Preventable adverse drug reactions

Query 16-03: Preventable adverse drug reactions (ADR) as percentage of total ADRs

This project was funded in June 2016 for two years. The query will be addressed in two phases. In phase I, we are conducting a retrospective chart review of patients who were diagnosed with an ADE to determine the preventability of the event, identify contributing factors, determine the ADE-related harm and interventions required, and identify the kind of drug re-exposure that would likely cause a future repeat ADE. In phase II, we will link phase I data to BC health data (PharmaNet) to determine the proportion of ADE patients that were re-exposed to contraindicated medications.

At this point in time, we have completed phase I data collection. Data of 1234 patients were studied and 1356 ADEs were found. ADEs due to adverse drug reactions (35%) and non-adherence (19%) were most common, most moderate (65%) or severe (31%) and two-thirds required either major or minor interventions in hospital.  We deemed 64% (95%CI:62-67%) of ADEs to be preventable and 29% (95%CI:26-31%) were repeat events. The most commonly implicated drug classes were coumarin derivatives (9%), and opiate agonists (9%), and common contributing factors included inadequate patient counselling (16%), lack of follow-up after a change in regimen (12%), and insufficient laboratory monitoring (11%). On multivariable patient-level analyses, mental health diagnoses, diabetes, and a prior ADE to the same drug were associated with patients having preventable ADEs. Diabetes and renal failure were significant in association with patients having repeat ADEs.

We are currently waiting for data delivery for Phase II.

Hohl et al. Repeat exposures to culprit drugs contribute to adverse drug events in emergency department patients. 2017 (CAEP abstract).

Hohl et al. Preventable adverse drug events in Canadian emergency departments. 2017 (CAEP abstract).

Woo et al. Factors contributing to the development of adverse drug events treated in emergency departments. 2017 (CAEP abstract).

Wickham et al. Preventable and repeat adverse drug events in Canadian emergency department patients. 2017 (CAHSPR abstract).

Woo et al. Preventable adverse drug events in Canadian emergency departments. 2019 (CAEP abstract).

Hohl et al. Repeat adverse drug events to outpatient medications. (Manuscript accepted March 2019 to CMAJ Open).

Woo SA, Cragg A, Wickham ME, Peddie D, Balka E, Scheuermeyer F, Villanyi D, Hohl CM. Methods for evaluating adverse drug event preventability in emergency department patients. BMC Red Res Methodol. 2018;18:160.

Hohl et al. Repeat adverse drug events to outpatient medications. CMAJ Open (Accepted)

For more information contact: Jessica (Lifang) Wang. Research Coordinator. [email protected]   514.934.1934 ext.44718

Retinal conditions: anti-VEGF injections

Query 15-11: Intravitreal bevacizumab for retinal conditions: real-world safety assessment

This project was originated with a query by CADTH and funded in June 2016 for one year. The objective of this study is to examine complications of anti-VEGF injections in four different cohorts: i) neovascular age-related macular degeneration cohort (AMD cohort); ii) diabetic retinopathy cohort; iii) diabetic macular edema cohort; and iv) retinal neovascularisation cohort.

We evaluated the risk associated with current exposure of anti-VEGF agents, examined as both therapeutic class and individual drugs, on primary and secondary outcomes in Marketscan data (2011-2015). We also presented updated results of the AMD cohort for anti-VEGF agents examined as individual drugs, using one additional year of Markescan data (2011-2016) in a report to DSEN in July 2018. We presented these alongside results from one previously published population-based nested case-control study using health care data sets in Ontario (April 2006-March 2011) comparing serious adverse events between bevacizumab and ranibizumab. We noted that bevacizumab was widely used in Ontario prior to public formulary coverage through the Ontario Drug Benefit (ODB) program. The use of bevacizumab for retinal diseases has become negligible in Ontario among patients 65 years of age and older (ODB eligible population) since the initiation of coverage within the ODB formulary for the Health Canada approved drug ranibizumab.

Summary of the results

Our Marketscan results suggested similar risk of primary (ocular) outcomes between bevacizumab or aflibercept versus the comparator ranibizumab.

Similar results were found in our analysis for systemic events. For the analysis with the composite of systemic outcomes using Marketscan cohort  the adjusted HR was 1.11 (95% CI: 0.86-1.44) for bevacizumab and 0.86 (95% CI: 0.68-1.09) for aflibercept, both compared to ranibizumab.

Comparing specific systemic outcomes in the Marketscan data and the Ontario study  several results appear to have roughly the same risk direction and risk magnitude. In the Ontario study although there was no definite statistical difference, the adjusted estimates did include the possibility that AMI events were slightly more associated with bevacizumab versus ranibizumab (adjusted OR, aOR: 1.23; 95% CI: 0.85-1.77). In the Marketscan cohort, we found even less suggestion of greater association of bevacizumab with AMI (adjusted HR, aHR: 1.17; 95% CI: 0.86-1.57, comparator was ranibizumab). The risk of stroke and CVA were also very similar between the two cohorts (aOR: 1.03; 95% CI: 0.67-1.60, in the Ontario study, and aHR: 1.00; 95% CI: 0.77-1.29, in the Marketscan cohort). For venous thromboembolism and DVT, both estimates showed indeterminant results. In the Ontario study, the aOR was 0.92 comparing bevacizumab to ranibizumab users (95% CI: 0.51-1.69), while in the Marketscan cohort the aHR was 1.38 (95% CI: 0.75-2.53).

We are close to finalizing agreements with Canadian Partnership for Tomorrow Cohorts (CPTP) the Ontario Health Study and the BC Generations Project, as well as with the Canadian Institute for Health Information (CIHI)’s National Prescription Drug Utilization Information System Metadata (NPDUIS). This will provide updated analysis on new agents. We have also initiated an application with CPTP’s Alberta’s Tomorrow Project as well as beginning the process to access administrative health data from Atlantic PATH.

This query has been finalized, a full report was submitted in December 2018. Our real-world population-based samples suggest that different anti-VEGF agents have similar safety profiles regarding systemic events. In the direct comparisons of different anti-VEGF agents in diabetic retinal conditions, we found an overall greater risk of adverse ocular outcomes (aHR: 1.52; 95% CI: 1.34-1.72) for bevacizumab versus ranibizumab. We also found a lower risk of vitreous hemorrhage (aHR: 0.75; 95% CI: 0.60-0.94) with aflibercept versus ranibizumab. However, total adverse ocular outcomes were not clearly different for aflibercept versus ranibizumab. In AMD patients, for aflibercept versus ranibizumab, we found a higher risk of uveitis (aHR: 1.67; 95% CI: 1.02 -2.74), and a lower risk of vitreous hemorrhage (aHR: 0.49; 95% CI: 0.26-0.94). However, total adverse ocular outcomes were not clearly different for aflibercept versus ranibizumab in AMD.

Moura et al. Safety of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections for the treatment of patients with age-related macular degeneration (AMD). 2017 (ICPE abstract)

Machado et al. Safety of intravitreal injections for the treatment of patients with diabetic retinopathy: a population-based study. 2017 (ICPE abstract)

Full report submitted to DSEN and query submitters.

For more information contact: Jessica (Lifang) Wang. Research Coordinator. [email protected]   514.934.1934 ext.44718

Hypertension in non-diabetic patients: thiazide diuretics and ACE inhibitors

Query 11-03: How do thiazide diuretics compare to ACE inhibitors and combination antihypertensive products in terms of effectiveness (and cost-effectiveness) for the management of hypertension in non-diabetic patients?

This project, which originated with a query by British Columbia Ministry of Health, was funded in 2013 for 3 years. Initial results have been generated and discussed with DSEN and Health Canada. Additional analysis have been conducted with Marketscan database (2011-2014). We constructed a retrospective cohort of non-diabetic hypertensive adults who were new users of thiazide diuretics (TD), converting enzyme inhibitor (ACEi), calcium-channel blockers (CCB), or angiotensin-2 antagonists (ARB) as monotherapy. We performed Cox regression models to assess the risk for drug discontinuation, adding a drug or switching to a new drug, and a composite outcome of clinical events including myocardial infarction, unstable angina, stroke, and heart failure. The TD group was more likely to discontinue therapy versus ACEI (HR=0.79 95%CI 0.74-0.84), ARB (HR=0.66 95%CI 0.61-0.72) and CCB (HR=0.86 95%CI 0.80-0.92). Similar trends were found for adding a drug or switching to a new drug. There was a higher risk for the clinical events in ACEi (HR=1.46 95%CI 1.08-1.96) or CCB (HR=1.54 95%CI 1.13-2.11) groups versus TD, while the comparison with ARB were inconclusive.

Machado et al. Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population-based study. J Clin Hypertens (Greenwich). 2017 Oct;19(10):999-1009.

Moura et al. Comparison of the Effect of Thiazide Diuretics and Other Antihypertensive Drugs on Central Blood Pressure: Cross-Sectional Analysis Among Nondiabetic Patients; J Clin Hypertens. 2015;17:848–854

Moura et al. Hypertension treatment and cross-sectional relationship with peripheral and central blood pressure in non–diabetic participants from the CARTaGENE Cohort Study. 2014. (CAPT abstract)

Machado MAA et al. Comparative effectiveness of thiazide diuretics and other monotherapies for nondiabetic individuals with hypertension. 2016. (CAPT abstract)

For more information contact: Jessica (Lifang) Wang. Research Coordinator. [email protected]   514.934.1934 ext.44718