Studies – clinical trials (randomized clinical trials, quasi-randomized clinical trials, controlled clinical trials) and observational studies (case-control, cohort, case-crossover, case-time-control, controlled before after studies and interrupted time series), case series/reports, safety bulletins and primary surveillance data from drug regulatory agencies
Time – studies of all durations
Other - No other restrictions will be imposed (e.g., language, publication status, or year of dissemination).
An experienced librarian (Perrier) will conduct the literature search and the search strategy will be peer reviewed by another librarian using the Peer Review of Electronic Search Strategies (PRESS) checklist. We will search the following electronic databases from inception onwards: Medline (1946 to present), EMBASE (1947 to present), Cochrane Central Register of Controlled Trials (CENTRAL). We will use the metaRegister of trial protocols to simultaneously search multiple trial registry sites (http://www.controlled-trials.com/mrct/) and conference abstracts (e.g., American Academy of Pain Medicine annual meeting, American Pain Society annual meeting, International Congress for Neuropathic Pain, American Academy of Neurology annual meeting) for difficult to locate or unpublished (i.e., grey) literature. The following Regulatory Authority safety alerts will be searched: Food and Drug Administration MedWatch (United States), European Medicines Evaluation Agency's European Public Assessment Reports, Medicines and Healthcare products Regulatory Agency (United Kingdom), Australia Adverse Drug Reactions Bulletin, Health Canada MedEffect and the Canadian Adverse Drug Information System. We will also search the World Health Organization Uppsala Monitoring Centre.
Types of study to be included
Inclusion: clinical trials (randomized clinical trials, quasi-randomized clinical trials, controlled clinical trials) and observational studies (case-control, cohort, case-crossover, case-time-control, controlled before after studies and interrupted time series), case series/reports, safety bulletins and primary surveillance data from drug regulatory agencies
Exclusion: qualitative studies
Condition or domain being studied
Heart failure and edema
Inclusion: Adults (age=18 years) newly started on pregabalin
Exclusion: Children (age=17 years), animal studies
Inclusion: Newly started pregabalin, any dose.
Exclusion: Start date of pregabalin unknown.
Inclusion: Placebo, conventional medical care, gabapentin
Time – We will include studies of all durations
No other restrictions will be imposed (e.g., language, publication status, or year of dissemination).
Heart failure (primary)
Edema, weight gain
Data extraction, (selection and coding)
The eligibility criteria will be pilot-tested on a random sample of 50 citations, which will be screened by the entire team. A kappa statistic will be calculated to measure inter-rater reliability and screening will only commence when =60% agreement is achieved. Using the online SysRev Tool (proprietary software available at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital), two reviewers will subsequently screen the literature search results at citation (titles and abstracts) and full-text article screening levels in duplicate. Conflicts will be resolved by discussion between the reviewers or with a third reviewer, if necessary.
Some of the included study reports might be studies examining pregabalin amongst the same patient population (i.e., companion reports). To identify studies that generate multiple reports (duplication bias), we will record the authors' names, study location and setting, dose and frequency of pregabalin administration (intervention), number of participants and baseline data, and date and duration of the study. Once identified, we will link these reports. We will consider the report with the longest duration of follow up or primary outcome of interest as the major publication and the rest will be considered companion reports, providing supplementary information.
This is a systematic review of adverse events, which are often underreported in randomized clinical trials. To ensure that trials not reporting this information are not systematically different than those that do (i.e., outcome reporting bias), study authors of trials that do not report on our outcomes of interest will be contacted. We will exclude nonrandomized studies that do not include our primary or secondary outcome.
Data collection process
A data abstraction form will be developed and amended following a pilot-test on a 5% random sample of the included studies by all reviewers. Two reviewers will subsequently perform all data abstraction in duplicate. Conflicts will be resolved by discussion or if necessary, a third reviewer will be involved. We will attempt to contact study authors to verify data, as necessary. Data categories that will be collected are included below.
The following data categories will be collected:
1. Patient characteristics:
a) Total number (at baseline, study end)
c) Diagnostic criteria
d) Age (median, interquartile range)
e) Sex (% female)
j) Date of study
2. Study characteristics:
a) Report ID (created by review author)
b) Citation and contact details
c) Confirm eligibility for review
d) Reason for exclusion
e) Study design
g) Setting (outpatient, inpatient)
h) Publication status
i) Intervention and comparator descriptions (dosage, intensity, frequency)
k) Allocation to groups (concealed randomization, quasi-randomization, by other action of researchers, time differences, location differences, policy/public health decisions, cluster/individual preferences)
l) Prospective. Whole vs. which parts (ID of participating clusters, assessment of baseline, allocation to intervention, assessment of outcomes, generation of hypotheses)
m) Duration of invention and follow-up
n) Outcomes examined
o) Variables that were assessed between groups (potential confounders, baseline assessment of outcome variables)
p) Funding source
q) Key conclusions of the study authors
r) Miscellaneous comments from study authors
3. Quality/Risk of bias
a) Cochrane 5.1 collaboration's tool for assessing risk of bias categories (randomized controlled trials)
b) Newcastle-Ottawa Scale for assessing risk of bias categories (cohort and case-control studies)
c) Effective Practice and Organization of Care (EPOC) for assessing risk of bias of controlled clinical trials, controlled before-after trials and interrupted time series.
d) Naranjo Adverse Drug Reporting Probability Scale for case reports/series.
e) McMaster Quality Assessment Scale for Harms Study (McHarm)
b) Number of events in intervention and control/comparison groups
e) Resulted in withdrawals
f) Collected at follow-up (frequency of follow-up)
g) Collected by patient diary or checklist or spontaneous reporting
h) Early vs. late withdrawal
i) Other adverse events reported
Risk of bias (quality) assessment
Risk of bias
For randomized clinical trials, we will use the Cochrane Collaboration's 5.1.0 tool for assessing risk of bias. This 7-item tool assesses for selection bias, performance bias, detection bias, attrition bias, and reporting bias.
For nonrandomized studies and observational studies, a risk of bias tool has not been validated. As such, we will use a combination of the Newcastle-Ottawa Scale, the Effective Practice and Organisation of Care Risk of Bias Tool and the McMaster Quality Assessment Scale for Harms, and for case reports/series, the Naranjo Probability Scale for case reports/series.
The following are variables which are confounders or sources of bias for pregabalin and the risk for edema or heart failure, which should be controlled for in the nonrandomized studies:
5. Medications that can exacerbate or trigger congestive heart failure: NSAIDs, steroids, thiazolinediones
6. Medications associated with severe neuropathic pain: opioids
7. Medications associated with other indications for pregabalin: anticonvulsants, benzodiazepines, antidepressants
We will record which studies adjusted for which variables, their crude and adjusted measures of effect size (e.g. odds ratio, relative risk).
Strategy for data synthesis
Synthesis of results
If the studies are clinically, statistically, and methodologically homogenous, a meta-analysis will be conducted randomized controlled trials and cohort studies separately using the random-effects model. Statistical heterogeneity will be assessed using the I-squared statistic. If >10 studies are meta-analyzed, publication bias will be assessed using a funnel plot. The results of case series, case reports, and case-control studies will be summarized descriptively and will not be meta-analyzed.
Analysis of subgroups or subsets
Extensive heterogeneity, defined as I-squared >60%, will be addressed with meta-regression if there are more than 10 studies reporting relevant outcomes. Meta-regression analysis will be conducted to explore the effect of variables such as pregabalin dose and patient age on the outcomes. Sub-group analysis for patients with postherpetic neuralgia and diabetic neuropathy will also be conducted, if deemed necessary.
With this systematic review, we will gain a better appreciation of pregabalin’s risk of heart failure and edema. The results of this review will be of interest to clinicians and the thousands of patients worldwide who are administered this heavily marketed medication. Given that pregabalin is not yet covered under the Ontario Drug Benefit program, this systematic review may be beneficial to health policy makers should they reconsider this drug’s coverage status.
Our knowledge exchange strategies include a publication in a peer-reviewed journal and presentations at upcoming conferences such as the Drug Safety and Effectiveness Network.
Dr Joanne Ho, Department of Medicine, University of Toronto Dr Andrea Tricco, Li Ka Shing Knowledge Institute, St. Michael’s Hospital Ms Laure Perrier, Li Ka Shing Knowledge Institute, St. Michael’s Hospital Ms Maggie Chen, Li Ka Shing Knowledge Institute, St. Michael’s Hospital Dr David Juurlink, Department of Health Policy, Management and Evaluation, University of Toronto Dr Sharon Straus, Li Ka Shing Knowledge Institute, St. Michael’s Hospital
Dr David Juurlink, Department of Health Policy, Management and Evaluation, University of Toronto
Anticipated or actual start date
01 October 2012
Anticipated completion date
31 December 2012
Joanne Ho is a trainee with the University of Toronto Department of Medicine Clinician Scientist Training Program and the online Li Ka Shing Knowledge Institute Systematic Review course (co-directed by Drs. Straus and Tricco).
No funding was provided for this review Andrea Tricco is funded by a CIHR/Drug Safety and Effectiveness Network New Investigator Award in Knowledge Synthesis. Sharon Straus is funded by a Tier 1 Canada Research Chair in Knowledge Translation.
The authors have no conflicts of interest to declare.
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.