Cluster headache is a primary headache disorder that can be highly disabling. In this thesis we look at the treatment landscape of cluster headache with a scoping review of preventive and acute therapies for cluster headache as identified in randomized controlled trials and two-arm observational studies. We subsequently compare these therapies where data are available using network meta-analysis of randomized trials, and we attempt subgroup analyses again where data are available for acute treatments of episodic and chronic cluster. We identify the ranking of treatments for acute cluster headache, and certain acute therapies that may be beneficial in episodic and chronic cluster headache. Based on our findings, we also identify future directions for cluster headache trials.

This thesis consists of two related studies presented as three separate manuscripts (all three have been published in peer-reviewed journals) and a study protocol that has been submitted for peer-reviewed funding. The over-arching theme of this thesis was to better characterize the efficacy of different intravenous fluids used for the resuscitation of intensive care unit (ICU) patients with severe sepsis or septic shock. We performed an extensive search including multiple databases which found 20 randomized controlled trials (RCTs) that examined the effects of different intravenous fluids used in septic patients and met our a priori inclusion and exclusion criteria. In the first manuscript, we described in detail the composition of the 19 unique fluid products that were used in the various studies. This description included the fluid type, trade name, osmolality, tonicity, electrolyte content, molecular composition, pH, and manufacturer. We reviewed manufacturer’s websites, product monographs, and emailed industry representatives or study authors for more information regarding the fluids as required. The results of this study and systematic review led us to the second and third manuscripts which reported on a Bayesian network meta-analysis (NMA) of all fluid type comparisons. Despite multiple well-done RCTs, comparative data regarding the clinical effect of different resuscitative fluids when used for sepsis was incomplete. Most RCTs used 0.9% saline (normal saline) as control fluid and very few studies compared colloids directly. The advantage of using an NMA model in this setting was the ability to include indirect data into the overall point estimates. Data was abstracted from the 14 studies which focused on adult ICU patients and analyzed examining the outcomes of mortality (manuscript #2) and the use of renal replacement therapy (RRT) (manuscript #3). Certainty of evidence was evaluated for both outcomes using the GRADE approach. Results of the analysis clearly document the harm of starch-based fluids when used in septic patients. Albumin containing fluids and crystalloids (such as normal saline and Ringer’s Lactate) are better options. Lower chloride solutions, such as Ringer’s Lactate, showed a signal towards decreased mortality and a decreased use of renal replacement therapy when compared to higher chloride fluids, such as normal saline, however this was based on indirect data, not statistically significant, and warrants direct comparison trials. The final component of this thesis is a pilot study protocol for a study assessing the feasibility of a larger RCT examining the effect of low chloride versus high chloride fluids for resuscitation in patients with sepsis and septic shock. This protocol has been submitted as part of a peer-reviewed grant with the hopes of addressing this clinically important and timely question. / Thesis / Master of Science (MSc) / This thesis examines the ideal intravenous fluid to be given to patients with severe infection causing low blood pressure. A review of the current literature is presented with a protocol for future work.

Fragility fractures caused by loss of bone mass due to postmenopausal osteoporosis represent a growing morbidity worldwide. Bisphosphonates are first-line medications for fracture treatment and prevention. In the first phase, we updated a Cochrane systematic review of randomized controlled trials on alendronate, assessing its efficacy for five types of fracture prevention, quality of life, and various safety outcomes. In the second phase, we combined indirect and direct evidence to perform a network meta-analysis including alendronate and nine other bisphosphonates evaluating the comparative efficacy and safety of these treatments. Overall, 58 studies were included in the review and 83 studies in the network. Most evidence was of moderate to high quality. Alendronate and zoledronic acid were effective for preventing the most types of fractures, while off-label and unapproved bisphosphonates showed poor efficacy. More evidence is required to evaluate long-term treatment and rare adverse events.

Osteoporosis is a growing cause of morbidity and mortality in aging populations worldwide, especially in postmenopausal women. Bisphosphonates are widely prescribed for fracture prevention in osteoporosis. Meta-analyses have been performed for alendronate, risedronate, and etidronate, examining their effectiveness versus placebo in fracture prevention. Total withdrawals and adverse event withdrawals were examined as safety outcomes. Systematic reviews were performed for two other bisphosphonates, ibandronate and zoledronic acid and the results combined with previously obtained data for the other bisphosphonates. Indirect treatment comparisons of the drugs against each other and versus placebo were performed using Bayesian and frequentist methods. Both types of analyses yielded almost identical results: zoledronic acid and alendronate were the most effective bisphosphonates for preventing vertebral fractures. No differences were found regarding withdrawals. Subgroup analyses found that fracture prevention was generally more effective with longer therapy (greater than or longer than 3 years).

Testosterone products comprise a multi-billion dollar industry; however, Health Canada and the United States Food and Drug Administration have issued statements of concern about their safety, and their benefits are unclear. In the first phase of this study, we performed a systematic review of the current evidence for the benefits of testosterone replacement therapy. In the second phase, we analyzed the evidence from randomized controlled trials for the benefits of testosterone replacement therapy (depression, quality of life, erectile function, libido, total testosterone level). In the third phase, we analyzed data for harms (cardiovascular death, myocardial infarction, stroke, newly diagnosed prostate cancer, coronary artery disease or diabetes, serious adverse events, withdrawals due to adverse events, erythrocytosis) from randomized controlled trials and non-randomized studies. In general, most included studies had a short duration and were poorly reported. Additional high-quality research into the long-term safety of testosterone products is needed.

As the HIV-positive population ages, managing non-AIDS-related comorbidities such as cardiovascular disease (CVD) complicates HIV care. Effectively treating risk factors for CVD will help reduce its burden in the HIV-infected population. However, the evidence base for the efficacy of statins as lipid-lowering therapies in HIV-infected patients has yet to be synthesized. Most trials do not compare statins directly to each other. In the absence of head-to-head evidence, the relative treatment effects of different statins can be indirectly obtained through a network meta-analysis (NMA). This NMA aims to evaluate the use of statins for treating dyslipidemia in HIV-infected individuals. Bayesian methods were used for obtaining treatment effect estimates and probabilistic rankings of treatments. Among lipid-lowering therapies, statins were most effective in treating dyslipidemia. All statins were found to offer the same treatment benefits. To our knowledge, this is the first NMA on this topic. It provides clinicians, health economists, and policy decision-makers with precise and reliable estimates for making definitive recommendations for the use of statins in dyslipidemic HIV-positive patients.

BACKGROUND AND OBJECTIVES: Standard meta-analysis compares two treatments whereas network meta-analysis compares multiple treatments. In light of the increasing number of treatments available, we have seen a shift from using standard meta-analysis towards using network meta-analyses to support regulatory and reimbursement decisions. This thesis (composed of nine separate papers) applied network meta-analysis to a series of real world problems which simultaneously addressed many of these methodological issues while also supporting healthcare decision making. METHODS: In the first chapter, background information on network meta-analysis and outline the rationale for each of the subsequent chapters is provided. In Chapter 2, an applied example is presented where we use FDA Public Summary documents to populate a network meta-analysis of antithrombotic therapies for atrial fibrillation. In Chapter 3, the advantages and disadvantages of rapid network meta-analysis using ClinicalTrials.gov are investigated by re-doing Chapter 3 but only using data available in ClinicalTrials.gov and examining concordance. In Chapter 4, the application of network meta-analysis when events are rare are investigated using an illustrative example investigating the risk of serious infection in biologics. In Chapter 5, the application of network meta-analysis to a complex network – triptans for migraine – are presented where there are a large number of studies and treatments. In Chapter 6 a network meta-analysis which assesses both a benefit and harm and integrates findings using a benefit harm methodology is presented. In Chapter 7, methods to incorporate non-randomized studies into network meta-analysis are investigated using data on riskof myocardial infarction derived from the Mini-Sentinel distributed data network. FINDINGS AND CONCLUSION: Pragmatic research around methodological areas in network meta-analysis were conducted to address real world problems for decision makers. It is my hope that this thesis and the approaches used in this thesis for the application of network meta-analysis will be disseminated to enhance research capacity in conducting network meta-analysis in Canada.

Objective Postpartum hemorrhage (PPH) is a major cause of maternal mortality world-wide; misoprostol is a relatively cheap, easily administered, and an efficient medication to be given after the delivery of the baby to prevent PPH, thus posing it as a first choice in resource-poor communities. The aim of this study is to answer questions regarding the most appropriate dose (400 µg versus 600 µg), effect of labour settings (community or clinical), and management of labour on misoprostol effectiveness and safety in preventing PPH. Methods We developed a search strategy and conducted a search within five key databases. Two reviewers screened the articles for predefined inclusion/exclusion criteria, quality, and performed data extraction. Discrepancy was dealt with by reaching consensus. In article 1, we only included randomized controlled trials, we performed a random-effects Bayesian network meta-analysis comparing 400 µg to 600 µg misoprostol over five outcomes of interest: blood loss ≥500 ml, blood loss ≥1000 ml, using additional uterotonics, shivering, and pyrexia. In article 2, we included any experimental trial, we performed a random effects model meta-analysis, pooling the incidence of PPH from each misoprostol arm. Subsequently, a meta-regression model was performed on identified potential effect-modifiers, including clinical settings and labour management. Results Of 444 identified records, 46 trials met the inclusion/exclusion criteria in article 1, and 56 trials in article 2. The odds ratio (OR) of misoprostol 400 µg vs. 600 µg for bleeding ≥ 500 ml is 0.86 [95% Credible Intervals: 0.46 − 1.54], for bleeding ≥ 1000 ml the OR is 0.83 [95% CrI 0.54 – 1.26], for additional uterotonics is 0.75 [95% CrI 0.40 – 1.40], for pyrexia and shivering an OR of 0.57 [95% CrI 0.15 – 2.18] and 0.63 [95% CrI 0.29 – 1.31] respectively. The overall incidence of PPH was 6.62 per 100 pregnancies (95%CI 4.71 per 100 – 8.53 per 100). Labour settings and other aspects of active management of labour had no statistically significant effect on the incidence of post-partum hemorrhage. Conclusion We found no difference between the administration of misoprostol 400 µg or 600 µg for the prevention of PPH and side effects of misoprostol, as well as no effect of labour settings and management of labour on misoprostol effectiveness.

Treatment of acute Achilles tendon ruptures has long been controversial. Several treatment options exist for patient with variable harms and benefits to each. Recognizing that decision of treatment option is preference-sensitive, this thesis focused on updating the current literature on Achilles tendon rupture management to facilitate the creation of a patient decision aid. A network meta-analysis of all treatment options for acute Achilles tendon ruptures was performed. Results demonstrated that minimally invasive surgery options were associated with lower complications and lower complications requiring surgery. Return to sport was similar amongst all treatment groups. With guidance from the Ottawa Decision Support Framework and the International Patient Decision Aid Standards, a three-tiered protocol for development, alpha testing and field-testing a novel patient decision aid is outlined next. The patient decision aid will be reviewed and revised iteratively by multi-disciplinary steering group. This protocol will act as a framework for further orthopaedic patient decision aid development.

<p>Meta-analysis is a method of synthesizing results of different studies conducted to answer a specific question. Meta-analysis applications have been published in a wide range of disciplines including medicine, education, psychology and many others. However, for many years, only pair-wise and direct comparisons have been made using standard meta-analysis methods. It is only recently that network meta-analysis emerged enabling the comparison of multiple treatments based on estimates from different studies. With network meta-analysis, the relative efficacy (or safety) of a particular intervention versus competing interventions can be obtained even in the absence of head-to-head evidence via a common comparator.</p> <p>An increasing number of methodologies related to network meta-analysis, assessments of underlying assumptions, and strategies for presentation of results have been proposed by several researchers. But only few simulation studies have been done to investigate different characteristics of this emerging statistical method. Hierarchical Bayesian meta-analysis model is commonly used in network meta-analysis to estimate effect of each intervention relative to every other. This model facilitates the calculation of the rank probabilities of a set of alternative treatments. However, various factors can determine the performance of the model which needs to be considered before using results for decision.</p> <p>This project aimed to investigate how the Bayesian hierarchical model estimates the rank probability of the best overall most effective treatment (i.e., the treatment ranked first) under different scenarios for modelling a binary outcome. Different network geometries, numbers of studies per comparison, sets of probabilities of success for treatments and sample sizes were investigated in our simulation study for binary outcome.</p> <p>Our simulation study showed that the estimates of treatments under consideration can be affected by network structures. Similar geometries affect the estimate in similar ways. Unbalanced number of studies per comparison influenced estimates of treatments in the geometries we considered. When a superior treatment is involved in the network, the hierarchical Bayesian mixed treatment model correctly identified it regardless of network patterns, number of studies and individual study sample size.</p> / Master of Science (MSc)