Jean-Pascal Fournier

Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain

IMPORTANCE Tramadol is a weak opioid analgesic whose use has increased rapidly, and it has been associated with adverse events of hypoglycemia. OBJECTIVE To assess whether tramadol use, when compared with codeine use, is associated with an increased risk of hospitalization for hypoglycemia. DESIGN, SETTING, AND PARTICIPANTS A nested case-control analysis was conducted within the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database of all patients newly treated with tramadol or codeine for noncancer pain between 1998 and 2012. Cohort and case-crossover analyses were also conducted to assess consistency of the results. MAIN OUTCOMES AND MEASURES Cases of hospitalization for hypoglycemia were matched with up to 10 controls on age, sex, and duration of follow-up. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated comparing use of tramadol with codeine. A cohort analysis, with high-dimensional propensity score-adjusted hazard ratios (HRs) and 95% CIs, was performed comparing tramadol with codeine in the first 30 days after treatment initiation. Finally, a case-crossover analysis was also performed, in which exposure to tramadol in a 30-day risk period immediately before the hospitalization for hypoglycemia was compared with 11 consecutive 30-day control periods. Odds ratios and 95% CIs were estimated using conditional logistic regression analysis. RESULTS The cohort included 334,034 patients, of whom 1105 were hospitalized for hypoglycemia during follow-up (incidence, 0.7 per 1000 per year) and matched to 11,019 controls. Compared with codeine, tramadol use was associated with an increased risk of hospitalization for hypoglycemia (OR, 1.52 [95% CI, 1.09-2.10]), particularly elevated in the first 30 days of use (OR, 2.61 [95% CI, 1.61-4.23]). This 30-day increased risk was confirmed in the cohort (HR, 3.60 [95% CI, 1.56-8.34]) and case-crossover analyses (OR, 3.80 [95% CI, 2.64-5.47]). CONCLUSIONS AND RELEVANCE The initiation of tramadol therapy is associated with an increased risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.

Drug interactions between antihypertensive drugs and non‐steroidal anti‐inflammatory agents: a descriptive study using the French Pharmacovigilance database

Drug–drug interactions (DDIs) between antihypertensive drugs and non‐steroidal anti‐inflammatory drugs (NSAIDs) can lead to adverse drug reactions (ADRs). Guidelines are available to help prescribers deal with these drug associations, but their implementation is not well evaluated. The aims of this study were to assess the prevalence of NSAIDs exposure in patients treated with antihypertensive drugs, using the French Pharmacovigilance database, and explore the ADRs related to DDIs between antihypertensive drugs and NSAIDs. Over the 11, 442 notifications of ADRs recorded in this database in patients treated with oral antihypertensive drugs between 2008 and 2010, 517 (4.5 and 95% CI: 4.1–4.9) also included exposure to NSAIDs. These subjects were more frequently women, took more drugs in general, and were younger and less frequently treated with antiplatelet drugs. In 24.2% of them (125 patients), a DDI between NSAIDs and antihypertensive drugs was potentially the cause of the reported ADR. Acute renal failure caused by DDIs between NSAIDs and angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or diuretics was the most frequently reported ADR (20.7%). Finally, in the French Pharmacovigilance database, around one‐fourth of associations NSAIDs + antihypertensive drugs are associated with a ‘serious’ ADR (mainly acute renal failure), suggesting that this well‐known DDI is not enough taken into account by prescribers.

Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus

Background: Small cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with type 2 diabetes mellitus. Methods: Using the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort. Results: A total of 5689 patients with treated hypothyroidism and 59 937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v. 125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09–2.20), with the highest risk in the 90–180 days after initiation (adjusted HR 2.30, 95% CI 1.00–5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69–1.36). Interpretation: In this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.

Rates, Delays, and Completeness of General Practitioners’ Responses to a Postal Versus Web-Based Survey: A Randomized Trial

Background Web-based surveys have become a new and popular method for collecting data, but only a few studies have directly compared postal and Web-based surveys among physicians, and none to our knowledge among general practitioners (GPs). Objective Our aim is to compare two modes of survey delivery (postal and Web-based) in terms of participation rates, response times, and completeness of questionnaires in a study assessing GPs’ preventive practices. Methods This randomized study was conducted in Western Switzerland (Geneva and Vaud) and in France (Alsace and Pays de la Loire) in 2015. A random selection of community-based GPs (1000 GPs in Switzerland and 2400 GPs in France) were randomly allocated to receive a questionnaire about preventive care activities either by post (n=700 in Switzerland, n=400 in France) or by email (n=300 in Switzerland, n=2000 in France). Reminder messages were sent once in the postal group and twice in the Web-based group. Any GPs practicing only complementary and alternative medicine were excluded from the study. Results Among the 3400 contacted GPs, 764 (22.47%, 95% CI 21.07%-23.87%) returned the questionnaire. Compared to the postal group, the participation rate in the Web-based group was more than four times lower (246/2300, 10.70% vs 518/1100, 47.09%, P<.001), but median response time was much shorter (1 day vs 1-3 weeks, P<.001) and the number of GPs having fully completed the questionnaire was almost twice as high (157/246, 63.8% vs 179/518, 34.6%, P<.001). Conclusions Web-based surveys offer many advantages such as reduced response time, higher completeness of data, and large cost savings, but our findings suggest that postal surveys can be still considered for GP research. The use of mixed-mode approaches is probably a good strategy to increase GPs’ participation in surveys while reducing costs.

More on the "Triple Whammy": antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury - a case/non-case study in the French pharmacovigilance database.

Abstract It has been suggested that the risk of acute kidney injury (AKI) increases with the number of drugs associated between non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEis) [or angiotensin receptor blockers (ARBs)] and diuretics. We aimed to investigate whether the number of drugs associated between NSAIDs, ACEis, ARBs and diuretics was associated to disproportionate reporting of AKI in the French Pharmacovigilance Database. In reports of Adverse Drug Reactions (ADRs) recorded between 01 January 2008 and 31 December 2010, we selected patients whose medications included at least one oral antihypertensive drug. We used a case/non-case methodology. Cases were AKI and non-cases were all the remaining reports. Among the 11,442 ADR reports in patients under antihypertensive drug recorded in the French Pharmacovigilance Database, 837 ADRs were AKI (7.3%, 95% CI 6.8–7.8). AKI and the number of drugs associated were disproportionately reported (one drug alone: adjusted ROR 2.19, 95% CI: 1.65–2.89, two drugs: adjusted ROR 5.27, 95% CI: 4.00–6.94, three and more: adjusted ROR 16.46, 95% CI: 11.38–23.80). There was no significant association between NSAIDs’ half-lives and reporting of AKI (adjusted ROR = 0.54, 95% CI: 0.25–1.15). Given the widespread use of these hazardous drugs in general population, caution is needed when they are associated.

Concurrent use of statins and hormone therapy and risk of venous thromboembolism in postmenopausal women: a population-based case-control study.

ObjectiveStatins and hormone therapy (HT), often used concurrently in postmenopausal women, have antagonist effects on the risk of venous thromboembolism (VTE). This study aims to determine whether statins attenuate the increased VTE risk associated with HT. MethodsWe conducted a nested case-control study within a population-based cohort of women aged 50 to 79 years between January 1, 1987 and March 1, 2008, who were identified from the UK General Practice Research Database. Cases of VTE occurring during follow-up were identified and each matched with up to 10 controls from the cohort. Odds ratios (ORs) for the effects of concurrent HT and statin use on the risk of VTE were estimated using conditional logistic regression with interaction terms. ResultsThe cohort included 955,582 postmenopausal women, with 23,505 cases of VTE matched with 231,562 controls. Regardless of any HT use, current use of statins was associated with a decreased risk of VTE (OR, 0.83; 95% CI, 0.78-0.87). The interaction between statin use and HT use was of borderline significance (P = 0.053). Consequently, among nonusers of statins, the risk of VTE was elevated with current use of oral estrogen and progestogen combinations (OR, 1.55; 95% CI, 1.45-1.66) but this risk was not elevated among users of statins (OR, 0.98; 95% CI, 0.56-1.73). There was no such modification of the OR with statins and other HT types and formulations. ConclusionsStatins could potentially attenuate the increased risk associated with HT combinations of oral estrogens and progestogens. This observation needs further confirmation in other large cohorts.

Predictors of Cardiovascular Hospitalization in Giant Cell Arteritis: Effect of Statin Exposure. A French Population-based Study.

Objective. To identify predictors and protectors for cardiovascular hospitalization in a giant cell arteritis (GCA) population-based cohort. Methods. Using the French National Health Insurance system, we included patients with incident GCA from the Midi-Pyrenees region, southern France, from January 2005 to December 2008 and randomly selected 6 controls matched by sex and age at calendar date. We used a Cox model to identify independent predictors for cardiovascular hospitalization [combining stroke, coronary artery disease (CAD), heart failure, peripheral arterial disease, or cardiac arrhythmias]. Results. Among 103 patients with GCA followed 48.9 ± 14.8 months, the incidence rates of hospitalization for cardiovascular disease, atherosclerotic disease (combining stroke, CAD, and peripheral arterial disease), heart failure, and cardiac arrhythmias were 48.6, 17.5, 14.8, and 9.8 events per 1000 person-years versus 14.9, 4.6, 6.2, and 2.5 events per 1000 person-years among controls, respectively. In patients with GCA, cardiovascular comorbidities at diagnosis (HR 6.2, 2.0–19.2), age over 77 years (HR 5.0, 1.40–17.54), as well as the cumulative defined daily dose of statins (HR 0.993, 0.986–0.999) were independent predictors for subsequent cardiovascular hospitalization. None of the 25 patients with GCA who were taking platelet aggregation inhibitors experienced a cardiovascular hospitalization during followup. Conclusion. Patients with GCA present a high risk of cardiovascular hospitalization after diagnosis. In patients with incident GCA from the Midi-Pyrenees region, southern France, statin therapy was associated with reduced cardiovascular hospitalizations.

Identifying competencies required for medication prescribing for general practice residents: a nominal group technique study

BackgroundTeaching of medication prescribing is a specific challenge in general practice curriculum. The aim of this study was to identify and rank the competencies required for prescribing medication for general practice residents in France.MethodsQualitative consensus study using the nominal group technique. We invited different stakeholders of the general practice curriculum and medication use in primary care to a series of meetings. The nominal group technique allowed for the quick development of a list of consensual and ranked answers to the following question: “At the end of their general practice curriculum, in terms of medication prescribing, what should residents be able to do?”.ResultsFour meetings were held that involved a total of 31 participants, enabling the creation of a final list of 29 ranked items, grouped in 4 domains. The four domains identified were ‘pharmacology’, ‘regulatory standards’, ‘therapeutics’, and ‘communication (both with patients and healthcare professionals)’. Overall, the five items the most highly valued across the four meetings were: ‘write a legible and understandable prescription’, ‘identify specific populations’, ‘prescribe the doses and durations following the indication’, ‘explain a lack of medication prescription to the patient’, ‘decline inappropriate medication request’. The ‘communication skills’ domain was the domain with the highest number of items (10 items), and with the most highly-valued items.ConclusionThe study results suggest a need for developing general practice residents’ communication skills regarding medication prescribing.

Overview of preventive practices provided by primary care physicians: A cross-sectional study in Switzerland and France

Background A range of preventive practices are recommended to reduce the burden of chronic diseases. The aim of our study was to describe the preventive practices of French-speaking primary care physicians. Methods A cross-sectional survey was conducted in 2015 in a randomly selected sample of 1100 primary care physicians (700 in Switzerland, 400 in France). The physicians were asked how often they performed the following recommended preventive practices: blood pressure, weight and height measurements, screening for dyslipidemia, screening for alcohol use and brief intervention, screening for smoking (and brief advice for smokers), colon and prostate cancer screening, and influenza immunization. Response options on the five points Likert scale were never, rarely, sometimes, often, always. The physicians were considered to be performing the preventive practice regularly if they declared performing it often or always. Results 518 participants (47%) returned the questionnaire. The most commonly reported preventive practices were: blood pressure measurement (99%), screening for smoking (95%) and brief advice for smokers (95%). The least frequently reported practices were annual influenza immunization for at-risk patients <65 years (37%), height measurement (53%), screening for excessive alcohol use (60%) and brief advice for at-risk drinkers (67%). All other practices were reported by 70 to 90% of participants. Conclusion Whereas some preventive practices now appear to be part of primary care routine, others were not applied by a large proportion of primary care physicians in our study. Further studies should explore whether these findings are related to miss-knowledge of common guidelines, or other implementation barriers in this primary care context.

Tramadol for Noncancer Pain and the Risk of Hyponatremia

BACKGROUND Case reports have signaled a possible association between tramadol, a weak opioid analgesic, and hyponatremia. The objective of this study was to determine whether the use of tramadol is associated with an increased risk of hyponatremia, when compared with codeine. METHODS Using the UK Clinical Practice Research Datalink and Hospital Episodes Statistics database, a population-based cohort of 332,880 patients initiating tramadol or codeine was assembled from 1998 through 2012. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for hyponatremia associated with the use of tramadol, compared with codeine, in the first 30 days after initiation. A similar analysis was conducted within a highly restricted sub-cohort, which additionally excluded patients with any serum sodium level abnormality in the year before cohort entry. All models were adjusted for propensity score quintiles. RESULTS The incidence rates of hospitalization for hyponatremia were 4.6 (95% CI, 2.4-8.0) and 1.9 (95% CI, 1.4-2.5) per 10,000 person-months for tramadol and codeine users, respectively. In the adjusted model, the use of tramadol was associated with a 2-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 2.05; 95% CI, 1.08-3.86). In the highly restricted sub-cohort, the use of tramadol was associated with an over 3-fold increased risk of hospitalization for hyponatremia, compared with codeine (adjusted HR 3.54; 95% CI, 1.32-9.54). CONCLUSIONS In this first population-based study, the use of tramadol was associated with an increased risk of hyponatremia requiring hospitalization.