Causality assessment of adverse drug reaction: A narrative review to find the most exhaustive and easy-to-use tool in post-authorization settings.

BACKGROUND: The core motive of pharmacovigilance is the detection and prevention of adverse drug reactions (ADRs), to improve the risk-benefit balance of the drug. However, the causality assessment of ADRs remains a major challenge among clinicians, and none of the available tools of causality assessment used for assessing ADRs have been universally accepted. OBJECTIVE: To provide an up-to-date overview of the different causality assessment tools. METHODS: We conducted electronic searches in MEDLINE, EMBASE, and the Cochrane database. The eligibility of each tool was screened by three reviewers. Each eligible tool was then scrutinized for its domains (the reported specific set of questions/areas used for calculating the likelihood of cause-and-effect relation of an ADR) to discover the most comprehensive tool. Finally, we subjectively assessed the tool's ease-of-use in a Canadian, Indian, Hungarian, and Brazilian clinical context. RESULTS: Twenty-one eligible causality assessment tools were retrieved. Naranjo's tool and De Boer's tool appeared the most comprehensive among all the tools, covering 10 domains each. Regarding "ease-of-use" in a clinical setting, we judged that many tools were hard to implement in a clinical context because of their complexity and/or lengthiness. Naranjo's tool, Jones's tool, Danan and Benichou's tool, and Hsu and Stoll's tool appeared to be the easiest to implement into various clinical contexts. CONCLUSION: Among the many tools identified, 1981 Naranjo's scale remains the most comprehensive and easy to use for performing causality assessment of ADRs. Upcoming analysis should compare the performance of each ADR tool in clinical settings.

The French Pregnancy Cohort: Medication use during pregnancy in the French population.

PURPOSE: We described the medication use during pregnancy in the French population using the French Pregnancy Cohort (FPC). METHODS: The FPC was built with the sampling of all pregnant women included in the French Echantillon généraliste des bénéficiaires (EGB), which is a 1/97th representative sample of the population covered by the French health insurance. The EGB includes anonymized information on the socio-demographic and medical characteristics of beneficiaries, and the health care services they have received such as diagnoses and procedure codes as well as data on filled reimbursed medication; EGB also includes data on hospital stays in all public and private French health facilities. Each filled prescription record contains information on drug brand and generic names, date of prescription and date of dispensing, quantity dispensed, mode of administration, duration of prescription, dosage, and prescribing physician specialty. FPC includes data on all pregnancies of women in the EGB (2010-2013). Date of entry in the FPC is the first day of pregnancy regardless of pregnancy outcome (spontaneous abortions or planned abortions (with or without medical reasons), deliveries), and data on women are collected retrospectively for a period of one year before pregnancy, and prospectively during pregnancy, and up to one year after delivery. The prevalence of prescribed medications before, during and after pregnancy was compared; comparison was also done between trimesters. Pregnancy outcomes are described and include spontaneous and planned abortions, livebirths, and stillbirths. RESULTS: FPC includes data on 36,065 pregnancies. Among them, 27,253 (75.6%) resulted in a delivery including 201 stillbirths (0.7%). The total number of spontaneous abortions was 6,718 (18.6%), and planned abortions 2,094 (5.8%). The prevalence of filled medication use was 91.1%, 89.9%, and 95.6% before, during and after pregnancy, respectively. Although there was a statistically significant decrease in the proportion of use once the pregnancy was diagnosed (first trimester exposure, 76.4% vs. exposure in the year prior to pregnancy, 91.1% (p < .01)), post-pregnancy medication use was above the pre-pregnancy level (95.6%). Maternal depression was the most prevalent comorbidity during pregnancy (20%), and post-partum depression was higher in those who delivered a stillborn infant (38.8%) as well as in those with a spontaneous (19.5%) or planned abortion (22.4%) compared to those with a liveborn (12.0%). CONCLUSION: FPC is an excellent tool for the study of the risk and benefit of drug use during the perinatal period. FPC has the advantage of including a representative sample of French pregnant women, and study medications only available in France in addition to others available worldwide.

Can We Rely on Pharmacy Claims Databases to Ascertain Maternal Use of Medications during Pregnancy?

BACKGROUND: Administrative databases are increasingly used to measure drug exposure in perinatal pharmacoepidemiology. We aimed to estimate the concordance between records of prescriptions filled in pharmacies and self-reported drug use during pregnancy. METHODS: Data on self-reported medication use were collected at each trimester of pregnancy among a sub-sample from the Organization of Teratology Information Specialists Antidepressants in Pregnancy Cohort. Women were eligible if they were Quebec resident and provided their pharmacist's contact information. Maternal self-reports were compared with prescriptions filled in pharmacies, which are transferred to pharmaceutical services files of Quebec provincial health plan database (Régie de l'asssurance maladie du Québec). Positive and negative predictive values (PPV and NPV) for medications taken chronically (antidepressants, thyroid hormones), acutely (antibiotics), and as needed (antiemetics, asthma medications) were calculated. RESULTS: Among the 93 participants (mean age = 30.2 ± 3.8 years), 41.9% (n = 39) took at least one antidepressant during pregnancy according to self-reports, and 39.8% (n = 37) according to pharmacy records. Other commonly used drugs were antiemetics (self-reported 22.6%, pharmacy record 24.7%), antibiotics (20.4%, 16.1%), asthma medications (15.1%, 15.1%), and thyroid hormones (10.8%, 8.6%). PPVs and NPVs were: (1) chronic medication: antidepressants PPV = 100% (95% confidence interval [CI], 100-100%), NPV = 96% (95% CI, 92-100%); thyroid hormones PPV = 100% (95% CI, 100-100%), NPV = 98% (95% CI, 95-100%); (2) Acute medication: antibiotics PPV = 87% (95% CI, 70-100%), NPV = 92% (95% CI, 86-98%); (3) as needed medications: antiemetics: PPV = 78% (95% CI, 62-95%), NPV = 96% (95% CI, 91-100%); asthma: PPV = 33% (95% CI, 3-64%), NPV = 99% (95% CI, 97-100%). CONCLUSION: The high PPV and NPV validate the use of filled prescription data in large databases as a measure of medication exposure. Birth Defects Research 109:423-431, 2017. © 2017 Wiley Periodicals, Inc.

Study of the costs and morbidities of late-preterm birth.

OBJECTIVE: To compare late-preterm infants (33-36 weeks) with term infants (≥37 weeks) on incidence of morbidities in the first 3 years of life and healthcare costs during the first 2 years of life and third year of life. METHODS: Administrative health records of live infants born between January 1, 1997, and December 31, 2000 with 3 years follow-up data (N=35733) were linked. First, diagnoses of morbidities were compared between late-preterm and term infants using Cox's proportional hazards models. Healthcare costs expressed as mean total costs and cost ratios, accrued following initial hospital discharge after birth, were also examined. RESULTS: The three most common reasons for hospitalisation in late-preterm and term infants were acute bronchitis, otitis media and pneumonia. The most frequent reasons for physician visits included acute upper respiratory infections, otitis media and bronchiolitis. The highest HR were detected for chronic bronchitis 1.64 (1.13-2.39), hearing loss 1.56 (1.14-2.15) and bacterial diseases 1.28 (1.09-1.49). The mean total cost for late-preterm infants during the first 2 years of life was $2568 CAD compared with $1285 CAD for term infants, cost ratio =1.99 (95% CI 1.90 to 2.09). In the third year of life, the cost ratio reduced to 1.46 (95% CI 1.39 to 1.54). CONCLUSIONS: Late-preterm infants are at higher risk of specific morbidities compared with term infants. Their mean total costs fall from almost double that of term infants during the first 2 years of life, to just 46% greater in the third year of life.

Quality assessment of clinical practice guidelines for the prescription of antidepressant drugs during pregnancy.

Antidepressant use during the gestational period remains a controversial issue. The objective of this study was to appraise the quality of the available clinical practice guidelines (CPGs) that includes recommendations for antidepressant use during pregnancy. We systematically searched for documents published between January 2000 and September 2010 in MEDLINE / TRIP database and on clearing houses and main scientific societies' websites. Four appraisers evaluated each guideline using the Appraisal of Guidelines for Research and Evaluation tool (AGREE II). Intra-class correlation coefficients (ICC) with 95% confidence intervals (CI) were calculated as an overall indicator of agreement. Twelve CPGs were included from a total of 539 references. Only two guidelines were specifically addressed to pregnant women. The overall agreement among reviewers was high (ICC: 0.94, 95% CI: 0.86-0.98). The mean scores and standard deviation (SD) for each of the AGREE II domains were: scope and purpose: 84.4% (12); stakeholder involvement: 67.4% (29.8); rigor of development: 68.6% (19.8); clarity and presentation: 83.4% (17.4); applicability: 44% (37.3); and editorial independence: 62.1% (30.4). After standardizing the scores of the 12 guidelines, 5 were considered as being "recommended", 5 as "recommended with modifications, and 2 as "not recommended". Among the five recommended guidelines, two were specifically conceived to the gestational period. CPGs containing recommendations for antidepressant use during pregnancy were of moderate to high quality. Future guidelines should take into account the observed drawbacks in some domains, and specifically focus a more in depth approach of depression during pregnancy.

Impact of adherence to antihypertensive agents on clinical outcomes and hospitalization costs.

BACKGROUND: Cardiovascular diseases (CVD) represent a heavy economic burden on individuals, health services, and society. Low adherence to antihypertensive (AH) agents is acknowledged as a major contributor to the lack of blood pressure control, and may have a significant impact on clinical outcomes and healthcare costs. OBJECTIVES: To evaluate the impact of low adherence to AH agents on cardiovascular outcomes and hospitalization costs. METHODS: A cohort of 59,647 patients with essential hypertension was reconstructed from the Régie de l'assurance maladie du Québec and Med-Echo databases. Subjects included were between 45 and 85 years of age, without any evidence for symptomatic CVD, newly treated with AH agents between 1999 and 2002 and followed-up for a 3-year period. Adherence to AH agents was categorized as >or=80% or <80%. The adjusted odds ratio (OR) for CVD events between the 2 adherence groups was estimated using a polytomous logistic analysis. A 2-part model was applied for hospitalization costs. RESULTS: Patients with low adherence were more likely to have coronary disease (OR, 1.07; 95% confidence interval [CI], 1.00-1.13), cerebrovascular disease (OR, 1.13; 95% CI, 1.03-1.25), and chronic heart failure (OR, 1.42; 95% CI, 1.27-1.58) within the 3-year follow-up period. Among hospitalized patients, low adherence to AH therapy was associated with increased costs by approximately $3574 (95% CI, $2897-$4249) per person within a 3-year period. CONCLUSIONS: Low adherence to AH agents is correlated with a higher risk of vascular events, hospitalization, and greater healthcare costs. An increased level of adherence to AH agents should provide a better health status for individuals and a net economic gain.

Relationship between adherence level to statins, clinical issues and health-care costs in real-life clinical setting.

OBJECTIVE: Statins have been shown to reduce the risk of major cardiovascular disease. We recognize that there is a major gap between the use of statins in actual practice and treatment guidelines for dyslipidemia. Low adherence to statins may have a significant impact on clinical issues and health-care costs. The objective is to evaluate the impact of low adherence to statins on clinical issues and direct health-care costs. METHODS: A cohort of 55,134 patients newly treated with statins was reconstructed from the Régie de l'Assurance Maladie du Québec and Med-Echo databases. Subjects included were aged between 45 and 85, initially free of cardiovascular disease, newly treated with statins between 1999 and 2002, and followed-up for a minimum of 3 years. Adherence to statins was measured in terms of the proportion of days' supply of medication dispensed over a defined period, and categorized as >or=80% or <80%. The adjusted odds ratio (OR) of cardiovascular events between the two adherence groups was estimated using a polytomous logistic analysis. The mean costs of direct health-care services were evaluated. A two-part model was applied for hospitalization costs. RESULTS: The mean high adherence level to statins was around to 96% during follow-up; and this value was at 42% for the low adherence level. The patients with low adherence to statins were more likely to have coronary artery disease (OR 1.07; 95% confidence interval [CI], 1.01-1.13), cerebrovascular disease (OR 1.13; 95% CI 1.03-1.25), and chronic heart failure within 3-year period of follow-up (OR 1.13; 95% CI 1.01-1.26). Low adherence to statins was also associated with an increased risk of hospitalization by 4% (OR 1.04; 95% CI 1.01-1.09). Among patients who were hospitalized, low adherence to statins was significantly associated with increase of hospitalization costs by approximately $1060/patient for a 3-year period. CONCLUSION: Low adherence to statins was correlated with a higher risk of cardiovascular disease, hospitalization rate, and hospitalization costs. An increased level of adherence to statins agents should provide a better health status for individuals and a net economic gain.

Validity of perinatal pharmacoepidemiologic studies using data from the RAMQ administrative database.

BACKGROUND: The RAMQ prescription claims database (RAMQ-Rx) is increasingly being used in perinatal pharmacoepidemiologic studies; but, there are reasons to believe that results generated with the RAMQ-Rx might not be generalizable to all patient populations. OBJECTIVES: Compare characteristics between pregnant women insured by the RAMQ-Rx and those insured by a private drug insurance plan. METHODS: A prospective study performed within the population of pregnant women receiving prenatal care at different obstetrics and gynecology clinics affiliated to the University of Montreal, Canada, was conducted from October 2004 to March 2006. Women were eligible if they were > or =18 years of age, < or =16 weeks of gestation at the time of their first prenatal visit, and able to read and understand French or English. Eligible women were asked to fill out a self-administered questionnaire. RESULTS: Three hundred and sixty-three women met inclusion criteria, of which 99 (27%) had RAMQ-Rx coverage, and 264 (73%) had a private drug insurance coverage. Compared to those who were covered by private drug insurance plans, those insured by the RAMQ-Rx were younger (30.7yrs vs. 32.1yrs; P=0.03), more likely to be immigrant (60% vs. 24%; P<0.01), and have a household income below poverty level (39% vs. 2%; P<0.01). They were also less likely to be Caucasian (69% vs. 86%; P<0.01), employed (51% vs. 87%; P<.01), and have a post-secondary education (76% vs. 95%; P<0.01). No differences were observed on smoking status and alcohol use during pregnancy. CONCLUSIONS: There are substantial differences between pregnant women insured by the RAMQ-Rx and those insured by private drug insurance plans. However, these differences will most likely limit generalizability, but not internal validity, of studies using data from the RAMQ-Rx database.

Antidepressant therapy during pregnancy: an insight on its potential healthcare costs.

BACKGROUND: Information on healthcare costs associated with poorly treated psychiatric disorders during and after pregnancy is limited. OBJECTIVE: To compare the direct healthcare costs, during and after pregnancy, between women who continue their antidepressant therapy during the whole gestational period and those who discontinue their treatment during the first trimester. METHODS: Data from a 'Medications and Pregnancy' registry were used. Eligible women were 1) aged 15 - 45, 2) insured by the Quebec drug plan for > or =12 months prior to, during, and > or =3 months after pregnancy, 3) had > or =1 diagnoses of psychiatric disorders before pregnancy, 4) used antidepressants for . or =30 days in the year before pregnancy, and 5) had delivered. Women who continued their antidepressant therapy throughout pregnancy (Group 1) were compared to those who discontinued during the first trimester (Group 2). Healthcare costs, expressed as mean total costs and cost ratios, were determined during and after pregnancy. RESULTS: In total, 2822 women met inclusion criteria. Of these, 501 (17.8%) were in Group 1, and 676 (23.4%) in Group 2. The median number of days of antidepressant use before pregnancy was higher in Group 1 (260 days vs. 144 days, p<.01); the proportion of women visiting a psychiatrist was also higher in Group 1 (33.7% vs. 26.8%, p<.01). The mean total cost during pregnancy in Groups 1 and 2 were $2981.5 vs. $1842.9 (p<.01), respectively, and after pregnancy were $1761.2 vs. $1024.9 (p<.01), respectively. When prescription costs were excluded, these differences in costs were no longer significant. CONCLUSIONS: Women who use antidepressants during pregnancy are likely to have disorders of greater severity compared to those who discontinue during the first trimester. They incur significantly greater healthcare costs. However, this increased cost is attributable to higher prescription costs.

Patterns and utilization of isotretinoin for acne from 1984 to 2003: is there need for concern?

OBJECTIVES: To (1) describe the patterns and trends of isotretinoin utilization between 1984 and 2003, (2) describe the characteristics of isotretinoin users within that same time period, (3) identify and quantify predictors of isotretinoin use, and (4) describe the impact of guidelines on isotretinoin utilization between 1984 and 2003. METHODS: Using the Régie de l'Assurance Maladie du Québec (healthcare utilization, medications) and Med-Echo (hospitalizations) administrative databases, we conducted a descriptive study on a population-based sample of first-time isotretinoin users from 1984 to 2003. We determined the characteristics of these users, predictors of an isotretinoin treatment >or=20 weeks, and impact of guidelines on the number of new isotretinoin users. Guidelines included the implementation of the Pregnancy Prevention Program (PPP - 1988) and the Dear Healthcare Professional Letter regarding possible psychiatric risks issued to Canadian physicians (DHPL - 2001). RESULTS: Mean (SD) age was 23.9 (7.6) years; 50% males, 52% welfare recipients, 77% urban dwellers, and 55% of prescriptions were written by dermatologists. Sixty-four percent of patients did not receive any anti-acne medications in the 12 months prior to receiving isotretinoin. Thirty-five percent of patients had an isotretinoin treatment >or=20 weeks suggested by product guidelines. The odds ratio of having a treatment >or=20 weeks significantly increased after the implementation of the PPP and other guidelines. There was no statistically significant decrease in the number of new isotretinoin users following the implementation of the PPP and DHPL. CONCLUSION: These data suggest inappropriate isotretinoin utilization, even more so after guidelines were promulgated.