The role and essence of pilot trials and subgroup analysis in cardiovascular research: the IMPI trial experience

Background Randomised control trials (RCTs) are capital-intensive projects and demand substantial human and capital resources. Therefore, proper planning, precise research questions and adequate thoughts are required in areas such as acceptability of the intervention, participant recruitment, and selection of measurable outcomes. Ensuring all these are possible before delving into the main work can be forecasted through pilot trials. They help in determining the feasibility of the intended critical endpoints and ensure the applicability of the result findings. However, no matter how noble and vital the results are, improper reporting can make them unusable. The thesis brings to the fore the importance of pilot trials in low- and medium-income countries and how they can help make a case for more extensive definitive trials. It then focuses on how subgroup analysis can be used as an essential statistical tool for fully understanding clinical trial results and can be used to unearth non-apparent results in RCT. In the thesis, we highlight the need for accurate, systematic and complete reporting of pilot trials, by critically appraising the literature on abstract reporting in heart failure. The thesis discusses several aspects of pilot trial processes to understand better its unique role in helping refine the components of RCT, to make the running smooth and findings affirmative. Leveraging on the experience of working as a clinical research fellow in the second Investigation for Management of Pericarditis in Africa (IMPI-2) trial, the lessons learnt in planning, designing, implementation, recruitment and reporting of the IMPI-2 pilot forms the nucleus of this thesis. The experience acquired in the process and how they can help in planning future definitive studies are discussed in different sections of the thesis. Methodology The thesis uses the experience gained in critical appraisal of the literature, participation in preliminary planning and active participation in a multicentre randomised control trial to understand the importance of some issues during an RCT. These areas include the need for specific objective setting, identification of research participants and collaborators, the acceptability of research intervention, proper identification of possible outcome measures, retention of participants and quality reporting of research findings. It begins with an overview of pilot trials, subgroup analysis and tuberculous pericarditis which is the primary disease focus of the IMPI project. Each subsequent chapter of the thesis is presented either as a published manuscript or prepared for submission as a manuscript. The quality of reporting of pilot trials is then examined by systematically surveying the reporting of abstracts of pilot trials in heart failure using the checklist of the Consolidated standard for reporting of trials (CONSORT) extension for pilot trials. A subgroup analysis of IMPI-1 trial planned a priori on the modification of the effect of prednisolone by baseline pericardiocentesis status of trial participants is used to highlight the role subgroup analysis can play in unmasking the group effect in the randomised control trial. The thesis then goes on to present the preliminary report of the IMPI-2 pilot study, highlighting the lessons learned and aspirations in need of refining. Retention of study participants is essential to achieve success in clinical trials, one way of ensuring this is by letting the study participants understand the objectives and processes of the research and gaining their confidence. Thus, in chapter six, we piloted the use of the University of California San Diego Brief Assessment of Capacity to Consent (UBACC), a screening tool for evaluation of informed consent (IC) comprehension as a training tool for iterative learning and evaluation of consent comprehension among IMPI-2 pilot trial participants. Results and Conclusion Enormous resources expended in clinical research can yield good returns before the main work commences, a well-planned micro trial run in the form of a pilot study is undertaken. Our systematic survey of abstracts of pilot trials in heart failure showed that reporting of abstracts of pilot trials is currently suboptimal. Deciding ahead of time on what to report by systematically identifying the different sections needed to inform the audience can improve the quality adequately. Planning subgroup analysis during the design of main studies can help reveal unsuspected findings. The subgroup analysis result showed that pericardiocentesis, despite its essential use among patients with pericardial effusion, did not significantly influence the effect of prednisolone on the primary critical outcomes among IMPI-1 participants. The preliminary report of IMPI-2 trial was designed as a two-phase study; phase 1 results showed that at 50mg, intrapericardial alteplase was safe in facilitating complete pericardiocentesis, while phase two showed that it was feasible to recruit, randomised and follow up patients in line with the study protocol. However, we identified participant retention as a considerable challenge. The result of the pilot revealed that more effort should be expended on participants’ education on the clinical condition, the reason for the trial and the need for follow-up adherence. There is also a need to make adequate provision for the use of field workers for contact tracing to reduce the dropout rate. In the main trial protocol, there may also be a need to reconsider the patient's selection and use of fibrinolysis in malignant effusion, judging from the high rate of 3 months mortality in this group of patients. The results of the informed consent study showed that an improved level of comprehension followed the use of iterative learning, a higher level of education and non-use of interpreters during informed consent delivery. These finding led us to conclude that every effort should be made to ensure that research participants entirely buy into the research they are asked to be part of through thorough information delivery. Doing so can help improve participants adherence to the trial follow-up

Contributions of pulmonary hypertension to HIV-related cardiac dysfunction

AbstractBackground/AimTo evaluate the prevalence of pulmonary hypertension among patients living with HIV/AIDS and to determine its contribution to cardiac dysfunction.MethodA hospital based cross sectional study was carried out over a 6-month period at the Jos University Teaching Hospital. The subjects were 200 confirmed HIV positive patients, ≥18 years of age who consented to the study. Physical examination, laboratory investigations, 2 dimensional and Doppler echocardiography were conducted on the subjects.ResultsThe mean age of the patients was 38 ± 9 years, and there were 142 females (71%).Females were younger, mean age 36 ± 8 years versus 41 ± 10 years for males (p-value <0.01). The median CD4 cell count was 312 cells/μl, there were no homosexual or intravenous drug user among the subjects.Eight of the subjects had pulmonary hypertension, with a case prevalence of 4%, and this had no relationship to CD4 cell count. Both systolic and diastolic functions were worse in subjects with pulmonary hypertension, with a negative correlation between mean pulmonary arterial systolic pressure (mPASP) and parameters like ejection fraction (r = −0.28, p-value 0.0003), fractional shortening (r = −0.21, p-value 0.003), deceleration time (r = −0.13. p-value 0.09).ConclusionImmune-suppression affects the cardiac function adversely and coexisting pulmonary hypertension contributes to poor systolic and diastolic function in affected patients. The subtle nature of presentation of pulmonary hypertension and other cardiac dysfunctions in HIV/AIDS patients demand a high-index of suspicion and early intervention if detected, to ensure better care for these emerging threats to our patients

Quality of pilot trial abstracts in heart failure is suboptimal: a systematic survey

Background: Pilot trials are miniature researches carried out with the sole aim of acting as the precursor for larger more definitive studies. Abstracts are used to summarize and introduce the findings to the reading audience. There is substantive empirical evidence showing that abstracts, despite their important roles, are not informative enough, lacking the necessary details. This systematic survey was designed to assess the quality of reporting of heart failure pilot trial abstracts. The quality of reporting was defined as the completeness of reporting based on adherence to the CONSORT extension for reporting of pilot trial abstracts. We also identified factors associated with reporting quality. Methods: We searched MEDLINE (PubMed), Cochrane Controlled Trials Register, Scopus, and African-wide information databases for abstracts from heart failure pilot trials in humans published from 1 January 1990 to 30 November 2016. These were assessed to determine the extent of adherence to CONSORT extension checklist for reporting of abstracts of pilot trials. We screened identified studies for inclusion based on title and abstract. Data were independently extracted by two reviewers using the checklist. We used regression analysis to assess the association between completeness of reporting (measured as the number of items in the CONSORT extension checklist for reporting of abstracts in pilot trials contained in each abstract) and factors influencing the quality of the reports. Results: Two hundred and twenty-eight (228) articles were retrieved, of which 92 met the inclusion criteria. The mean CONSORT extension score was 8.3/16 (standard deviation 1.7); the least reported items were the source of funding (1% [1/92]), trial registration (13% [12/92]), randomization sequence (13% [12/92]), number randomized to each arm (16% [15/92]), and number analyzed in each arm (16% [15/92]). Multivariable regression analysis showed that pharmacological intervention pilot trials [incidence rate ratio (IRR) = 0.88; 95% confidence interval (CI), 0.81–0.97] were significantly associated with better reporting. Other factors such as structured abstract (IRR = 1.10; 95% CI, 0.99–1.23) and CONSORT endorsement (IRR = 1.10; 95% CI, 0.99–1.23) only showed minimal relationship with better reporting quality. Conclusion: The quality of reporting of abstracts of heart failure pilot trials was suboptimal. Pharmacological intervention was significantly associated with better reporting. These findings are consistent with previous research on reporting of trials

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants.

BACKGROUND: Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. METHODS: We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. FINDINGS: The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. INTERPRETATION: Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. FUNDING: WHO

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. Copyright (C) 2021 World Health Organization; licensee Elsevier

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Contributions of pulmonary hypertension to HIV-related cardiac dysfunction

Background/Aim: To evaluate the prevalence of pulmonary hypertension among patients living with HIV/AIDS and to determine its contribution to cardiac dysfunction. Method: A hospital based cross sectional study was carried out over a 6-month period at the Jos University Teaching Hospital. The subjects were 200 confirmed HIV positive patients, ≥18 years of age who consented to the study. Physical examination, laboratory investigations, 2 dimensional and Doppler echocardiography were conducted on the subjects. Results: The mean age of the patients was 38 ± 9 years, and there were 142 females (71%). Females were younger, mean age 36 ± 8 years versus 41 ± 10 years for males (p-value <0.01). The median CD4 cell count was 312 cells/μl, there were no homosexual or intravenous drug user among the subjects. Eight of the subjects had pulmonary hypertension, with a case prevalence of 4%, and this had no relationship to CD4 cell count. Both systolic and diastolic functions were worse in subjects with pulmonary hypertension, with a negative correlation between mean pulmonary arterial systolic pressure (mPASP) and parameters like ejection fraction (r = −0.28, p-value 0.0003), fractional shortening (r = −0.21, p-value 0.003), deceleration time (r = −0.13. p-value 0.09). Conclusion: Immune-suppression affects the cardiac function adversely and coexisting pulmonary hypertension contributes to poor systolic and diastolic function in affected patients. The subtle nature of presentation of pulmonary hypertension and other cardiac dysfunctions in HIV/AIDS patients demand a high-index of suspicion and early intervention if detected, to ensure better care for these emerging threats to our patients

Quality of abstracts of pilot trials in heart failure : a protocol for a systematic survey

CITATION: Isiguzo, G., et al. 2017. Quality of abstracts of pilot trials in heart failure : a protocol for a systematic survey. Contemporary Clinical Trials Communications, 8:258-263, doi:10.1016/j.conctc.2017.11.004.The original publication is available at https://www.sciencedirect.comIntroduction: Pilot trials are initial small-scale studies done to inform the design of larger trials. Their findings like other studies are usually disseminated as peer-reviewed journal articles. Abstracts are used to introduce the contents to readers, and give a general idea about the full reports and sometimes are the only source of information available to readers. Despite their importance, the contents of abstracts of trial reports are usually not informative enough and lack the essential details. Methods and analysis: This is a protocol for a planned systematic survey with a primary aim of analyzing the reporting quality measured as the completeness of the reporting of pilot trial abstracts in heart failure. The secondary aim will be to explore factors associated with better reporting quality. Abstracts of heart failure pilot trials in humans (journal and conference abstracts) published in the English language from 1 January 1990 to 30 November 2016 will be assessed to determine the reporting quality, based on the CONSORT 2010 statement extension to randomized pilot and feasibility trials. All non-pilot/feasibility trials and non-human pilot trials will be excluded. We will search Medline (PUBMED), Cochrane controlled trials register, Scopus and African wide information databases for pilot trials in heart failure. Title and abstracts of identified studies will be screened for inclusion and data extracted independently by two reviewers in duplicate without using the full text. Reported and unreported items on the abstracts will be presented as frequencies and percentages, a descriptive analysis will be used to interpret the reporting quality and regression analysis used for characteristics associated with greater statistical reporting at 95% confidence interval.https://www.sciencedirect.com/science/article/pii/S2451865417301242?via%3DihubPublisher's versio