Antithrombotic Therapy Recommendations in the European Society of Cardiology Guidelines: How Robust Are the Randomized Controlled Trials Underpinning Them?

Abstract Introduction Criticisms have been raised against the sole use of p-value in interpreting results from randomized controlled trials (RCTs). Additional tools have been suggested, like the fragility index (FI), a measure of a trial's robustness/fragility, and derivative measures. The FI is the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for a result to lose statistical significance. Objective This study aimed to evaluate RCT supporting European Society of Cardiology (ESC) guidelines regarding antithrombotics, using the FI and FI-related measures. Methods FI, fragility quotient (FQ), and FI minus LTF lost to follow-up (FI − LTF) were calculated for the RCT underpinning recommendations regarding antithrombotic therapy from the updated ESC guidelines. LTF was compared with FI. Results were calculated for the total group of studies, as per guideline and as per recommendation type. Results Overall, 61 studies were included. The median FI was 24.5 (interquartile range [IQR]: 9.0–60.0) and median FQ was 0.0035 (IQR: 0.0019–0.0056). Median FI − LTF was 2.0 (IQR: 0.0–38.0). Twenty (32.8%) of the studies had one primary or main safety outcome with LTF exceeding FI. Peripheral arterial disease guideline and chronic coronary syndrome guideline had the lowest (2.5; IQR: 1.8–3.3) and the highest (48.5; IQR: 23.8–73.0) FI, respectively. Conclusion The median FI suggests robustness of clinical trials evaluating antithrombotic drugs cited in the guidelines, but about one-third of them had LTF larger than FI. This emphasizes the need for assessing trials' robustness when constructing guidelines.

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Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary

European Heart Journal Acute Cardiovascular Care ◽

10.1177/2048872616649859 ◽

2016 ◽

Vol 8 (8) ◽

pp. 745-754

Author(s):

Héctor Bueno ◽

Pieter de Graeff ◽

Isabelle Richard-Lordereau ◽

Joseph Emmerich ◽

Keith AA Fox ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Randomized Controlled Trials ◽

European Society ◽

Round Table ◽

Controlled Trials ◽

New Agents ◽

Coronary Syndrome ◽

Randomized Controlled ◽

Guidance Documents ◽

European Society Of Cardiology

Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.

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The Fragility of Statistical Significance in Cartilage Restoration of the Knee: A Systematic Review of Randomized Controlled Trials

Cartilage ◽

10.1177/19476035211012458 ◽

2021 ◽

pp. 194760352110124

Author(s):

Robert L. Parisien ◽

Michael Constant ◽

Bryan M. Saltzman ◽

Charles A. Popkin ◽

Christopher S. Ahmad ◽

...

Keyword(s):

Articular Cartilage ◽

Randomized Controlled Trials ◽

Statistical Significance ◽

Fragility Analysis ◽

Cartilage Defects ◽

Controlled Trials ◽

Randomized Controlled ◽

Number Of Patients ◽

Cartilage Restoration ◽

Articular Cartilage Defects

Objective The purpose of this study was to utilize fragility analysis to assess the robustness of randomized controlled trials (RCTs) evaluating the management of articular cartilage defects of the knee. We hypothesize that the cartilage restorative literature will be fragile with the reversal of only a few outcome events required to change statistical significance. Design RCTs from 11 orthopedic journals indexed on PubMed from 2000 to 2020 reporting dichotomous outcome measures relating to the management of articular cartilage defects of the knee were included. The Fragility Index (FI) for each outcome was calculated through the iterative reversal of a single outcome event until significance was reversed. The Fragility Quotient (FQ) was calculated by dividing each FI by study sample size. Additional statistical analysis was performed to provide median FI and FQ across subgroups. Results Nineteen RCTs containing 60 dichotomous outcomes were included for analysis. The FI and FQ of all outcomes was 4 (IQR 2-7) and 0.067 (IQR 0.034-0.096), respectively. The average number of patients lost to follow-up (LTF) was 3.9 patients with 15.8% of the included studies reporting LTF greater than or equal to 4, the FI of all included outcomes. Conclusions The orthopedic literature evaluating articular cartilage defects of the knee is fragile as the reversal of relatively few outcome events may alter the significance of statistical findings. We therefore recommend comprehensive fragility analysis and triple reporting of the P value, FI, and FQ to aid in the interpretation and contextualization of clinical findings reported in the cartilage restoration literature.

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Effects of Diet, Aerobic Exercise, or Both on Non-HDL-C in Adults: A Meta-Analysis of Randomized Controlled Trials

Cholesterol ◽

10.1155/2012/840935 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

George A. Kelley ◽

Kristi S. Kelley

Keyword(s):

Aerobic Exercise ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Statistical Significance ◽

Density Lipoprotein ◽

Control Group ◽

Controlled Trials ◽

Mixed Effect ◽

Randomized Controlled ◽

Effect Model

Purpose. To use the meta-analytic approach to examine the effects of diet (D), aerobic exercise (E), or both (DE) on non-high-density lipoprotein cholesterol (non-HDL-C) in adults. Methods. Randomized controlled trials in adults ≥18 years of age were included. A mixed-effect model was used to combine effect size (ES) results within each subgroup and to compare subgroups (Qb). Heterogeneity was examined using the Q and I2 statistics, and 95% confidence intervals (CI) were also calculated. Statistical significance was set at P≤0.05, while a trend for statistical significance was set between P>0.05, and ≤0.10. Results. A statistically significant exercise minus control group decrease in non-HDL-C was found for DE (7 ESs, 389 participants, x¯=-11.1 mg/dL, 95% CI=−21.7 to −0.6, P=0.04, Q=2.4, P=0.88, I2=0%), a trend for the D group (7 ESs, 402 participants, x¯=−8.5 mg/dL, 95% CI=−18.6 to 1.6, P=0.10, Q=0.76, P=0.99, I2=0%), and no change for the E group (7 ESs, 387 participants, x¯=3.0 mg/dL, 95% CI=−7.1 to 13.1, P=0.56, Q=0.78, P=0.99, I2=0%). Overall, no statistically significant between-group differences were found (Qb=4.1, P=0.12). Conclusions. Diet combined with aerobic exercise may reduce non-HDL-C among adults in some settings.

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COVID-19 and Vitamin D (Co-VIVID Study): a systematic review and meta-analysis of randomized controlled trials

10.1101/2021.08.22.21262216 ◽

2021 ◽

Author(s):

Seshadri Reddy Varikasuvu ◽

Balachandar Thangappazham ◽

Hemanth Raj

Keyword(s):

Vitamin D ◽

Randomized Controlled Trials ◽

Literature Search ◽

Meta Analysis ◽

Statistical Significance ◽

Cochrane Library ◽

Controlled Trials ◽

Randomized Controlled ◽

Individual Outcomes ◽

Vitamin D Levels

Background: Vitamin D levels have been reported to be associated with COVID-19 susceptibility, severity and mortality events.. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the use of vitamin D intervention on COVID-19 outcomes. Methods: Literature search was conducted using PubMed, Cochrane library, and ClinicalTrials.gov databases (latest search on August 5, 2021). We included RCTs reporting the use of vitamin D intervention to control/placebo group in COVID-19. Two independent researchers did literature search, abstracted data, and the risk of bias assessment. Results: A total of 6 RCTs with 551 COVID-19 patients were included. The overall collective evidence pooling all the outcomes across all RCTs indicated the beneficial use of vitamin D intervention in COVID-19 (relative risk, RR = 0.60, 95% CI 0.40 to 0.92, Z=2.33, p=0.02, I2 = 48%). However, no statistical significance was observed for individual outcomes of ICU care (RR = 0.11, 95% CI 0.15 to 1.30, Z=1.48, p=0.14, I2 = 66%) and mortality (RR = 0.78, 95% CI 0.25 to 2.40, Z=0.66, p=0.02, I2 = 33%), though decreased rates were noted. The rates of RT-CR positivity was significantly decreased in the intervention group as compared to the non-vitamin D groups (RR = 0.46, 95% CI 0.24 to 0.89, Z=2.31, p=0.02, I2 = 0%). Conclusion: COVID-19 patients supplemented with vitamin D are more likely to demonstrate fewer rates of ICU admission, mortality events and RT-PCR positivity. However, no statistical significance has been achieved for individual outcomes of ICU and deaths. More RCTs and completion of ongoing trials largely needed to precisely establish the association between vitamin D use and COVID-19.

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Duration of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome Treated With New Generation Stents: A Meta-Analysis of Randomized Controlled Trials

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.615396 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wen-Jiao Zhang ◽

Xuan Qiao ◽

Wen-Fen Guo ◽

Xi-Ying Liang ◽

Yan Li ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Randomized Controlled Trials ◽

Major Bleeding ◽

Meta Analysis ◽

Cardiovascular Death ◽

Controlled Trials ◽

Target Vessel Revascularization ◽

Coronary Syndrome ◽

Randomized Controlled ◽

New Generation

Background and Objective: The optimum duration of dual antiplatelet therapy (DAPT) remains uncertain in patients with acute coronary syndrome treated with new generation stents. This meta-analysis was performed to investigate ischemia and bleeding outcomes with different DAPT strategies.Methods: PubMed, Embase, Cochrane and Web of science from inception to May 27, 2020, were systematically searched. Randomized controlled trials were included to compare short-term (6 months or less) with standard (12 months) DAPT in patients with acute coronary syndrome treated with new generation stents. The primary endpoints were myocardial infarction, definite or probable stent thrombosis and major bleeding. The secondary endpoints included all-cause death, cardiovascular death, stroke, target vessel revascularization and net adverse clinical events. Random effect model and fixed effect model were used to calculate the odds ratio (OR) and 95% confidence interval (CI) of each endpoint.Results: Four randomized controlled trials and seven subgroup analyses of larger randomized controlled trials, including a total of 21,344 patients with acute coronary syndrome, met our inclusion criteria. The shorter DAPT was associated with significantly lower major bleeding compared with the standard DAPT (OR 0.71, 95% CI 0.56–0.90, P = 0.005, I2 = 25%), while without increasing the risk of myocardial infarction (OR 1.18, 0.88–1.58, P = 0.28, I2 = 20%), definite or probable stent thrombosis (OR 1.60, 0.98–2.59, P = 0.06, I2 = 0%). No significantly difference was observed in the risk of all-cause death (OR 0.96, 0.72–1.27, P = 0.76, I2 = 2%), cardiovascular death (OR 0.91, 0.62–1.33, P = 0.62, I2 = 0%), stroke (OR 0.84, 0.54–1.30, P = 0.43, I2 = 0%), target vessel revascularization (OR 1.14, 0.84–1.55, P = 0.41, I2 = 8%), and net adverse clinical events (OR 0.93, 0.80–1.07, P = 0.3, I2 = 18%) between the two groups.Conclusions: In patients with acute coronary syndrome treated with new generation stents, the shorter DAPT leads to a marked reduction in the risk of major bleeding compared with the standard DAPT. This benefit is achieved without increasing the risk of mortality or ischemic outcomes. The study protocol was registered in PROSPERO (CRD42020189871).

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The effects and safety of telerehabilitation in patients with lower-limb joint replacement: A systematic review and narrative synthesis

Journal of Telemedicine and Telecare ◽

10.1177/1357633x20917868 ◽

2020 ◽

pp. 1357633X2091786

Author(s):

Miia M Jansson ◽

Arja Rantala ◽

Jouko Miettunen ◽

Ari-Pekka Puhto ◽

Minna Pikkarainen

Keyword(s):

Systematic Review ◽

Physical Therapy ◽

Randomized Controlled Trials ◽

Physical Functioning ◽

Joint Replacement ◽

Lower Limb ◽

Controlled Trials ◽

Narrative Synthesis ◽

Randomized Controlled ◽

Number Of Patients

Introduction As the number of patients undergoing primary lower-limb joint replacement has risen continuously, hospital-based healthcare resources have become limited. Delivery of any ongoing rehabilitation needs to adapt to this trend. This systematic literature aimed to examine the effects and safety of telerehabilitation in patients with lower-limb joint replacement. Methods A systematic review of randomized controlled trials was conducted according to procedures by the Joanna Briggs Institute. Studies published prior to February 2020 were identified from Medline Ovid, Scopus, Ebsco Databases and Web of Science. Reference lists of relevant studies were also manually checked to find additional studies. Two researchers conducted study selection separately. The Joanna Briggs Institute Critical Appraisal Checklist for Randomized Controlled Trials was used to evaluate the quality of the relevant studies published. A narrative synthesis was used to report the results whereas effect sizes were estimated for different outcomes. Results Nine studies with 1266 patients were included. Study quality was predominantly affected by the lack of blinding. The patients who completed telerehabilitation showed an improvement in physical functioning that was similar to that of patients completing conventional in-person outpatient physical therapy without an increase in adverse events or resource utilization. The effect of telerehabilitation on physical functioning, however, was assessed as heterogeneous and moderate- to low-quality evidence. Discussion Telerehabilitation is a practical alternative to conventional in-person outpatient physical therapy in patients with lower-limb joint replacement. However, more robust studies are needed to build evidence about telerehabilitation.

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Effects of a proposal to alter the statistical significance threshold on previously published orthopaedic trauma randomized controlled trials

Injury ◽

10.1016/j.injury.2019.08.012 ◽

2019 ◽

Vol 50 (11) ◽

pp. 1934-1937 ◽

Cited By ~ 2

Author(s):

Austin L. Johnson ◽

Sheridan Evans ◽

Jake X. Checketts ◽

Jared T. Scott ◽

Cole Wayant ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Statistical Significance ◽

Controlled Trials ◽

Orthopaedic Trauma ◽

Randomized Controlled ◽

Significance Threshold

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Evaluating the reporting of adverse events in controlled clinical trials conducted in 2010–2015 on migraine drug treatments

Cephalalgia ◽

10.1177/0333102418759785 ◽

2018 ◽

Vol 38 (12) ◽

pp. 1885-1895

Author(s):

Peer Tfelt-Hansen ◽

Janus Kaufmann Lindqvist ◽

Thien Phu Do

Keyword(s):

Adverse Events ◽

Randomized Controlled Trials ◽

International Headache Society ◽

Controlled Trial ◽

Migraine Treatment ◽

Controlled Trials ◽

Acute Administration ◽

Drug Trials ◽

Randomized Controlled ◽

Number Of Patients

Background In 2008, the International Headache Society published guidelines on the “evaluation and registration of adverse events in clinical drug trials on migraine”. They listed seven recommendations for reporting adverse events in randomized controlled trials on migraine. The present study aimed to evaluate adherence to these recommendations, and based on the results, to recommend improvements. Methods We searched the PubMed/MEDLINE database to identify controlled trials on migraine drugs published from 2010 to 2015. For each trial, we noted whether five of the recommended parameters were presented. In addition, we noted whether adverse events were reported in abstracts. Results We identified 73 trials; 51 studied acutely administered drugs and 22 studied prophylactic drugs for migraine. The number of patients with any adverse events were reported in 74% of acute-administration and 86% of prophylactic drug trials. Only 30 (41%) of the 73 studies reported adverse events with data in the abstracts, and 27 (37%) abstracts did not mention adverse events. Conclusion Adverse events, both frequency and symptoms, should be reported to allow a fair judgement of benefit/tolerability ratio when randomized controlled trials in migraine treatment are published. Clinically significant adverse events should be included in the abstract of every randomized controlled trial in migraine treatment.

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Short Dental Implants (≤7mm) Versus Longer Implants in Augmented Bone Area: A Meta-Analysis of Randomized Controlled Trials

The Open Dentistry Journal ◽

10.2174/1874210601812010354 ◽

2018 ◽

Vol 12 (1) ◽

pp. 354-365 ◽

Cited By ~ 7

Author(s):

Priscila N. Uehara ◽

Victor Haruo Matsubara ◽

Fernando Igai ◽

Newton Sesma ◽

Marcio K. Mukai ◽

...

Keyword(s):

Survival Rate ◽

Bone Loss ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Statistical Significance ◽

Controlled Trials ◽

Bone Area ◽

Marginal Bone Loss ◽

Randomized Controlled ◽

Short Implants

Aim: The aim of this systematic review was to compare the survival rate and the marginal bone loss between short implants (≤7 mm) placed in the atrophic area and longer implants placed in the augmented bone area of posterior regions of maxillaries. Methods: Electronic search using three databases was performed up to May 2017 to identify Randomized Controlled Trials (RCT) assessing short implants survival with a minimal follow-up of 12 months post-loading. For the meta-analysis, a Risk Difference (RD) with the 95% Confidence Interval (CI) was used to pool the results of implant failure rate for each treatment group. For the marginal bone changes, Mean Differences (MD) with 95% CI were calculated. Results: Seven randomized controlled trials met the inclusion criteria, being included in qualitative and quantitative analyses. The RD between the short implant group and the control group was -0.02 (95% CI: -0.04 to 0.00), I2=0 and Chi2=3.14, indicating a favorable survival rate for short implant, but with no statistical significance (p=0.09). Discussion: For marginal bone loss, the mean difference was -0,13 (95%CI: -0.22 to -0.05), favoring the test group with statistical significance (p=0.002). The studies showed more heterogeneity for bone loss compared to survival rate. Short and longer implants showed similar survival rates after one year of loading, however the marginal bone loss around short implants was lower than in longer implants sites. Conclusion: Placement of implants ≤7 mm of length was found to be a predictable alternative for the rehabilitation of atrophic posterior regions, avoiding all the disadvantages intrinsic to bone augmentation procedures.

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Is patient self-reporting more accurate than clinician reporting of symptoms for predicting survival in patients with cancer? Meta-analysis of 30 closed EORTC randomized controlled trials

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9597 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9597-9597

Author(s):

A. Bottomley ◽

C. Coens ◽

M. King ◽

D. Osoba ◽

M. J. Taphoorn ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Prognostic Value ◽

Meta Analysis ◽

Symptom Assessment ◽

Controlled Trials ◽

Randomized Controlled ◽

Prognostic Accuracy ◽

Number Of Patients ◽

Patient Reported ◽

Clinician Assessment

9597 Background: This study investigated whether patient self-reporting of symptoms improved prediction of survival as compared to clinician reporting or whether it provided an additive value when taken together with clinician assessment of the same symptoms. Methods: Patients with advanced cancer from 30 European Organisation for Research and Treatment of Cancer (EORTC) Randomized Controlled Trials were included in this retrospective pooled analysis. Clinician [Common Toxicity Criteria (CTC)] and patient (EORTC QLQ-C30) symptom assessment were reported at entry into the study. Data were obtained for six symptoms: pain, fatigue, vomiting, nausea, diarrhea and constipation. The prognostic accuracy for survival was assessed by modeling the contrast in reporting using the Harrell's discrimination c-index (c). Results: Data were available from patient and clinician assessment for pain [number of trials (t) =8, number of patients (n) =1214], fatigue [t=5, n=1237], vomiting [t=5, n=824], nausea [t=6, n=1393], diarrhea [t=6, n=815] and constipation [t=4, n=751]. Fatigue (c=0.59 vs 0.55, p<.01) and constipation (c=0.57 vs 0.52, p=0.03) as reported by patients (vs clinicians) were significantly higher in predicting survival. Patient reported pain (c=0.59 vs 0.58, p=0.17), nausea (c=0.54 vs 0.52, p=0.51), vomiting (c=0.55 vs 0.52, p=0.21) and diarrhea (c=0.51 vs 0.52, p=0.49) did not predict survival any more accurately than clinician assessment. Patient and clinician assessment combined (vs clinicians alone) improved the prognostic accuracy for fatigue (c=0.61 vs 0.55, p=0.01), pain (c=0.60 vs 0.58, p<0.01), nausea (c=0.54 vs 0.52, p=0.04), vomiting (c=0.56 vs 0.52, p=0.04) and constipation (c=0.5 vs 0.52, p=0.01), but not for diarrhea (c=0.52 vs 0.52, p=0.44). Conclusions: Our results suggest that patients’ ratings of their own fatigue and constipation have more prognostic value than clinicians’ ratings of these symptoms. Further, the prognostic value of clinicians's ratings can be improved by combining them with patients’ assessments for the symptoms pain, fatigue, constipation, nausea and vomiting. No significant financial relationships to disclose.

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