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Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation | NEJM

Original Article from The New England Journal of Medicine — Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation...
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Drug safety assessment in clinical trials: methodological challenges and opportunities

Drug safety assessment in clinical trials: methodological challenges and opportunities | Clinical Endpoints Adjudication News | Scoop.it
Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially ...
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Safety of the Combination of PERC and YEARS Rules in Patients With Low Clinical Probability of Pulmonary Embolism: A Retrospective Analysis of Two Large European Cohorts - Gorlicki - 2019 - Academi...

Safety of the Combination of PERC and YEARS Rules in Patients With Low Clinical Probability of Pulmonary Embolism: A Retrospective Analysis of Two Large European Cohorts - Gorlicki - 2019 - Academi... | Clinical Endpoints Adjudication News | Scoop.it
Abstract Background This study aimed to determine the failure rate of a combination of the PERC and the YEARS rules for the diagnosis of pulmonary embolism (PE) in the emergency department (ED). Methods We performed a retrospective analysis of two European cohorts of emergency patients with low gestalt clinical probability of PE (PROPER and PERCEPIC). All patients we included were managed using a conventional strategy (D‐dimer test, followed, if positive, by computed tomographic pulmonary angiogram (CTPA). We tested a diagnostic strategy that combined PERC and YEARS to rule out PE. The primary endpoint was a thromboembolic event diagnosed in the ED or at 3‐months follow‐up. Secondary endpoints included a thromboembolic event at baseline in the ED and a CTPA in the ED. Ninety‐five percent confidence intervals (CIs) of proportions were calculated with the use of Wilson's continuity correction. Results We analyzed 1,951 patients (mean ± SD age = 47 ± 18 years, 56% women) with an overall proportion of patients with PE of 3.5%. Both PERC and YEARS strategies were associated with 11 missed PE in the ED: failure rate 0.57 (95% CI = 0.32–1.02). At 3‐month follow‐up, the overall failure rate was 0.83% (95% CI = 0.51–1.35). Among the 503 patients who underwent a CTPA (26%), the use of the PERC–YEARS combination would have ruled out PE without CTPA in 249 patients (50% [95%CI = 45%–54%], absolute reduction 13% (95% CI = 11%–14%]). Conclusion The combination of PERC then YEARS was associated with a low risk of PE diagnostic failure and would have resulted in a relative reduction of almost half of CTPA. The diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains challenging. The nonspecific presentation of this potential lethal pathology and wide accessibility to computed tomographic pulmonary angiogram (CTPA) led to a significant rise in resource utilization and number of diagnosed PE, with no clear benefit in terms of outcomes.1, 2 The conventional diagnostic strategy in Europe first mandates the assessment of the clinical probability of PE, with unstructured gestalt, Wells rule, or Geneva rule, in either their original or their simplified scheme. In patients with a low or moderate clinical probability this strategy includes D‐dimer testing, followed if positive by a CTPA, and is associated with a very low rate of failure (<0.2% in recent large trials).3-5 This very low rate is in part due to the ever‐decreasing prevalence of PE among this subset of patients, now below 5%.3, 4, 6 To safely limit ED resource use and especially reduce the number of CTPA examination, two rules were recently validated. The Pulmonary Embolism Rule‐out Criteria (PERC) is an eight‐item clinical decision rule that allows the emergency physician to obviate the need for D‐dimer in patients with a low clinical probability of PE and a PERC score of zero (i.e., age < 50 years, heart rate < 100 beats/min, SaO2 > 94%, no hemoptysis, no estrogen use, no surgery or trauma in the past 4 weeks, no unilateral leg swelling, and no previous venous thromboembolism).7 The YEARS rule, that can be seen as a simplified Wells rules with three binary items (namely “hemoptysis,” “clinical sign of deep vein thrombosis,” and “PE the most likely diagnosis”) also allowed a safe reduction in imaging studies by raising to 1000 μg/L (instead of 500 or age × 10) the threshold of D‐dimer in patients without any YEARS item compared to the two‐level Wells rule.8 These two rules were recently prospectively validated.3, 4, 9 The reported failure rate of PERC was < 1% in the PROPER and the PERCEPIC European cohorts, with a potential absolute reduction of more than 10% of CTPA.3 Similarly, the reported failure rate of YEARS was < 1%, associated with a 14% absolute reduction of CTPA.9 However, it is unclear whether these two rules could be safely combined and further reduce CTPA use in the ED. The main objective of this study was to determine whether the combination of PERC and YEARS strategies are associated with a low diagnostic failure rate in ED patients with a low gestalt clinical probability. The secondary objective was to assess the reduction in CTPA use with this strategy combination. Methods Study Design This study is a post hoc analysis of two European prospective cohorts of ED patients with low clinical probability of PE with 3‐month follow‐up. The PROPER cohort includes 1,916 patients recruited from 14 EDs in France, in 2015–2016 in a cluster randomized clinical trial that compared a PERC‐based strategy to the conventional diagnostic strategy for PE.3 In the control arm, the workup for PE included D‐dimer testing followed if positive by a CTPA. In the intervention arm, the PERC score was assessed. In patients with a PERC score of zero, PE was ruled out without any other testing. In patients with a positive PERC score, the workup for PE was similar as in the control arm. The PERCEPIC cohort includes 1,757 patients from an observational study on PERC performances recruited in 12 EDs France and Belgium in 2015 to 2016, including 1,052 low‐risk patients.4 In both studies, the clinical probability of PE was assessed by the emergency physicians with the use of implicit unstructured gestalt assessment. In the PROPER cohort, only patients with low gestalt probability were included, selected by the emergency physician as having a low clinical probability (<15%).10 In the PERCEPIC cohort, the emergency physician completed their implicit clinical probability assessment by ticking one of the three categories low, moderate, or high. Only patients with a low gestalt clinical probability were included in this analysis (Figure 1). Patients were followed‐up at 3 months by phone interview, and the presence of a thromboembolic event during follow‐up was confirmed by an independent adjudication committee, in both studies. In case of inability to perform the phone interview, the patient's general practitioner was contacted. For patients lost to follow‐up, death records from the administrative records of the patient's hometown were sought. All deaths that occurred during follow‐up were reviewed by the adjudication committee and a sudden unexplained death where a thromboembolic event could not be excluded was considered as a fatal PE. The study protocols were approved by local ethic committees and institutional review boards, and as a post hoc analysis on anonymized data, patient's consent was waived for this study. We adhered to the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) criteria for cohort studies.11 Selection of Participants Patients were included in the two cohorts if they had a clinical suspicion of PE defined by a new‐onset presence or worsening of shortness of breath or chest pain. Exclusion criteria composed other obvious causes for their acute presentation, or ongoing anticoagulant treatment, and pregnancy in the PROPER cohort.4, 12 In this study, we included patients with a low gestalt clinical probability of PE and managed under the conventional strategy of D‐dimer testing followed if positive (age‐adjusted threshold) by a CTPA.13, 14 In the two studies, a low gestalt clinical probability corresponded to an unstructured impression of the treating physician as a less than 15% risk of PE. We selected patients with a low clinical probability so that PERC rule can be applied.7 Furthermore, we excluded patients in the “intervention arm” of PROPER since some patients had their suspicion of PE ruled out with no D‐dimer testing, and therefore we would be unable to apply the YEARS strategy to them. For the same reasons, we also excluded patients with no D‐dimer testing in the other arm. Data Collection and Processing We tested a diagnostic strategy that combined PERC and YEARS: a PE is ruled out with no CTPA for patients with: PERC score of zero, or PERC positive and YEARS score of 0 and D‐dimer < 1000 μg/L, or PERC positive and YEARS positive and D‐dimer < the age‐adjusted threshold (age × 10 μg/L). PERC and Wells scores were prospectively collected in the both cohorts. The three items in the YEARS score are recorded in the Wells score, and hence both PERC and YEARS score were prospectively obtained. Since we did not include patients from the intervention group of PROPER and since YEARS score was not used in the ED, these two scores were retrospectively calculated on their prospectively collected components. Since the combination of PERC and YEARS could have been applied to the “intervention group” of PROPER, we performed a sensitivity analysis on the whole cohort of patients with low clinical probability. Outcome Measure The primary objective was to assess the safety of a diagnostic strategy that combined PERC and YEARS. The secondary objective was to assess the reduction of CTPA. The primary endpoint was the diagnosis of a thromboembolic event in the ED or at 3‐month follow‐up. Secondary endpoints included a diagnosis of thromboembolic event during the index visit at baseline in the ED and CTPA performed in the ED. A thromboembolic event was diagnosed in the presence of evidence of PE in the CTPA or at 3 months after confirmation by an independent adjudication committee in both studies. As the benefit of diagnosing an isolated subsegmental PE (i.e., without more proximal PE nor deep venous thrombosis) is unclear, we also performed a preplanned sensitivity analysis excluding isolated subsegmental PEs from the definition of the primary endpoint.15 Primary Data Analysis Baseline characteristics of the main analysis population were expressed as number (percentage) for qualitative variables, and mean (± standard deviation [SD]) or median (interquartile range [IQR]) for quantitative variables, depending on their distribution. The 95% confidence intervals (CIs) were calculated with Wilson continuity correction. To validate the safety of a decision rule in our population, we followed the recommendation of Dronkers et al.:16 with an overall proportion of patients with PE of 3.5%, the upper bound of the 95% CI of our primary endpoint should be below 1.84%. The analysis of the primary endpoint was performed on the main population that included all patients from both cohorts who were investigated as recommended by European guidelines, which mandates a D‐dimer testing (n = 1,951 of 2,006). However, we included patients with D‐dimer testing who were not managed as recommended (namely, positive D‐dimer and no CTPA or CTPA despite negative D‐dimer) and performed a sensitivity analysis for the secondary endpoints with the theoretical population without guidelines violation. A sensitivity analysis was performed on the whole population for the performance of the “PERC then YEARS” combination, but not for “YEARS” only as half of the PROPER cohort were already managed under PERC rules. We also performed a sensitivity analysis for the primary endpoint after the exclusion of isolated subsegmental PEs. Results Among the 2,968 patients with a low clinical probability included in the two cohorts, 962 were excluded was they were in the “intervention arm” of the PROPER cohort, and an additional 55 patients were excluded because they did not have D‐dimer testing. Therefore, the main sample of this study comprised 1,951 patient (mean ± SD age = 47 ± 18 years, 56% women). The main baseline characteristics are presented in Table 1. PROPER (n = 1,916) PERCEPIC (n = 1,052) Total (n = 2,968) Main analysis (n = 1,951) Age (years) 44 (±16.7) 49.6 (±19.1) 46 (±17.8) 47 (±18) Age > 50 years 684 (35.7) 507 (48.2) 1191 (40.2) 835 (42.8) Sex Male 936 (48.8) 448 (42.6) 1,384 (46.6) 854 (43.8) Female 980 (51.2) 604 (57.4) 1,584 (53.4) 1,097 (56.2) Heart rate 84 (17.2) 82 (17.8) 83 (17.4) 84 (18) Heart rate > 100 313 (16.3) 144 (13.7) 457 (15.4) 320 (16.4) SpO2 98.1 (±3.3) 97 (±3) 97.8 (±3) 97.7 (±3.2) Sat < 95% 100 (5) 117 (11.1) 217 (7.3) 156 (8) Temperature (°C) 36.7 (±0.5) 36.9 (±3.2) 36.8 (±1.8) 36.8 (±2.3) Risk factor for PE Estrogen use 160 (8.3) 131 (12.5) 291 (9.8) 226 (11.6) Clinical sign of DVT 103 (5.4) 32 (3) 135 (4.6) 94 (4.8) prolonged immobilization 48 (2.5) 53 (5) 101 (3.4) 82 (4.2) History of PE or DVT 70 (3.7) 76 (7.2) 146 (4.9) 112 (5.7) Hemoptysis 18 (0.9) 20 (1.9) 38 (1.3) 30 1.52) Active malignancy 18 (0.9) 33 (3.1) 51 (1.6) 38 (1.9) PE is the most likely diagnosis 201 (10.5) 41 (3.9) 242 (8.2) 192 (9.8) Simplified Geneva score 0 476 (24.8) 321 (30.5) 797 (26.8) 501 (25.7) 1 1,123 (58.6) 587 (55.8) 1,710 (57.6) 1,132 (58) 2 259 (13.5) 144 (13.7) 403 (13.6) 285 (14.6) 3 50 (2.6) 0 50 (1.7) 27 (1.4) 4 8 (0.4) 0 8 (0.3) 6 (0.3) Wells score <2 (low risk) 1,621 (84.6) 999 (95) 2,620 (88.3) 1,695 (86.9) 2–6 (intermediate risk) 281 (14.7) 53 (5) 334 (11.2) 245 (12.5) >6 (high risk) 14 (0.7) 0 14 (0.5) 11 (0.6) PERC score 0 826 (43) 337 (32) 1,163 (39.2) 685 (35) ≥1 1,090 (57) 715 (68) 1,805 (60.8) 1,266 (65) YEARS score 0 1,505 (78.5) 964 (91.6) 2,469 (83.2) 1,591 (81.6) 1 411 (21.5) 88 (8.4) 499 (16.8) 360 (18.4) Tested with D‐dimer 1,469 (76.7) 1,008 (95.8) 2,477 (83.5) 1,951 (100) Positive D‐dimer testa 366 (24.9) 338 (33.5) 704 (28.4) 570 (29) D‐dimer value (μg/L) 0–500 1,025 (79.8) 623 (61.8) 1,648 (66.5) 1,290 (66.1) 501–1,000 274 (18.7) 189 (19.4) 463 (18.7) 356 (18.3) >1,000 170 (11.5) 196 (18.8) 366 (14.8) 305 (15.6) CTPA in the ED 349 (18.2) 300 (28.5) 649 (21.9) 503 (26) PE diagnosed in the ED 40 (2.1) 44 (4.2) 84 (2.8) 69 (3.5) ISS PE 4 (0.2) 4 (0.4) 8 (0.3) 7 (0.4) PE diagnosed at 3 months 41 (2.2) 46 (4.4) 87 (3) 71 (3.7) ISS PE 4 (0.2) 4 (0.4) 8 (0.3) 7 (0.4) All‐cause death at 3 months 5 (0.3) 2 (0.2) 7 (0.2) 4 (0.2) Data are reported as mean (±SD) or n (%). CTPA = computed tomography pulmonary angiogram; DVT = deep venous thrombosis; ISS = isolated subsegmental; PERC = Pulmonary Embolism Rule‐out Criteria; PE = pulmonary embolism. a Positive D‐dimer if >500 μg/L in patients 50 years old and under and if > age × 10 μg/L in patients over 50 years old. The overall proportion of patients with PE at 3 months was 3.7% in our analysis population. Among the 1,951 low‐risk patients included in this study, 685 (35%) had a PERC score of zero and 1,427 (73%) a negative YEARS rule (i.e., YEARS score of zero and D‐dimer < 1,000 μg/L). The use of either PERC or YEARS would have missed 11 PEs in the ED, which corresponds to a failure rate of 0.57% (95% CI = 0.32%–1.02%) for the diagnosis of PE at 3 months (Table 2). Overall, 1,526 patients (78%) had a negative PERC rule or a negative YEARS rule. The combination of PERC then YEARS would have missed 16 PEs—a failure rate of 0.83% (95% CI = 0.51%–1.35%). After the exclusion of isolated subsegmental PEs, the failure rate of the combination was 0.68% (95% CI = 0.40%–1.15%). A sensitivity analysis on the whole cohort showed a similar failure rate of 0.76% (95% CI = 0.50%–1.14%) and also a similar failure rate when counting overall PEs at 3‐month follow‐up (Table 2). Strategy Missed PE (% [95% CI]) At 3 Months (n = 1,925) In the ED (n = 1,951) Main analysis population Usual 0.10 (0.00–0.27) (n = 2) 0 (n = 0) PERC 0.57 (0.32–1.02) (n = 11) 0.46 (0.24–0.87) (n = 9) YEARS 0.57 (0.32–1.02) (n = 11) 0.46 (0.24–0.87) (n = 9) PERC then YEARS 0.83 (0.51–1.35) (n = 16) 0.72 (0.43–1.20) (n = 14) Without isolated subsegmental PEs Usual 0.10 (0.00–0.27) (n = 2) 0 (n = 0) PERC 0.47 (0.25–0.89) (n = 9) 0.36 (0.17–0.74) (n = 7) YEARS 0.42 (0.21–0.82) (n = 8) 0.31 (0.14–0.67) (n = 6) PERC then YEARS 0.68 (0.40–1.15) (n = 13) 0.56 (0.32–1.00) (n = 11) Whole population (n = 2908) (n = 2968) PERC 0.52 (0.31–0.85) (n = 15) 0.40 (0.23–0.71) (n = 12) PERC then YEARS 0.76 (0.50–1.14) (n = 22) 0.64 (0.41–1.00) (n = 19) PE = pulmonary embolism; PERC = Pulmonary Embolism Rule‐out Criteria. Overall, 503 patients (26%) underwent a CTPA. Among them, 117 had a PERC score of zero, and 208 had a YEARS score of zero and a D‐dimer < 1,000 μg/L, which corresponds to 23 and 41% respective reductions of CTPA use. The combination of “PERC then YEARS” would have resulted in a total of 249 CTPA that could have been avoided, a relative reduction of 50% (95% CI = 45%–54%) and an absolute reduction of 13% (95% CI = 11%–14%; Table 3). Beside CTPA avoidance, the use of PERC would also have avoided an additional 685 (35%) patients with D‐dimer testing. The incremental value of the “PERC then YEARS” combination compared to the different strategies is reported in Table 3. The diagnostic yield of CTPA was 13% with the conventional strategy and would have been of 22% with the use of “PERC then YEARS” combination. Strategy Compared to PERC Then YEARS No. CTPA avoided Absolute Reduction, % (95% CI) Relative Reduction, % (95% CI) Usual 249 12.8 (11.3–14.3) 49.5 (45.0–54.0) PERC 132 6.8 (5.7–8.0) 26.2 (22.4–30.3) YEARS 45 2.3 (1.6–3.1) 8.9 (6.6–11.8) CTPA = computed tomography pulmonary angiography; PERC = Pulmonary Embolism Rule‐out Criteria. The overall adherence to European guidelines was 93.5%. On 570 CTPA that should have been ordered, 266 studies would have been avoided (a relative reduction of 47% [95% CI = 43%–51%]) Discussion In this retrospective analysis of two prospective cohort studies on low‐risk patients assessed for PE in the ED, we report that the use of PERC, YEARS, and their combination “PERC then YEARS” resulted in a low failure rate and therefore appeared safe, with a substantial reduction of CTPA use in the ED. The increasingly availability of CTPA and fear of missing a PE led to a rise in CTPA use and a decreased prevalence of PE among patients tested in the ED.2, 6 The challenge now is more to safely reduce exposure to irradiative and time‐consuming investigations than to further reduce the failure rate of our diagnostic strategies. In this context, several strategies were tested and validated such as limiting the indication for D‐dimer testing or raising the D‐dimer threshold with an age adjustment or a clinical decision rule.4, 5, 9, 12 After a meta‐analysis of 11 studies, PERC was considered a safe strategy for the early exclusion of PE.17 Two recent European prospective cohort studies confirmed this safety and the use of PERC should now be widely accepted among patients with low clinical probability. YEARS, on the other hand, has only been prospectively tested in one cohort in Netherlands and showed that, compared to a two‐level Wells rule, the YEARS rule safely allows a significant reduction of CTPA by raising the D‐dimer threshold to 1,000 μg/L. Our study supports the safe use of YEARS as this rule would have allowed a 41% relative reduction in the use of CTPA with only 11 missed PE (failure rate of 0.57% [95% CI = 0.32%–1.02%]). Historically, the diagnostic safety threshold was set at 2.7%–3%, which corresponded to the upper bound of the false‐negative rate of pulmonary angiogram.5, 18, 19 However, recent recommendations suggested that this threshold should be adjusted to the prevalence of PE in the studied population. A recent retrospective analysis of a part of the YEARS cohort suggested that this combination may not be safe for the exclusion of PE with a 1.4% failure rate and a wide 95% CI that did not lead to the conclusions that there is a sufficiently low failure rate. However, patients included in this study were not only those with a low clinical probability of PE, and PERC was intended to be used only in this specific population. The low rate of PERC‐negative patients (19%) in this study contrasts with the usual rate found in other studies aimed at low‐risk patients (30%–50%).12,20, 21 Moreover, the overall 14% PE prevalence of their study confirms that their population did not comprise only low‐risk patients.22 In this analysis, we report that combining PERC then YEARS resulted in a very low failure rate, with the upper bound of its 95% CI below the recommended threshold of 1.84%. Of note this upper bound is also below 1.4%, which is considered as the testing threshold for PE, below what testing for PE would be inappropriate because of the potential harm of unneeded diagnostic tests.23 This suggests that combining these two rules is safe for the exclusion of PE in low‐risk patients in the ED and that this would be associated with a 50% relative reduction in the rate of CTPA use compared to the conventional strategy. The reduction in CTPA achieved with the use of the combination of PERC then YEARS may seem close to the one achieved with YEARS only (8.9% relative reduction) with a slightly increased failure rate (0.72% vs. 0.46% for YEARS alone) and therefore can be seen of limited added value. However, this strategy would be also associated with a significant reduction in the rate of D‐dimer testing (35%). The use of this combination could have resulted in some more benefit, such as shorter ED length of stay or reduced number of patients exposed to undue anticoagulant therapy. A prospective trial should evaluate the effect of this combination in terms of ED resource use and economic benefit. Limitations Our study presents some limitations. First the YEARS items were not prospectively calculated. However, in the two cohort studies, all items from the Wells score were prospectively recorded; therefore, we believe that our calculation of YEARS is accurate. Second, all patients were tested for PE with D‐dimer, which could have led to some false‐positive findings or isolated subsegmental PEs that did not need to be diagnosed. The PE failure rate could be actually lower than the one we report here. A prospective study that would implement this combination rule may actually find a lower rate of missed PE, as was the case with the PROPER trial. We performed a sensitivity analysis with the exclusion of isolated subsegmental PEs; however, the presence of deep venous thrombosis were not systematically sought, and therefore we cannot ascertain that they were true “isolated” subsegmental PEs in whom equipoise remains on the benefit of anticoagulation. Third, the overall adherence was 93.5% and therefore the proportion of CTPA avoided following different strategies would have been different. However, we found this difference to be moderate as the relative reduction of CTPA from the use of “PERC then YEARS” would have been 47% instead of 50%. Finally, although we followed Dronkers et al.16 recommendation, we believe that the overall failure rate of a strategy may not be the optimal mean to assess the safety: the real false‐negative rate (i.e., number of PE missed divided by number of PE diagnosed or “1 – sensitivity”) could be an important marker for this, although it is rarely reported conversely to the overall failure rate being “1 – negative predictive value,” highly dependent on the prevalence. Conclusion The combination of PERC and YEARS was associated with a low risk of diagnostic failure, with an upper bound of the 95% confidence interval below the recommended maximal failure rate of 1.84%. This combination would have resulted in a relative reduction of almost half of computed tomographic pulmonary angiogram. References
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Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke | NEJM

Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke | NEJM | Clinical Endpoints Adjudication News | Scoop.it
Original Article from The New England Journal of Medicine — Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke...
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[...] The RESPECT trial was a multicenter, randomized, open-label, controlled clinical trial with blinded adjudication of end-point events. [...]

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DEDICATE Trial | European Heart Journal | Oxford Academic

DEDICATE Trial | European Heart Journal | Oxford Academic | Clinical Endpoints Adjudication News | Scoop.it
The DEDICATE Trial: An independent all-comers trial of transcatheter aortic valve implantation vs. surgical aortic valve replacement
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[...] Safety events will be adjudicated by an independent event adjudication committee; echocardiographic images will be evaluated by an independent echocardiographic core-laboratory.[...] 

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Effects of Molidustat in the Treatment of Anemia in CKD

Effects of Molidustat in the Treatment of Anemia in CKD | Clinical Endpoints Adjudication News | Scoop.it
![Figure][1]</img> Background and objectives The efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on dialysis (DaIly orAL treatment increasing endOGenoUs...
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[...] An independent adjudication committee assessed all deaths and any serious AEs of severe arrhythmias, thromboembolic events, syncope or symptomatic hypotension, or heart failure. [...]

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Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights fro...

Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights fro... | Clinical Endpoints Adjudication News | Scoop.it
Latest Medical News & Articles...
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[...] Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. [...]

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Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work - Robinson - - The Journal of Pathology: Clinical Research - Wiley Online Library

Abstract While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed ‘pathological complete response’, have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology‐derived data builds confidence around trial‐specific findings and is necessarily focused on the reproducibility of pathological data, including ‘estimates of uncertainty of measurement’, emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter‐observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever‐expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence‐base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials. Introduction A Quality Assurance in Clinical Trials Workshop was convened by the UK National Cancer Research Institute Cellular‐Molecular Pathology Initiative (NCRI CM‐Path). The workshop was held on 21 March 2017 with representation from the UK Medicines and Healthcare products Regulatory Agency (MHRA), industry and pathology. Four subgroups were formed to tackle issues around regulation: training: trial oversight: and scoring and reporting. The subject areas were researched by the subgroup members prior to the workshop and presented by the subgroup leads for general discussion by the workshop participants. This article provides an overview of the discussions around scoring and reporting of pathology parameters in clinical trials. Discussions around the benefits and challenges in using digital pathology and image analysis were wide‐ranging and will therefore be presented in a separate article. The workshop formulated ‘practice points’ to help pathologists navigate the development, set up and delivery of clinical trials and these are placed in italics at the end of each section and compiled in Table 1. Scoring and reporting should be carried out blinded to treatment allocation and clinical outcomes. The effect of diagnostic drift and chronological bias should be considered throughout the trial, in particular if scoring and reporting is carried out over several years and/or if new reporting guidelines are published. Double reporting and/or central review should be considered to increase confidence in the pathology data. The formation of a ‘Pathology Working Group’ should be considered to oversee the pathology aspects of a study. Training requirements for pathologists participating in clinical trials need to be addressed and will depend on whether the parameter is an established clinical test or a novel biomarker. Auto‐stainers should be used for immunohistochemistry in preference to manual staining. Staining should be carried out in an ISO15189:2012‐accredited laboratory or laboratory working to GCP standards and is mandatory for primary or secondary endpoints of CTIMP clinical trials. Measures to assure confidence in the reproducibility of pathologist scoring should be considered, for example, by reporting levels of inter and intra‐observer agreement. The pathologists in the trial should agree what is considered background staining and thus filtered out of pathologist scoring and this should be kept under review during the trial. Companion and complementary diagnostic tests should be used in preference to laboratory‐devised assays. Manufacturers' instructions must be followed to produce a reliable result. Estimates of uncertainty, defined in ISO 15189:2012, should be made for clinical trial tests where possible. The requirement for pathologist calibration should be considered prior to the trial opening. If an external quality assurance scheme (e.g. UK NEQAS ICC & ISH) is available for the trial test then trial laboratories should participate. Clear definitions of reporting of pathological complete response and SOPs for standardised assessment need to be agreed and established prior to the trial opening. Pathologists should be actively involved in developing trial specific bio‐resources. Pathologists' contributions to clinical trials are wide ranging and should be recognised and appropriately funded. Early pathologist engagement and input into trial design is essential. Scoring and reporting of pathology parameters is an interpretive skill; consequently there is an acknowledged subjective variation in clinical practice from pathologist to pathologist, even within the same centre. For clinical trials, the challenge is to control for variations in individual pathologist practice to limit the introduction of bias and errors. Common pathology parameters used in clinical trials include: diagnosis; grading; staging; biomarker scoring; pathological complete response (pCR); resection margins and recurrence. Diagnosis, grading and staging are routinely carried out in clinical practice following well‐established guidelines (e.g. Royal College of Pathologists, College of American Pathologists, Union for International Cancer Control, American Joint Committee on Cancer). The information can be collected from participating sites using a carefully designed ‘pathology case report form’ (Pathology CRF). Central review of at least a proportion of specimens is desirable for quality assurance purposes, but the extent of review will depend on the aims and objectives of the trial, diagnostic confidence, reproducibility of grading schemes and the ease of application of staging systems. Immunohistochemistry, in situ hybridisation or molecular profiling of tumours may be used for trial entry, patient stratification and randomisation into treatment arms. If a trial is multicentre, it must be considered whether testing will be carried out at the participating sites or co‐ordinated by a central laboratory. Generally, it is preferable that biomarker testing is carried out at the participating sites as they benefit from proximity to patient care and this mitigates against delays in the patient pathway. In the case where laboratory tests are not generally available or are specialised tests developed for the trial, then a central laboratory with the requisite expertise and appropriate level of accreditation is necessary to run the trial effectively. It is important to consider realistic turnaround times when considering central laboratory testing and to manage the expectations of the participating sites and trial co‐ordinators. Trial sample logistics, laboratory capacity and likelihood of repeat tests need to be considered. Whether tests are delivered at participating sites or a central laboratory, quality assurance measures need to be considered and implemented. It is well known that the results of laboratory tests are influenced by a myriad of variables (Table 2) 1. Pre‐analytical variables are those associated with preservation and preparation of tissue prior to testing. Analytical variables are specific to the test carried out. Post‐analytical variables, particularly associated with immunohistochemistry, are a consequence of subjective assessment by the pathologist, which is at best semi‐quantitative, but variability can be estimated by measuring the degree of inter‐observer and intra‐observer agreement. Molecular testing of tissue homogenates using ‘grind and bind’ techniques benefit from quantitative results, but each specific assay has characteristic technical challenges and they lack the morpho‐molecular features of tests carried out on intact tissue sections 2. Variable Description Examples Pre‐analytical Tissue preservation Time to fixation, warm and cold ischaemia times Type of fixative, concentration, pH, temperature and duration Size of sample versus volume of fixative Tissue processing Dehydration and clearing schedules Section preparation Section thickness, temperature and duration of section drying Fresh cut sections versus stored sections versus paraffin wax ‘dipped’ sections Block storage Temperature and duration of block storage Analytical Laboratory test Type of proprietary auto‐stainer Tissue conditioning, unmasking reagents, pH, temperature and incubation time Blocking reagent Primary antibody, concentration, incubation time Detection system Post‐analytical Pathologist Experience Specialist reporting Biomarker scoring training and accreditation Pathology reporting in clinical trials Ideally, assessment of pathology‐based clinical trial endpoints should be masked or blinded to randomisation and clinical outcomes. For exploratory outputs, a staged approach may be more appropriate, such as that proposed by the Society for Toxicological Pathology 3. The first stage is an un‐blinded comparison of treated and control specimens to identify consistent changes and to develop scoring criteria. This strategy facilitates identification of subtle, treatment related findings that can be consistently differentiated from those that occur in controls 4. An independent pathology peer review with targeted blinding may also help minimise bias 5. Scoring and reporting should be carried out blinded to treatment allocation and clinical outcomes. Diagnostic drift and chronological bias Diagnostic drift and chronological bias should be considered when setting up a clinical trial. Diagnostic drift is a gradual change in nomenclature, grading of lesions, or scoring of a biomarker within a single study over time. It is a source of inconsistency that can negatively affect detection of treatment‐related changes or the determination of ‘no‐effect’ levels 3. Chronological bias is defined as the evolutionary process of a grading system, whereby more sensitive and specific criteria for grade assignment are clarified, learned and disseminated. As pathologists gain experience, subtleties of the evolving system are applied to interpretation of tissue sections 6. This is also a source of inconsistency that can negatively affect detection of treatment‐related changes or the determination of the ‘no‐effect’ levels 4. Plans for monitoring diagnostic drift and chronological bias should be considered for trials projected to recruit over several years. Comparison of pathology data at planned intervals throughout the life of the study, for example at the beginning, middle and end of the study, is recommended. The effect of diagnostic drift and chronological bias should be considered throughout the trial, in particular if scoring and reporting is carried out over several years and/or if new reporting guidelines are published. Double reporting and central review Double reporting to verify pathological parameters such as diagnosis, grade, stage and biomarker scores is recommended, but may not be feasible in real time. Pathology review of cases should be considered as part of the trial design. The extent of the review process will depend on the number of cases, the complexity of the scoring, and the contribution of pathology parameters to the trial endpoints. Statistical advice should be sought when designing the review strategy. Central review by a lead pathologist or a group of pathologists should be completed before final data analysis and trial publication. For example, Speight et al (2015) described a system for review of cases from patients with oral epithelial dysplasia that involved four pathologists with adjudication of disagreements towards a consensus diagnosis as the gold standard for clinical trials 7. Central pathology review may be ‘blinded’, meaning independent assessment without knowledge of the participating site data or ‘un‐blinded’ where the original pathology report or pathology CRF is available and data are simply checked for any disagreements. Double reporting and/or central review should be considered to increase confidence in the pathology data. Pathology working groups Pathology working groups have been used in some trials to good effect. For example, ProtecT (Prostate Testing for Cancer and Treatment), a randomised controlled trial comparing active monitoring, radiotherapy and radical prostatectomy in patients with localised prostate cancer, employed a Pathology Working Group that oversaw the pathology aspects of the trial and published impactful pathology‐specific papers from the trial 8, 9. Such groups enhance the quality of a study by actively engaging pathologists in the development of trial protocols, providing training, formulating pathology standard operating procedures (SOPs), conducting central review, resolving discrepancies and disseminating the trial findings to the pathology community. The formation of a ‘Pathology Working Group’ should be considered to oversee the pathology aspects of a study. Providing quality assured pathology tests To ensure that pathology laboratory tests are scored and reported in a consistent manner it is recommended that a systematic process is established comprising, in sequence, education, training and calibration. Education and training Pathologists are most likely to be asked to provide immunohistochemistry‐based tests for clinical trials. Such tests may form part of the recommended datasets for the histopathological reporting of cancer, in which case the expertise is likely to be already established, for example the scoring of oestrogen and HER2 receptors in breast cancer 10, 11. Furthermore, they are likely to be supported by external quality assurance programmes (Table 3) 12. For novel biomarkers, where expertise is not established, it is essential that participating pathologists understand the clinical context of the test and the role of the test in the trial; screening, recruitment, stratification or randomisation. Knowledge of the performance characteristics of the test is essential in order to recognise sub‐optimal tests. For example, assessment of external analyte controls (same‐slide based proprietary cell line controls or characterised tissue controls) and review of expected staining of internal controls are required before scoring the tumour. Trial‐specific training may be delivered by face‐to‐face site meetings, establishing trial‐specific pathology working groups or using on‐line training modules 13. Such meetings can also be used to collect feedback from the participating pathologists on the SOPs associated with tissue collection, processing, staining and scoring. In some circumstances, particularly with more complex SOPs, it is best practise to run trial‐specific protocols, prior to the trial opening, to identify any operational problems. Disease Test Drug Breast cancer Oestrogen receptors Progesterone receptors HER2 Tamoxifen Aromatase inhibitors Trastuzumab Gastric cancer HER2 Trastuzumab Alimentary tract – Lynch syndrome MLH1, PMS2 MSH2, MSH6 Not applicable Alimentary tract – Gastrointestinal stromal tumour (GIST) CD117 (c‐Kit), DOG‐1 Imatinib Non‐small cell lung cancer ALK PD‐L1 (pilot scheme) Crizotinib Nivolumab Pembrolizamab Training requirements for pathologists participating in clinical trials need to be addressed and will depend on whether the parameter is an established clinical test or a novel biomarker. Immunohistochemistry Guidance on validation of immunohistochemistry assays in a clinical service is already available 14. This guidance can be followed when incorporating immunohistochemistry into a clinical trial. The assay must be assessed for accuracy and analytical sensitivity/specificity. Once validation is completed, the assay should be regularly monitored and performance against known external positive controls assessed 14. In the UK, in the setting of a clinical trial, if immunohistochemistry forms part of the primary or secondary outcomes, then this must be performed to a standard to satisfy the MHRA, who inspect laboratories undertaking laboratory work for Clinical Trial of an Investigational Medicinal Product (CTIMP) trials. Immunohistochemistry can be performed manually or on a proprietary automated stainer (auto‐stainer). The latter produce highly reliable tests and should be used in preference to manual staining. Ideally, clinical trial tests should be carried out in an ISO15189:2012‐accredited laboratory or a laboratory working to Good Clinical Practice (GCP) standards. Such stringency may not be required for exploratory tests, where biomarker development is the aim. Auto‐stainers should be used for immunohistochemistry in preference to manual staining. Staining should be carried out in an ISO15189:2012‐accredited laboratory or laboratory working to GCP standards and is mandatory for primary or secondary endpoints of CTIMP clinical trials. Scoring of immunohistochemistry Numerous scoring methods have been devised for the assessment of immunohistochemical staining. The majority are based on the assessment of two parameters: intensity of the staining and proportion of the tumour that is stained (Table 4) 15. Occasionally the scoring system includes an assessment of the tumour and the immune cells; an example is PD‐L1 testing in non‐small cell lung cancer 16. Scoring systems associated with recognised predictive and prognostic markers should be scored according to guidelines 10, 11, 17. For exploratory tests, researchers should investigate the literature and implement validated scoring systems or devise a scoring system to adequately capture the data and to facilitate the development of clinically relevant ‘cut‐offs’. Tumour heterogeneity is recognised as an important variable and needs to be considered when devising scoring systems. Whilst it is recognised that pathologist scoring is semi‐quantitative and subjective, measurement of inter‐observer and intra‐observer agreement provides evidence of the reproducibility of the scoring system and increases the degree of confidence in the data 18. For example, a study that examined Ki‐67 (MIB‐1) scoring across eight laboratories and a central reference laboratory demonstrated high intra‐laboratory reproducibility (intraclass correlation = 0.94; 95% CI 0.93–0.97), but only moderate inter‐laboratory reproducibility (intraclass correlation = 0.71, 95% CI = 0.47–0.78). Factors contributing to inter‐laboratory discordance were tumour region selection, counting method and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation 19. There is considerable interest and investment in developing quantitative image analysis for scoring immunohistochemistry 1. Scoring method Intensity score (IS) Proportion score (PS/%) Calculation H score 0, 1, 2, 3 0–100% (continuous) H score = (1 × %IS1) + (2 × %IS2) + (3 × %IS3) Range 0–300 Allred score 0, 1, 2, 3 1 = <1 2 = 1–10 3 = 10–33 4 = 33–66 5 = >66 Allred score = IS + PS Range 0, 2–8 Additive quick score 0, 1, 2, 3 1 = 0–4 2 = 5–19 3 = 20–39 4 = 40–59 5 = 60–79 6 = 80–100 Additive quick score = IS + PS Range 0–9 Multiplicative quick score 0, 1, 2, 3 1 = 0–4 2 = 5–19 3 = 20–39 4 = 40–59 5 = 60–79 6 = 80–100 Multiplicative quick score = IS × PS Range 0–18 Measures to assure confidence in the reproducibility of pathologist scoring should be considered, for example by reporting levels of inter and intra‐observer agreement. Filtering Individual pathologists have different thresholds for observing and recording incidental morphological changes, background staining or unexpected staining patterns, called filtering. Recording such data, particularly for novel biomarkers, may be important as the information contributes to an understanding of the characteristics of a particular test and informs biomarker development and refinement. The pathologists in the trial should agree what is considered background staining, and thus filtered out of pathologist scoring, and this should be kept under review during the trial. Companion and complementary diagnostic tests Increasingly, the development of new drugs requires specific diagnostic tests to guide treatment, called companion and complementary diagnostic tests. Companion tests are mandatory prior to administering a targeted drug, whereas complementary tests are used to guide patient selection for treatment, but are not used as ‘gate‐keepers’ for access to the drug. The rationale for recommending such tests is based on the principle of precision medicine: delivering the right drug to the right patient at the right time, but is also driven by the requirements of regulatory bodies such as the US FDA and the UK MHRA. The paradigm for companion testing is breast cancer where HER2 receptor testing (e.g. HercepTest, Agilent Dako, Glostrup, Denmark) is required prior to treatment with Trastuzumab. Such diagnostic tests are manufactured to high standards and satisfy the requirements for an in vitro diagnostic (IVD) medical device, accredited by regulatory bodies. Furthermore, UK National External Quality Assurance Scheme (NEQAS) immunocytochemistry (ICC) and in situ hybridisation (ISH) have shown that laboratories using IVD tests outperform those using laboratory developed assays 20. One of the issues around the use of IVDs is that the tests tend to be expensive and the manufacturers' instructions need to be followed precisely to produce a valid test result. Typically, the instructions specify the use of a specific proprietary auto‐stainer, which may not be available in participating laboratories. The problem can be resolved by setting up central laboratory testing at a site with the designated staining platform that can deliver quality assured tests. Companion and complementary diagnostic tests should be used in preference to laboratory‐devised assays. Manufacturers' instructions must be followed to produce a reliable result. Estimates of uncertainty Scoring immunohistochemistry may be subject to ‘estimates of uncertainty of measurement’. ISO 15189:2012 states that ‘the laboratory shall at least attempt to identify all the components of uncertainty and make a reasonable estimation, and shall ensure that the form of reporting of the result does not give the wrong impression of uncertainty’. This applies to numerical counts of immunohistochemically positive cells and working examples are provided in guidelines provided by the UK Royal College of Pathologists 21. The recommendations include consideration of the best methods to achieve clinically reliable measurements, ensuring that these are defined in SOPs and working to ensure that the measurement procedures are consistent between pathologists 21. Estimates of uncertainty, defined in ISO 15189:2012, should be made for clinical trial tests where possible. Calibration It may be necessary to calibrate the laboratories and pathologists prior to opening a trial. This can be achieved by providing a ‘test set’ of cases and compiling the results across the centres and providing feedback. This can be an iterative process aimed at achieving a pre‐specified level of performance or more formal accreditation of the laboratory for the trial. Typically, accredited laboratories would have high levels of agreement with a reference laboratory or demonstrate high levels of agreement with other laboratories taking part in the trial. Statistical tests, such as Cohen's Kappa coefficient (ĸ) 22 or intraclass correlation coefficient, can be used to measure inter‐laboratory or inter‐observer agreement. In the case of Cohen's Kappa coefficient to assess categorical variables, the acceptable level of agreement is controversial. Some researchers consider a ĸ of >0.6 (moderate agreement) acceptable, whereas others stipulate a ĸ of >0.8 (strong agreement) 22. A statistician should be consulted for advice on the most appropriate statistical tests to use. Ideally, the statistician should analyse the data independently of the pathologist(s) to ensure objective assessment. The requirement for pathologist calibration should be considered prior to the trial opening. External quality assurance For established biomarkers, where external quality assurance programmes already exist (e.g. UK NEQAS for ICC and ISH), trial laboratories should participate in such schemes and demonstrate satisfactory performance (Table 3) 12. If an external quality assurance scheme (e.g. UK NEQAS ICC & ISH) is available for the trial test then trial laboratories should participate. Genomic testing Factors such as acceptable testing platforms, nucleic acid extraction kits, modality of testing and the thresholds for positive results need to be set out in SOPs. Fresh‐frozen tissue is the gold standard for techniques where nucleic acid quality requirements are high, for example whole genome sequencing. Formalin‐fixed paraffin‐embedded samples may be acceptable but are subject to the numerous pre‐analytical variables listed in Table 2 1, 23. If an external quality assurance scheme for example, the UK NEQAS Molecular Genetics programme exists for a particular test, then laboratories should participate 24. Pathologists should review trial‐specific patient information sheets and consent forms to ensure that laboratory tests relating to germline mutations are disclosed and that the participant understands the consequence of a positive result and the implications for family members. Pathological complete response Pathological estimates of residual disease following trial‐specific interventions, termed ‘pathological complete response’, are being utilised to expedite the reporting of clinical trials, where previously only extended clinical follow up has been used 25-28. It is important that the participating pathologists have an understanding of the definition of pCR; for example in breast cancer trials, variable definitions have been used allowing or excluding ductal carcinoma in situ from the definition, which influences trial outcomes 29. Nevertheless, central pathology review of a phase 3 neoadjuvant breast cancer trial (ARTemis) has shown good concordance of pCR with participating centre assessment, even in the absence of guidelines and a trial‐specific reporting proforma 30. For colorectal cancer, the UK Royal College of Pathologists reporting guidelines specify that the entire scar should be embedded and three deeper levels cut on each block prior to calling a pCR. These principles should be followed in trials and it is recommended that all pCR cases are centrally reviewed. It is also important to specify whether residual nodal disease should contribute to pCR, as assessment of mesorectal lymph nodes has been shown to reduce the rate of pCR 31. Detailed SOPs are required to standardise block selection and sectioning protocols to ensure consistent assessment of patient specimens across the trial sites 26. Similar principles can be applied to other morphological parameters such as defining and measuring resection margins in surgical trials and processing sentinel lymph node specimens. Clear definitions of reporting of pathological complete response and SOPs for standardised assessment need to be agreed and established prior to the trial opening. Bio‐resource for translational research Tissue collected and curated as part of a clinical trial (frozen tissue and/or formalin‐fixed paraffin‐embedded tissue) is associated with high quality clinical data and pathological classification. Consequently, it is an important legacy that can be used for translational research; for example, the tissue can be used to develop and refine predictive tests. At trial inception, pathologists should actively promote tissue collection and incorporate the costs into the trial grant application or formulate applications for a companion study. The trial documentation, specifically the consent form and patient information sheet, must be worded appropriately. If samples are to be kept beyond the end of the trial, then consent needs to be enduring and ideally generic. Samples may be moved into a biobank with the correct consent provisions, ensuring that the relevant regulations are followed; for example, in England, tissue must be moved under an Human Tissue Authority (HTA) licence and meet HTA standards when the research ethics approval for the study expires. Pathologists should be actively involved in developing trial specific bio‐resources. Conclusion Our Quality Assurance in Clinical Trials Workshop highlighted the importance of ensuring reproducible scoring and reporting of pathology parameters in clinical trials. Key considerations include pathologist training and calibration, and measurement of inter‐observer variation. There are opportunities to evaluate image analysis systems in clinical trials, alongside conventional histological assessment, to moderate ‘uncertainty of measurement’. In any case, pathologists' engagement in clinical trials is essential to help deliver the reliable evidence‐base required for new treatments and robust pathology processes are vital to the credibility of studies. Pathologists' contributions to clinical trials are wide ranging and should be recognised and appropriately funded. Early pathologist engagement and input into trial design is essential. Acknowledgements The National Cancer Research Institute Cellular Molecular Pathology Initiative (NCRI CM‐Path) is funded by a collaborative venture between 10 organisations: Bloodwise, Breast Cancer Now, Cancer Research UK, the Chief Scientist Office (Scotland), the Department of Health (England), Health and Care Research Wales (Welsh Government), Health and Social Care (N Ireland), the Medical Research Council, Prostate Cancer UK and Tenovus Cancer Care. We acknowledge contributions from members of the NCRI CM‐Path Quality Assurance Panel. Part of CV's research time was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the Department of Health, the NHS or the NIHR. NCRI CM‐Path Quality Assurance Panel: Joseph Beecham, Nanostring, Washington, USA. Sarah Blagden, Department of Oncology, University of Oxford, Oxford, UK. Maria Da Silva, Sectra UK. Owen Driskell, Institute for Applied Clinical Sciences, University of Keele, Stoke‐on‐Trent, Staffordshire, UK. Andy Hall, Newcastle University, Newcastle upon Tyne, UK. Sidonie Hartridge‐Lambert, Bristol‐Myers Squibb, London, UK. Emily Howlett, Precision Medicine Team, Cancer Research UK, London, UK. Sidath Katugampola, Centre for Drug Development, Cancer Research UK, London, UK. Ilaria Mirabile, Experimental Cancer Medicine Centres Network, London, UK. James Morden, Institute of Cancer Research Clinical Trials and Statistics Unit, The Institute of Cancer Research, Surrey, UK. Gabrielle Rees, Department of Cellular Pathology, John Radcliffe Hospital, Oxford, UK. Manuel Salto‐Tellez, Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK. Laura Stevenson, Institute of Cancer Research Clinical Trials and Statistics Unit, The Institute of Cancer Research, Surrey, UK. Stephanie Traub, Centre for Drug Development, Cancer Research UK, London, UK. Newton Wong, Department of Cellular Pathology, Southmead Hospital, Bristol, UK. Author contributions statement CV conceived and chaired the NCRI CM‐Path Quality Assurance in Clinical Trials Workshop. All authors contributed to the workshop. CV and MR composed the first draft of the manuscript. All authors critically reviewed and approved the final version of the manuscript. References
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Validity of a Novel Point-of-Care Troponin Assay for Single-Test Rule-Out of Acute Myocardial Infarction

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https://www.linkedin.com/groups/8177210/

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Blogging Stroke – The Modified Treatment in Cerebral Ischemia Score: Does It Matter Who is Scoring It?

Blogging Stroke – The Modified Treatment in Cerebral Ischemia Score: Does It Matter Who is Scoring It? | Clinical Endpoints Adjudication News | Scoop.it
Mohammad Anadani, MD Zhang G, Treurniet KM, Jansen IGH, Emmer BJ, van den Berg R, Marquering HA, et al. Operator Versus Core Lab Adjudication of Reperfusion After Endovascular Treatment of Acute Ischemic Stroke. Stroke. 2018 Mechanical thrombectomy (MT) is the standard of care for acute ischemic stroke treatment. The goal of MT is to restore perfusion to the affected area. Hence, its efficiency is evaluated by the degree of reperfusion at the end of the procedure. The Modified Treatment in Cerebral Ischemia (mTICI) score is the most widely used reperfusion score, and it was used in most of the recent intra-arterial treatment landmark trials to assess the efficacy of mechanical thrombectomy. It was also used to compare different thrombectomy techniques, especially contact aspiration and stent retriever techniques. The mTICI score ranges from 0-3, where 0 means no perfusion and 3 means complete perfusion. In the randomized trial settings, mTICI is usually assessed by core laboratories to avoid overestimation. However, this notion of overestimation by local operators has not been supported by research studies. In this study, Zhang et al. and his colleagues conducted a study using the MR CLEAN registry to compare the operator mTICI with  the core lab mTICI. Patients with intracranial internal carotid artery or middle cerebral artery (M, M2, and M3) occlusions were included. mTICI score was determined by local operators of the participating centers and by core lab (consisting of 8 experienced neuropathologists blinded to the clinical characteristics). Of 1628 patients included in the registry, 1300 patients met inclusion criteria and were included in this study. The mTICI scores were assessed by both operator and core lab in 1182 patients. Successful reperfusion was achieved in 77% of patients according to operator assessment and in 67% according to core lab assessment (difference 10% [95% CI, 6%-14%]; p <0.001) (Figure 1).   The overall agreement between the operator and core lab mTICI scores was 56% (95% CI, 54%-59%). The mTICI was overestimated by operators in 33% of patients and underestimated in 10% of patients (Figure 2). Overestimations were more common with distal occlusions (M2, M3) than proximal occlusions (ICA, M1).   With respect to the functional outcome, successful reperfusion scored by core lab or local operators predicted functional independence (mRS 0-2) equally well. In summary, this study demonstrated a significant disagreement between core lab and local operator assessments, which was mostly related to overestimation of mTICI by the local operators. This study has multiple limitations. The main limitation, which was acknowledged by the authors, is that the mTICI score was assessed by one core lab member with no interrater agreement. In addition, the authors did not use mTICI 2c category in this study; therefore, the authors, in fact, evaluated TICI (Tomsick et al. 2008) and not mTICI score (Almekhlafi et al. 2014). Finally, TICI and mTICI scores were developed for M1 occlusion, and not well validated for more distal occlusions, especially M3 occlusions (Spiotta et al. 2018), which may explain the more noticeable disagreement in mTICI score in distal occlusions. References: Tomsick, T., J. Broderick, J. Carrozella, P. Khatri, M. Hill, Y. Palesch, J. Khoury, and I. I. Investigators Interventional Management of Stroke. 2008. ‘Revascularization results in the Interventional Management of Stroke II trial’, AJNR Am J Neuroradiol, 29: 582-7. Almekhlafi, M. A., S. Mishra, J. A. Desai, V. Nambiar, O. Volny, A. Goel, M. Eesa, A. M. Demchuk, B. K. Menon, and M. Goyal. 2014. ‘Not all “successful” angiographic reperfusion patients are an equal validation of a modified TICI scoring system’, Interv Neuroradiol, 20: 21-7. Spiotta, Alejandro M, David Fiorella, Adam S Arthur, Donald Frei, Aquilla S Turk, and Joshua A Hirsch. 2018. ‘The semiotics of distal thrombectomy: towards a TICI score for the target vessel’, J Neurointerv Surg: neurintsurg-2018-014353.
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[...] In summary, this study demonstrated a significant disagreement between core lab and local operator assessments, which was mostly related to overestimation of mTICI by the local operators.[...]
 
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Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: protocol for a systematic review and meta-analysis of individual participant data

Background In patients with a first, unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulant therapy (AT) is controversial due to tightly balanced risks and benefits of indefinite anticoagulation.
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Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: protocol for a systematic review [...] All events occurring during follow-up had to be documented by an adjudication committee, or by an investigator blinded to the planar V/Q scan results. [...]

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