Randomized Clinical Trials in Cardiovascular Medicine

• Author / Creator

  Sepehrvand, Nariman

• Cardiovascular (CV) diseases (CVD) have been the leading cause of death globally for decades. Effective prevention, treatment and management programs are needed to attenuate the negative impact of CVDs. Despite the efforts to provide the required evidence for these programs, the majority of recommendations issued by major professional organizations have not been supported by high-quality evidence generated by randomized clinical trials (RCT). RCTs have been considered the gold standard of the clinical research for many decades as they minimize the risk of bias and confounding through randomization. Despite the indisputable role of RCTs in evidence generation, impediments such as high cost, the need for large sample size, long study duration and so on, limit their ability to answer our persistently-growing clinical questions. In this thesis, the aim is to explore some of the important aspects of RCT design from endpoints to the level of pragmatism. We also designed and conducted a pilot RCT on the effects of supplemental oxygen therapy in patients with acute heart failure (AHF) for the first time and synthesized the data of similar RCTs from the acute myocardial infarction (AMI) setting.
  The first chapter is the introduction and provides some background about the importance of RCTs, their limitations and the need for optimizing their design and implementation.
  The second chapter is a retrospective cohort study using linked administrative data from Alberta to explore the provincial uptake of natriuretic peptides (NP) testing, which are biomarkers used in the diagnosis, prognostication, and management of patients with AHF. The study identified several factors including sex, urban residence, the type of healthcare provider and emergency department’s (ED) clinical volume as factors that are influencing the NP testing in clinical practice. Patients with AHF who were tested for NP had a higher rate of hospital admission from the ED and lower 7-day and 90-day repeated ED visit rates compared with those who were not assessed using NP.
  Endpoint adjudication is a common practice in many RCTs that consider clinical events as primary or secondary endpoints. The third chapter is a secondary analysis of the Providing Rapid Out of Hospital Acute Cardiovascular Treatment 3 (PROACT-3) trial, investigating the agreement between adjudication committee versus site-based diagnoses for clinical conditions. The study showed substantial agreement between the diagnosis of ED physicians and adjudication committee. Nevertheless, in the subgroup of patients where there was disagreement, there was significantly worse short-term and long-term mortality. This study provided evidence on where adjudication committee or site diagnoses can be used for outcome ascertainment.
  Pragmatism is one way to address the above-mentioned limitations of RCTs. The fourth chapter investigates the level of pragmatism in CV RCTs. We found a moderate increase in the level of pragmatism in CV RCTs published from 2000 to 2015. The increase occurred mainly in the eligibility, setting, flexibility of intervention delivery, and primary endpoint domains of the trial design. Knowing more about current RCTs can help us in the design and implementation of more efficient RCTs with broader application.
  In the fifth chapter, we presented the results of the HiLo-HF (High versus Low Oxygen therapy in acute Heart Failure) trial which was a pilot RCT about the effects of supplemental oxygen therapy in patients presenting to the ED with AHF. Titrating to high or low SpO2 targets did not result in changes in biomarkers, symptoms or clinical outcomes. Further RCTs with larger sample sizes are warranted to determine the efficacy and safety of oxygen therapy in patients with AHF.
  
  In chapter 6, we synthesized the evidence from RCTs to investigate the effects of supplemental oxygen therapy in patients with AMI. In this meta-analysis including 7,998 patients, oxygen therapy did not reduce the risk of in-hospital or 30-day mortality in those with AMI. It also had no effect on the cardiac troponin levels or the infarct size as defined by cardiac MRI.
  Trialists are required to make multitude of decisions in the trial design to ensure the validity and generalizability of the trial findings, whilst they rarely have the evidence at their disposal on the optimal practice for every single decision. This work identifies and tests potential areas that can be used to improve the design and implementation of RCTs in CV medicine.

• Subjects / Keywords

  • Cardiovascular Diseases
  • Supplemental oxygen therapy
  • Medicine
  • Randomized Clinical Trial
  • Trial Design

• Graduation date

  Spring 2020

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-38jh-s058

• License

  Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.