Risk of cancer with immunosuppressants compared to immunomodulators in multiple sclerosis: A nested case-control study within the French nationwide claims database.

PURPOSE: The objective was to compare the risk of malignancies in real-world settings between exclusive immunosuppressant (IS) and immunomodulator (IM) use in multiple sclerosis (MS). METHODS: A nested case-control study was designed within a new-user cohort of all patients with MS who initiated a first IM or IS between 2008 and 2014, and without cancer history, using the information of the SNDS nationwide French claims database. Incident cancer cases were matched with up to six controls on year of birth, sex, initiation date, and disease risk score of cancer. A conditional logistic regression (odds ratio [95% confidence interval]) was used to compare exclusive IS versus IM use during follow-up and according to three use durations. RESULTS: From 28 720 newly treated patients with MS, 407 incident cancers were observed during the follow-up with 2324 matched controls. A significant increase in cancer risk was observed for IS compared with IM (1.36 [1.05, 1.77]), with similar increases for the first 2 years of use but not for ≥2 years (1.06 [0.65, 1.75]). Similar increase was also observed for IS with indications other than MS (1.37 [1.04, 1.81]) but not for IS indicated only in MS (1.03 [0.45, 2.34]). CONCLUSIONS: Compared with IM, a 37% increase in cancer risk was observed for IS with indications other than MS and used for a short duration (≤2 years) but not for IS indicated only in MS. The absence of risk for prolonged exposure of IS with indications other than MS is not in favor of a causal relation with these drugs.

Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study.

INTRODUCTION: We previously reported an increased risk of being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA) after in utero exposure to metformin compared with insulin exposure. This follow-up study investigated if these observations remain when metformin exposure (henceforth, metformin cohort) is compared with non-pharmacological antidiabetic treatment of gestational diabetes mellitus (GDM; naïve cohort), instead of insulin. RESEARCH DESIGN AND METHODS : This was a Finnish population register-based cohort study from singleton children born during 2004-2016. Birth outcomes from metformin cohort (n=3964) and the naïve cohort (n=82 675) were used in the main analyses. Additional analyses were conducted in a subcohort, restricting the metformin cohort to children of mothers with GDM only (n=2361). Results were reported as inverse probability of treatment weighted OR (wOR), with the naïve cohort as reference. RESULTS  : No difference was found for the outcome of SGA between the cohorts in the main analyses (wOR 0.97, 95% CI 0.73 to 1.27) or in the additional analyses (wOR 1.01, 95% CI 0.75 to 1.37). No difference between the cohorts was found for the risk of LGA (wOR 0.91, 95% CI 0.75 to 1.11) in the main analyses but a decreased risk was observed in the additional analyses (wOR 0.72, 95% CI 0.56 to 0.92). CONCLUSIONS : This follow-up study found no increase in the risk of SGA or LGA after in utero exposure to metformin, compared with drug-naïve GDM. The decreased risk of LGA in mothers with GDM may suggest residual confounding. The lack of increased SGA risk aligns with findings from studies using metformin in non-diabetic pregnancies. In contrast, lower birth weight and increased SGA birth risk were observed in GDM pregnancies for metformin versus insulin. Metformin should be avoided with emerging growth restriction in utero. The interplay of intrauterine hyperglycemia and pharmacological treatments needs further assessment.

Quality and Characteristics of 4241 Case Reports of Lactic Acidosis in Metformin Users Reported to a Large Pharmacovigilance Database.

Objective: Metformin-associated lactic acidosis (MaLA) occurs rarely and is thus difficult to study. We analysed 4241 individual case safety reports of lactic acidosis (LA) that implicated metformin as a suspected drug reported to the pharmacovigilance database of Merck KGaA, Darmstadt, Germany. The primary objective was to review reports for quality and completeness of data to support diagnoses of MaLA. We also explored the correlations between reported biomarkers, and associations between biomarkers and outcomes. Research Design and Methods: Records were analysed for completeness in supporting diagnoses of LA or metformin-associated LA (MaLA), against commonly used diagnostic criteria. Correlations between indices of exposure to metformin and biomarkers of LA and mortality were investigated. Results: Missing data was common, especially for plasma metformin. Clinical/biomarker evidence supported a diagnosis of LA in only 33% of cases (LA subpopulation) and of MaLA in only 9% (MaLA subpopulation). The metformin plasma level correlated weakly with plasma lactate (positive) and pH (negative). About one-fifth (21.9%) of cases reported a fatal outcome. Metformin exposure (plasma level or dose) was not associated with increased mortality risk (there was a suggestion of decreased risk at higher levels of exposure to metformin). Plasma lactate was the only variable associated with increased risk of mortality. Examination of concomitant risk factors for MaLA identified renal dysfunction (including of iatrogenic origin) as a potential driver of mortality in this population. Conclusion: Despite the high frequency of missing data, this is the largest analysis of cases of MaLA supported by measurements of circulating metformin, and lactate, and pH, to date. Plasma lactate, and not metformin dose or plasma level, appeared to be the main driver of mortality in the setting of LA or MaLA. Further research with more complete case reports is required.

Real-World Effectiveness of Beta-Blockers versus Other Antihypertensives in Reducing All-Cause Mortality and Cardiovascular Events.

Aim: The aim of the study was to compare the effectiveness of beta-blockers with other antihypertensive classes in reducing all-cause mortality, cardiovascular-related mortality and the risk of cerebrocardiovascular events. Methods: This noninterventional study was conducted within the UK Clinical Practice Research Datalink. Hypertensive patients who initiated antihypertensive monotherapy were allocated to one of five cohorts: beta-blockers; angiotensin-converting enzyme inhibitors (ACEi); angiotensin II receptor blockers (ARB); calcium channel blockers (CCB); and diuretics. Differences in outcomes were assessed using Cox proportional hazard models with competing risks. Results: A total of 44,404 patients were prescribed beta-blockers (75% atenolol), 132,545 ACEi, 12,018 ARB, 91,731 CCB, and 106,547 diuretics. At baseline, patients in the beta-blocker cohort presented more frequently with angina, arrhythmia, and atrial fibrillation. The risk of all-cause mortality was lower for those treated with ACEi, ARB, and CCB, and no difference was observed compared with diuretics (adjusted hazard ratio versus beta-blockers (98.75% CI), for ACEi 0.71 (0.61, 0.83), ARB 0.67 (0.51, 0.88), CCB 0.76 (0.66, 0.88), diuretics 1.06 (0.93, 1.22)). No differences were seen in the risk of cardiovascular mortality for patients treated with beta-blockers, ARB, CCB, and diuretics, while a lower risk in patients treated with ACEi was observed (ACEi 0.63 (0.43, 0.91), ARB 0.64 (0.32, 1.28), CCB 0.71 (0.49, 1.03), diuretics 0.97 (0.69, 1.37)). Conclusions: These data add to the limited pool of evidence from real-world studies exploring the effectiveness of beta-blockers versus other antihypertensive classes. Discrepancies to previously published studies might be partly explained by differences in the selected populations and in the follow-up time.

Incidence of malignancies in patients with multiple sclerosis versus a healthy matched cohort: A population-based cohort study in the Netherlands using the PHARMO Database Network.

This study estimated the incidence of malignancy in patients with multiple sclerosis (MS) versus a matched general population cohort in the Netherlands. Adults with a diagnosis of MS between 2006 and 2014 in the General Practitioner (GP) Database of the PHARMO Database Network with ≥ 1 year of patient history were matched to four non-MS individuals based on year of birth, sex, and GP practice. Patients were followed-up until the earliest malignancy diagnosis, death, or end of data collection. Age-adjusted incidence rates (IR) were measured overall and by cancer type. Standardized incidence ratios (SIR) were calculated as the ratio of stratification-specific IRs in the MS and non-MS cohorts. A total of 1,692 MS patients were matched to 6,768 non-MS patients. Age-adjusted IR of any malignancy, excluding non-melanoma skin cancer (n = 27), in the MS cohort was 48.3 (95%CI:30.1-66.5) per 10,000 PY. An increased incidence of any malignancy was observed in the MS cohort versus the non-MS cohort (SIR 1.8 [95%CI:1.1-2.5]). The most commonly observed malignancies in the MS cohort were breast cancer (n = 8; IR 20.4 [95%CI:6.3-34.5] per 10,000 PY) and melanoma (n = 6; IR 14.8 [95%CI:3.0-26.7] per 10,000 PY). The corresponding SIR observed between cohorts was 1.4 (95%CI:0.4-2.4) and 3.4 (95%CI:0.7-6.2), respectively. While the small increased incidence of malignancy in the MS cohort could be an artefact created by a different distribution of risk factors, an increased incidence of malignancy in MS patients in the Netherlands cannot be excluded.

Effectiveness of bisoprolol versus other ß-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink.

Aim: To compare blood pressure (BP) and safety outcomes in patients with hypertension initiating bisoprolol, versus other ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, calcium channel blockers or diuretics. Materials & methods: New user cohort study. Patients initiating bisoprolol were matched with up to four patients, in each comparator cohort using propensity score. BP outcomes were compared using linear mixed models and safety outcomes using Cox proportional hazards. Results: Differences in average systolic and diastolic BP variation were ≤3 mmHg between bisoprolol versus the compared classes. No difference was observed in risk of diabetes, obesity or erectile dysfunction. An increased dyslipidemia risk was only observed versus diuretics (hazard ratio: 0.76; 98.75% CI: 0.58, 0.99). Conclusion: No differences in BP variation and safety outcomes.

An anchored simulated treatment comparison of uptitration of amlodipine compared with a low-dose combination treatment with amlodipine 5 mg/bisoprolol 5 mg for patients with hypertension suboptimally controlled by amlodipine 5 mg monotherapy.

OBJECTIVE: To compare changes in systolic and diastolic blood pressures (SBP, DBP) from baseline to following 8 weeks of treatment with a low dose combination of amlodipine 5 mg plus bisoprolol 5 mg versus up titration to the maximum daily dose of amlodipine 10 mg, in hypertensive patients uncontrolled by amlodipine 5 mg. METHODS: Individual patient data (IPD) from a randomized clinical trial (RCT) comparing the combination versus amlodipine 5 mg (EudraCT Number: 2019-000751-13) and aggregated data (AgD) from a published RCT comparing amlodipine 10 mg versus amlodipine 5 mg were utilized in an anchored simulated treatment comparison (STC). The RCT with IPD was used to create models assessing how patients might respond to the combination if they were more comparable to those patients in the RCT with AgD. A population-adjusted indirect comparison of the treatment strategies was then conducted, using amlodipine 5 mg as an anchor. RESULTS: In the efficacy analyses, a total of 261 patients were included in the amlodipine 10 mg arm of the RCT with AgD; and a total of 178 patients in the low-dose combination arm of the RCT with IPD. Respectively, in the Amlodipine 10 mg arm and in the low-dose combination arm, the mean age was 54.3 years-old (Standard deviation [SD] 10.6), and 57.1 years-old (13.7); 8.7% and 18.8% of patients were diabetics; and the mean baseline SBP/DBP was 149.3 (12.0)/96.5 (4.7) mmHg, and 148.8 (8.2)/90.2 (7.6) mmHg. The final model for SBP and DBP included the following variables: baseline SBP, baseline DBP, duration of hypertension, age, concomitant diabetes, sex, smoking history (final model for SBP only), and body mass index (final model for DBP only). Mean treatment differences (standard error [SE]) at 8 weeks between the combination and uptitration were -1.6 mmHg (1.9) for SBP; and -3.3 mmHg (1.3) for DBP. CONCLUSION: In this indirect comparison, a more important decrease was observed in DBP with the low-dose combination as compared to the alternative therapeutic approach of up-titration from amlodipine 5 mg to amlodipine 10 mg. No meaningful difference was seen for SBP.

Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study.

INTRODUCTION: This study aimed to investigate if maternal pregnancy exposure to metformin is associated with increased risk of long-term and short-term adverse outcomes in the child. RESEARCH DESIGN AND METHODS : This register-based cohort study from Finland included singleton children born 2004-2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). The primary outcomes were long-term offspring obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and challenges in motor-social development. In a sensitivity analysis, the primary outcomes were investigated only among children with maternal gestational diabetes. Secondary outcomes were adverse outcomes at birth. Analyses were conducted using inverse- probability of treatment weighting (IPTW), with insulin as reference. RESULTS  : Exposure to metformin or combination treatment versus insulin was not associated with increased risk of long-term outcomes in the main or sensitivity analyses. Among the secondary outcomes, increased risk of small for gestational age (SGA) was observed for metformin (IPTW-weighted OR 1.65, 95% CI 1.16 to 2.34); increased risk of large for gestational age, preterm birth and hypoglycemia was observed for combination treatment. No increased risk was observed for neonatal mortality, hyperglycemia, or major congenital anomalies. CONCLUSIONS : This study found no increased long-term risk associated with pregnancy exposure to metformin (alone or in combination with insulin), compared with insulin. The increased risk of SGA associated with metformin versus insulin suggests caution in pregnancies with at-risk fetal undernutrition. The increased risks of adverse outcomes at birth associated with combination treatment may reflect confounding by indication or severity.

Incidence and risk of cancer among multiple sclerosis patients: A matched population-based cohort study.

BACKGROUND AND PURPOSE: Studies have not yet found conclusive results on the risk of cancer in patients with multiple sclerosis (MS). This study aimed to compare the incidence of all cancers and of specific types of cancer between MS patients and the general population by age and by sex. METHODS: All prevalent MS patients identified between 2008 and 2014 in the nationwide French health care database (Système National des Données de Santé) and without history of malignancy were included in a cohort study and followed up until cancer occurrence, date of death, or 31 December 2015, whichever came first. MS patients were matched based on sex and year of birth to non-MS controls from the general population without cancer before index date. Incidence rate was reported per 100,000 person-years (PY), and risk of cancer was estimated by type of cancer, age, and sex using a Cox model (hazard ratio [HR] and its 95% confidence interval [CI]). RESULTS: Overall, 576 cancers per 100,000 PY were observed in MS patients versus 424 per 100,000 PY in the control population. The risk of cancer was higher among MS patients than among population controls whether considered overall (HR = 1.36, 95% CI = 1.29-1.43) or for prostate (HR = 2.08, 95% CI = 1.68-2.58), colorectal and anal (HR = 1.35, 95% CI = 1.16-1.58), trachea, bronchus, and lung (HR = 2.36, 95% CI = 1.96-2.84), and to a lesser extent, breast cancer (HR = 1.12, 95% CI = 1.03-1.23). CONCLUSIONS: MS patients were associated with increased risk of cancer compared to population controls.

Incidence of malignancy in multiple sclerosis: A cohort study in the Danish Multiple Sclerosis Registry.

BACKGROUND: The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed. OBJECTIVE: To determine the incidence of malignancy in patients with multiple sclerosis compared with the general population and in relation to disease-modifying therapy. METHODS: Patients with multiple sclerosis (1995 - 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios. RESULTS: The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis (n = 10,557) was 0.96 (95% CI 0.88 - 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort (n = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 - 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 - 1219.9) in patients newly treated with immunosuppressant-only. CONCLUSIONS: There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy.

Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer.

AIM: This study assessed whether cetuximab 500 mg/m2 administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m2 followed by 250 mg/m2 once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events. RESULTS: OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715-0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804-1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031-1.617]) and the rates of lung/liver metastases resection (1.419 [1.043-1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858-1.382). CONCLUSIONS: The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC.

In utero drug exposure and hearing impairment in 2-year-old children A case-control study using the EFEMERIS database.

INTRODUCTION: As the ear development extends from the 4th to the 30th week of pregnancy, in utero exposure to ototoxic drugs might lead to hearing impairment in the fetus. The main study objective was to assess the association between in utero drug exposure and the occurrence of hearing impairment in 2-year-old children. METHODS AND MATERIALS: A case-control study was carried out using the EFEMERIS database, recording medications dispensed during pregnancy and the compulsory health certificates for child at 8 days, 9 and 24 months. Cases were defined as children with an abnormal hearing examination recorded on the 24-month certificate and controls as children with a normal hearing examination. Exposure was defined as at least one prescription and dispensation to the mother of drugs grouped at the 3rd level of the Anatomical Therapeutic and Chemical Classification level, compared to no exposure. Univariate logistic regressions were carried out. If the 95% confidence interval (95% CI) of the odds ratio (OR) was significant, a multivariable logistic regression was performed, adjusted on confounders. RESULTS: A total of 1,245 cases with abnormal hearing evaluation and 28,046 controls were selected for analysis. Case and control mothers were comparable in terms of age, education and congenital infection. Cases and controls were comparable in terms of prematurity, asphyxia and weight at birth. However, among cases (versus controls), there were more ear deformities (0.6% vs 0.0% p≤0.001), and more recurring otitis (11.3% vs 5.3% p≤0.0001). When adjusted on confounders, the following drugs remained significant versus no exposure: acetylsalicylic acid at low dosage (OR 95% CI 1.61 [1.09-2.37]), valproic acid or valpromide (OR 95% CI 5.20 [1.93-14.00]), systemic corticosteroids (OR 95% CI 0.75 [0.61-0.93]. In a sensitivity analysis which excluded children with recurrent otitis at 24 months, these three results remained significant. CONCLUSIONS: This is the first study evaluating the risk of hearing disorders due to in utero exposure to drugs. Hearing loss was associated with valproic acid and low-dose acetylsalicylic acid exposure during pregnancy. Conversely, children with normal hearing were more likely to have been exposed in utero to corticosteroids than children with hearing loss.