Comparison of the Accuracy and Completeness of Records of Serious Vascular Events in Routinely Collected Data vs Clinical Trial–Adjudicated Direct Follow-up Data in the UK

Abstract Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of ponatinib of pts in a clinical trial of frontline ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after ponatinib DC. Survival was calculated from the time of ponatinib DC to the time of last follow up. Results: All 51 patients DC ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post ponatinib survival (Figure-1) and median post ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-ponatinib TKIs, 5 required 2 post-ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on ponatinib and 1 new vascular event within 3 months of ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on ponatinib, developed cerebral infarct within 1 month post ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of ponatinib DC (history of MI while on ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on ponatinib were under control after DC of ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC ponatinib, and most pts were able to maintain/improve the responses achieved on ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on ponatinib. Figure 1. Post ponatinib survival in patients Figure 1. Post ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) – study protocol for a randomised controlled trial

European Stroke Journal ◽

10.1177/2396987320972566 ◽

2021 ◽

Vol 6 (2) ◽

pp. 222-228

Author(s):

Peter Kelly ◽

Christian Weimar ◽

Robin Lemmens ◽

Sean Murphy ◽

Francisco Purroy ◽

...

Keyword(s):

Clinical Trial ◽

Ischaemic Stroke ◽

Usual Care ◽

Artery Stenosis ◽

Cardioembolic Stroke ◽

Lipid Lowering ◽

Large Artery ◽

Vascular Events ◽

Anti Inflammatory

Background Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events. Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. Design CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. Outcome The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). Summary CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. Schedule First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

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Challenges in accessing routinely collected data from multiple providers in the UK for primary studies: Managing the morass.

International Journal for Population Data Science ◽

10.23889/ijpds.v3i3.432 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 4

Author(s):

Fiona V Lugg-Widger ◽

Lianna Angel ◽

Rebecca Cannings-John ◽

Kerenza Hood ◽

Kathryn Hughes ◽

...

Keyword(s):

Data Access ◽

Application Process ◽

Individual Level ◽

Routinely Collected Data ◽

Multiple Data ◽

Linkage Methods ◽

Data Application ◽

Study Population ◽

The Uk

IntroductionResearchers are increasingly using routinely collected data in addition to, or instead of, other data collection methods. The UK government continues to invest in research centres to encourage use of these data, and trials and cohort studies utilise data linkage methods in the follow-up of participants. This does not come without its limitations and challenges, such as data access delays. ObjectiveThis paper outlines the challenges faced by three projects utilising individual-level routinely-collected linked data for the longer-term follow-up of participants. MethodsThese studies are varied in design, study population and data providers. One researcher was common to the three studies and collated relevant study correspondence, formal documentary evidence such as data sharing agreements and, where relevant, meeting records to review. Key themes were identified and reviewed by other members of the research teams. Mitigating strategies were identified and discussed with a data provider representative and a broader group of researchers to finalise the recommendations presented. ResultsThe challenges discussed are grouped into five themes: Data application process; Project timelines; Dependencies and considerations related to consent; Information Governance; Contractual. In presenting our results descriptively we summarise each case study, identify the main cross-cutting themes and consider the potential for mitigation of challenges. ConclusionsWe make recommendations that identify responsibilities for both researchers and data providers for mitigating and managing data access challenges. A continued conversation within the research community and with data providers is needed to continue to enable researchers to access and utilise the wealth of routinely-collected data available. The suggestions made in this paper will help researchers be better prepared to deal with the challenges of applying for data from multiple data providers.

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Comparison of Triflusal with Aspirin in the Secondary Prevention of Atherothrombotic Events; Α Randomised Clinical Trial

Current Vascular Pharmacology ◽

10.2174/1570161116666180605090520 ◽

2019 ◽

Vol 17 (6) ◽

pp. 635-643

Author(s):

Kallirroi I. Kalantzi ◽

Ioannis V. Ntalas ◽

Vasileios G. Chantzichristos ◽

Maria E. Tsoumani ◽

Dimitrios Adamopoulos ◽

...

Keyword(s):

Clinical Trial ◽

Secondary Prevention ◽

Ischaemic Stroke ◽

Primary Efficacy ◽

Primary Efficacy Endpoint ◽

Bleeding Events ◽

Vascular Events ◽

Once Daily ◽

To Receive

Background: Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events. Objective: We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor. Methods: Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. Results: At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2). Conclusion: The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. : (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).

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Investigation and treatment of pelvic vein reflux associated with varicose veins: Current views and practice of 100 UK vascular specialists

Phlebology The Journal of Venous Disease ◽

10.1177/0268355519848621 ◽

2019 ◽

Vol 35 (1) ◽

pp. 56-61

Author(s):

Bruce Campbell ◽

Stephen Goodyear ◽

Ian Franklin ◽

Isaac Nyamekye ◽

Keith Poskitt

Keyword(s):

Clinical Trial ◽

Varicose Veins ◽

Substantial Variation ◽

Pelvic Vein ◽

Clinical Trial Evidence ◽

Internal Iliac ◽

The Uk ◽

Trial Evidence ◽

Vein Reflux

Objective Management of pelvic vein disorders possibly contributing to leg varicose veins remains variable and controversial. This survey investigated practice in the UK. Methods Email questionnaire to 328 members of the Vascular Society. Results One hundred and four (32%) questionnaires were returned. Of 100 respondents treating varicose veins, 9% do not recognise pelvic vein reflux and 11% never investigate or treat it. Indications for investigation include labial (94%) and buttock/upper thigh (70%) varicose veins: 46% use magnetic resonance venography and only 16% transvaginal duplex. Treatments used are coil embolization (89%), sclerotherapy via thigh veins (47%) and transcatheter sclerotherapy (26%). Thirty-four per cent treat only ovarian veins (not internal iliac tributaries). Follow-up is by clinical response (100%): only 14% use duplex. Only 5% treat >10 patients annually. Conclusions There is substantial variation in the management of pelvic vein reflux in the UK. There is need for further consensus and good clinical trial evidence to guide practice.

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