Title and abstract
1a. Identification as a randomised trial in the title
Figure 1: Title of the study.
The title as stated above indicates that the study design is a randomized trial, meaning that the participants were randomly assigned to their comparison groups.
1b. Structured summary of trial design, methods, results, and conclusions.
A typical abstract includes structured summary of trial design, methods, results and conclusion. An abstract provides the overview of the study and should be written clearly, transparent with enough detail.
Abstract should only contain accurate information which is included in the full content of the paper and not otherwise. This is to allow the readers to make quick assessment on its relevance and to retrieve other related reports. (1)
The trial design for this study is mentioned under Method as “randomized, double-blind, controlled study”.
The abstract contains sufficient information about the trial and can serve as an accurate record of its conducts and findings. It has optimal information about the trial in such a confined space. Harms of this trial are mentioned in the abstract. This is important because without mentioning the harm of the study, it may cause serious misleading on someone’s interpretation of the trial findings.
Introduction
Background and objectives
2a. Scientific background and explanation of rationale.
The authors provide the background by explaining that prevention of stroke is very important because unavailability of common effective acute treatment for stroke.
Further clarification was given that many still suffer from stroke even with the optimal strategies. This includes 25% of recurrence cases and 25% who suffer recurrence stroke during the period of 5 years. Thus, there is a need for new therapeutic targets and how to treat those in high risk to improve long-term results.
2b. Specific objectives or hypotheses
The primary objectives are stated in Introduction, for the need to find new therapeutic targets and way to treat high risk individuals to better long-term results.
The hypothesis is also in Introduction, mentioning that patients suffering from recent stroke can improve cerebrovascular reactivity with XO inhibitor allopurinol.
Methods
Trial Design
3a. Description of trial design (such as parallel, factorial) including allocation ratio.
In the method of abstract part, the research clearly stated that it is a randomized, double-blind and controlled study. However, authors fail to mention the trial design such as parallel or factorial design. It is stated that participant were randomized on a 1:1 basis.
3b. Important changes to methods after trial commencement (such as eligibility criteria), with reasons.
According to the study, all drug treatments remained unchanged throughout the study period, except in one participant who was commenced on dipyridamole and perindopril during the study.
Participants
4a. Eligibility criteria for participants.
The eligibility criteria is describe sufficiently. The inclusion and exclusion criteria were clearly stated. According to the trial, the inclusion trial stated were:
The common distinction between inclusion and exclusion criterion has been clearly defined. It is also mentioned that informed consents were given to the patient.
4b. Settings and locations where the data are collected
The study was performed in the University Division of Cardiovascular and Medical Services at the Western Infirmary, Glasgow.
Interventions
5. The interventions for each group with sufficient details to allow replication, including how and when they were actually administered.
This article significantly clarifies that a 15 mg kg-1 ml-1 infusion of acetazolamide was rendered intravenously for 3 minutes with a maximum dose of 1 g upon completion of peripheral pulse wave analysis and pulse wave velocity measurements and assessment of ICA and MCA. Assessment of all the parameters and assessment mentioned were repeated at 15 minutes. The intervention of the trial was stated clearly in the article.
Outcome
6a. Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed.
All outcome measures, whether primary or secondary, should be identified and completely defined. The article has clearly stated primary and secondary outcome measure . However, this trial has only one primary outcome, therefore the problem of multiplicity of analysis will not occur because they do not have several primary outcome.
The article also did not mention how and when they assessed the outcome measure.
6b. Any changes to trial outcomes after trial commenced with reasons.
No changes to trial outcome after trial commencement (such as eligibility criteria) are reported.
Sample Size
7a.How sample size was determined.
The article did not mention any calculation of sample size and how the sample size is determined. It only stated that 50 participants were recruited before the study.
7b. When applicable, explanation of any interim analyses and stopping guidelines.
Authors should report whether they took multiple “looks” at the data and, if so, how many there were, what triggered them, the statistical methods used (including any formal stopping guidelines), and whether they were planned before the start of the trial, before they saw any interim data by allocation. This information is often not included in this published trial report.
Randomisation: Sequence generation
8a. Method used to generate the random allocation sequence.
The authors only stated that two groups of subject are randomised into allopurinol vs placebo without clearly define how the randomisation is performed and the ways used to generate the random allocation sequence.
8b. Type of randomisation; details of any restriction (such as blocking and block size)
Simple randomisation is used in this study. However, any restriction or problem such as blocking and block size during randomisation are not mentioned in the article.
Allocation concealment mechanism
9. Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until intervention were assigned.
Extract:
Following baseline assessment, participants were randomised on a 1:1 basis to receive either 300mg of allopurinol or placebo orally once daily.
Explanation:
The allocation concealment steps should be taken by the authors which involves enclosing assignments in sequentially numbered and sealed envelopes to prevent foreknowledge of treatment assignment which prevents bias in the enrolment of patients. However, this article did not mention about the allocation concealment steps, which means the result may be biased.
Implementation
10. Who generated the allocation sequence, who enrolled participants, and who assigned participants to interventions.
Extract:
Randomisation was performed by the pharmacy department and the randomization code was held by an independent study pharmacist.
Explanation:
The study pharmacist perform the random allocation sequence using randomisation code by the pharmacy department of Western Infirmary Hospital. However, it was not mentioned that who enrolled the participants to the study. The sequence generation, allocation concealment and implementation of the study was not clearly stated in the journal.
11. Blinding
11(a). If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how.
Prior to the assessment of the concordance therapy between allopurinol tablets and the placebo tablets via questioning, study treatments were gathered by one of the investigators on the day of baseline. Throughout the entire study, investigators remained blinded to serum uric acid data to prevent unnecessary unmasking of treatment allocation. Subsequently, this may reduce ascertainment bias due to low subjective judgement in reporting, evaluation, data processing, and analysis due to knowledge of treatment.
11(b). If relevant, description of the similarity of interventions.
The author solely states about the randomisation of the study was performed by the pharmacy department but the author fails to mention about the similarity of the interventions in terms of method of administration.
12. Statistical method
12a. Statistical method used to compare groups for primary and secondary outcomes.
According to the article, Mann-Whitney test was used to implement for all between-group comparisons in terms of primary and secondary outcomes. Other than that, the power of the study, the standard deviation as well as confidence interval of the study are being measured.
12b. Methods for addition analyses, such as subgroup analyses and adjusted analyses
According to the article, method for addition analyses such as subgroup analyses is not mentioned. However, adjusted analyses was implemented for between group differences in blood pressure treatments and the results are in line with the main analysis in terms of the cerebrovascular reactivity following allopurinol and placebo treatment.
3.4 Results
13. Participant flow (a diagram is strongly recommended)
13(a). For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome
A flow diagram is strongly recommended. However, this article did not provide any diagram. Besides, this result is not applicable as due to insufficient data for the numbers of participants in the primary outcome.
13(b). For each group, losses and exclusions after randomization, together with reasons.
According to Merriam-Webster, attrition refers to reduction in number resulting from resignation, retirement or even death. In this case, we will use the loss to follow up as attrition since this is unavoidable.(4) After randomisation, 5 out of 50 participants had been withdrawn from the study. Prior to the baseline visit, 2 participants did not continue the protocol as one was not feeling well following acetazolamide infusion whereas the other had an unreliable TCD window. Meanwhile, another participant fails to continue study medication as being not able to attend for the follow-up visit. The remaining 2 participants was withdrawn without mentioning the reasons.
14. Recruitment
14(a). Dates defining the periods of recruitment and follow-up.
Dates for recruiting 50 participants were between March 2006 and May 2008. However, the date of follow-up was not mentioned.
14b. Why the trial ended or was stopped
Under the Results, it is mentioned that the trial was stopped after recruiting of 50 participants. No other reason is given to explain the stoppage.
15. A table showing baseline demographic and clinical characteristics for each group.
Baseline data is presented in Table 1 with 2 trial groups, the allopurinol group and the placebo group. The baseline demographic of the participants includes the age and whether patients are smokers. The clinical characteristics of the participants include having hyperlipidaemia, hypertension, previous stroke, diabetes, undergoing anti-platelet therapy, ACE inhibitor or ARB therapy, diuretic therapy, CCB therapy, receiving Serum creatinine Serum creatinine, Serum glucose, Systolic blood pressure, MCAv among others.
Numbers Analysed
16. For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups.
Based on the table above, we have concluded that the denominator or the number of participants included in each analysis was by the original assigned groups. There are two types of analysis that the numbers can be grouped into which are the intention-to-treat as well as the per-protocol analysis. Intention-to-treat analysis is a comparison in which the number all the participants of a study is remained as it has been originally allocated after randomization. Whereas per-protocol analysis is a comparison that includes participants of a study who have completed the whole study after originally allocated.(2) The authors have followed the protocol of intention to treat (ITT) approach for determining the denominator of each analysis. Generally, Intention‐to‐treat analysis is favoured because it avoids bias associated with non‐random loss of participants. Regardless of whether authors use the term “intention‐to‐treat,” they should make clear which and how many participants are included in each analysis. However, it has not been stated or clearly defined in any part of the journal the method they have used to analyse the numbers. Intention‐to‐treat analysis underestimates the potential benefit of the treatment because it includes non-compliance with therapy. Therefore, per protocol analysis, may be considered as an additional analysis. It should be noted, however, that such analyses are often considerably flawed.
1. Shah P. Intention-to-treat and per-protocol analysis. Canadian Medical Association Journal. 2011;183(6):696-696.
17. Outcomes and estimation
17a. For each primary and secondary outcome, results for each group, and the estimate precision (such as 95% confidence interval)
The first primary results are reported under Result (Baseline response to acetazolamide infusion). It clarifies on the increase of MCA velocity at baseline visit and after acetazolamide infusion by providing the mean as well as standard deviation for the whole group. The corresponding values for the allopurinol group and placebo group are given in standard deviation plus number of participants.
For the results, the authors use 95% confidence interval to estimate the difference in medians for CVR after allopurinol treatment. The authors do not provide information on the effect size. This is because the study does not have binary outcomes. Examples of effect size for binary outcomes are odd ratio, risk ratio (relative risk) or risk difference.(1)
For the secondary results, the authors use mean to indicate the change in AI and PWV after allopurinol treatment.
17b. For binary outcomes, presentation of both absolute and relative effect sizes is recommended.
This criterion is not applicable because such study did not specify if there are any binary outcome. Therefore, absolute and relative effect sizes are not mentioned.
18. Ancillary analyses: Results of any other analyses performed, including subgroup analyses and adjusted a pre-specified from exploratory.
This criteria was not applicable to the study because no other study have been performed before this. No analyses was conducted for subgroup. The authors did report on conducting adjustment analyses in the blood pressure treatment based on the extract above.
19. Harms: All important harms or unintended effects in each group.
The report states two cases of adverse events occurring in the allopurinol group but they are not related to the study.
Discussion
20. Limitations: Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses.
One of the limitations in detecting small improvement may be due to huge variability in the change and measures of CVR. The other limitation is the inaccurate grouping of participants in which those who have withdrawn before or early after starting the medication had been randomized to the allopurinol group. For the baseline levels of CVR, there is substantial overlap in the literature of reported healthy volunteers and those with elevated cardiovascular risk, previous stroke and occlusive carotid disease. This resulted in difficulty to work out the impairment on baseline CVR in this study.
So far there is unavailability of data from previous study to recommend that CVR measurement is related to the different serum uric acid levels.
The result obtained for primary endpoint was imprecise. In the method, the author assumed the standard deviation to be 10%. However, the standard deviation found is higher than the acceptance range, This may be due to technical issue or random errors which may affect the validity of the result. The author did not state any sources of potential bias. The multiplicity of analyses is needed in this trial since the author cannot confirm the beneficial effect of allopurinol in patients with subcortical stroke. Further study is suggested by using other types of interim analyses.
Generalisability
21. Generalisability (external validity, applicability) of the trial findings.
Generalisability, also known as external validity or applicability, is the extent to which the results of a study can be generalised to other circumstances.(2) Based on the discussion of this study, the generalisability of the result were not explained by the authors. None of the external validity or applicability has been commented by the author to prove the generalisability of the results obtained in the present study to other circumstances. (2)
Interpretation
22. Interpretation consistent with results, balancing benefits and harms and considering other relevant evidence.
Based on the extract that was taken from the journal, it can be clearly seen that the authors had included comparison of similar study in the discussion. This extract shows that the interpretation was consistent with the results.
Based on the extract that was taken from the discussion, the author has clearly defined the benefits and harms of the primary end-point indicator that was used in the study. The authors has also defined what are other more appropriate measures that can be used in future studies.
Other information
Registration
23. Registration number and name of trial registry
Based on the extract above, the registration number and name of trial registry is shown in the methods section of the article.
Protocol
24. Where the full trial protocol can be accessed, if available.
Having a protocol can help to restrict the likelihood of undeclared post hoc changes to the trial methods and selective outcome reporting.(2) The article did not state where the full trial protocol can be accessed. However, the article can be accessed from Google Scholar. The British Pharmacological Society website also provides link to the full text of the study. (2)
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2125.2009.03497.x
Funding
25. Sources of funding and other support (such as supply of drugs), role of funders.
Based on the extract above, the source of funding was given by a grant from the West Endowments Research Fund (Grant Number 05REF004W). However, the supply of drugs was not stated whether it was funded or not.
Reference
Moher D, Hopewell S, Schulz K, Montori V, Gotzsche P, Devereaux P et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340(mar23 1):c869-c869.
Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. Open Med 2010; 4(1):60-8.
Definition of ATTRITION [Internet]. Merriam-webster.com. 2018 [cited 13 November 2018]. Available from: https://www.merriam-webster.com/dictionary/attrition
Conclusion
In conclusion, according to the CONSORT 2010 checklist, the authors have written most of the parts of the trial insufficiently. Therefore, some improvement can be done to further increase the validity, reliability and relevance of the study. Authors should elaborate more on the methodology, findings and results to give readers a clearer view of the study. Further study is required in order to prove the beneficial effects of allopurinol on the cerebral vasculature of patients with subcortical stroke.