Of 648 patients with breast cancer included in the study cohort, 353 (54%) received cardiotoxic chemotherapy. At baseline, patients who received cardiotoxic chemotherapy compared with patients receiving non-cardiotoxic chemotherapy, received less anticoagulants/haemostatics (5 vs. 11%; p = 0.012) and had been less often hospitalised for cardiovascular disease (1 vs. 5%; p = 0.007) 2 years before the cohort entry date. After 1-year follow-up, the incidence rate of cardiovascular events was 69/1000 person years (py) for patients with cardiotoxic chemotherapy and 98/1000 py for patients with non-cardiotoxic chemotherapy, which did not differ significantly (HR 0.74 95% confidence interval (CI): 0.39, 1.41). After total follow-up, this was 81/1000 py for patients with cardiotoxic and 92/1000 py for patients with non-cardiotoxic chemotherapy (HR 0.81, 95%CI: 0.54, 1.20). CONCLUSIONS: This study showed similar cardiovascular incidence rates during follow-up for breast cancer patients treated with cardiotoxic and non-cardiotoxic chemotherapy. Specialists seemed to take pre-existing cardiovascular diseases into account when treating the breast cancer patient.

Misclassification of exposure is high when interview data on drug use are used as a proxy measure of chronic drug use during follow-up.

BACKGROUND AND OBJECTIVE: In many observational studies, the association between drugs and disease is analyzed with information from a baseline interview. We investigated the magnitude and direction of exposure misclassification by comparing interview data at baseline with prospectively gathered pharmacy data. METHODS: The study population for this study consisted of a cohort of 2,487 participants aged 71 years or older from the Rotterdam Study. Data on drug use were gathered at the baseline interview and through pharmacies during the follow-up period between January 1, 1991, and January 1, 1999. We assessed the sensitivity, specificity, and positive and negative predictive value of interview data as proxy measures of chronic use of calcium channel blockers (CCB) in comparison with longitudinal medication records from the pharmacy. RESULTS: Only 3 of the 206 subjects (1.5%) who reported use at baseline did not use CCBs during follow-up. Of the 2,281 persons who reported no use of CCBs at baseline, however, 354 actually used CCBs during follow-up (15.5%). The difference between interview data and pharmacy records corresponded to a misclassification bias of 0.73 (95%CI: 0.52-1.02). CONCLUSION: Misclassification of exposure was high when interview data were used as a proxy measure of chronic use during follow-up.

The risk of cancer in users of statins.

PURPOSE: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. METHODS: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. RESULTS: In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). CONCLUSION: This observational study suggests that statins may have a protective effect against cancer.

No increased risk of non-Hodgkin's lymphoma with steroids, estrogens and psychotropics (Netherlands).

OBJECTIVE: Earlier studies with data on drug use from interview suggested that corticosteroids, estrogens and psychotropics may increase the risk of non-Hodgkin's lymphoma (NHL). The objective of this case-control study with complete pharmacy records was to investigate whether these results could be reproduced. METHODS: Cases were all subjects aged 20 years and older in a population of approximately 300,000 residents in the Netherlands who were registered with an incident primary discharge diagnosis of NHL between January 1, 1991 and December 31, 1998. Controls were matched to cases on sex, year of birth, community pharmacy, calendar period and total duration of medication history. Conditional logistic regression was used to evaluate the association between categories of cumulative drug use in days and the risk of NHL. RESULTS: 997 controls were matched to 251 cases of NHL that occurred during the study period. In multivariate analyses, there was no statistically significant risk increase of NHL after exposure to corticosteroids, estrogens or psychotropics. Moreover, long-term use of benzodiazepines showed an unexpected statistically significant protective effect (OR 0.34; 95% confidence interval 0.18-0.64). CONCLUSIONS: In our population-based study, corticosteroids, estrogens and psychotropics were not associated with an increased risk of NHL.

Prescription medications associated with a decreased risk of non-Hodgkin's lymphoma.

Earlier epidemiologic studies have suggested an inverse association between non-Hodgkin's lymphoma and exposure to histamine(2) (H(2)) blockers, nonsteroidal anti-inflammatory drugs, cholesterol-lowering drugs, and antibiotics. Data from the PHARMO database were used to conduct a nested, population-based case-control study that included 1985-1998 drug-dispensing records for 300,000 residents of six Dutch cities. Included were those subjects without a previous history of cancer who were aged >/=20 years and were registered with an incident primary discharge diagnosis of non-Hodgkin's lymphoma between 1991 and 1998. This paper includes data on 211 cases and 800 controls individually matched on sex, age, community pharmacy, calendar time, and duration of follow-up. Conditional logistic regression analysis was used to evaluate the association between non-Hodgkin's lymphoma and categories of cumulative drug use in days. In multivariate analyses, nonsignificant risk reductions were found for all drugs tested, and the negative association tended to increase with increasing duration of use. For women, the odds ratio for H(2) blockers was 0.29 (95% confidence interval: 0.12, 0.69) and for analgesics was 0.40 (95% confidence interval: 0.22, 0.71). Results support an inverse association between occurrence of non-Hodgkin's lymphoma and use of H(2) blockers and analgesics among women, and they warrant confirmation in larger studies.