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Bleeding and thrombotic complications during treatment with direct oral anticoagulants or vitamin K antagonists in venous thromboembolic patients included in the prospective, observational START2-register
  1. Gualtiero Palareti1,
  2. Emilia Antonucci1,
  3. Cristina Legnani1,
  4. Daniela Mastroiacovo2,
  5. Daniela Poli3,
  6. Paolo Prandoni1,
  7. Alberto Tosetto4,
  8. Vittorio Pengo5,
  9. Sophie Testa6,
  10. Walter Ageno7
  11. on behalf of the START2 Register Investigators
    1. 1Fondazione Arianna Anticoagulazione, Bologna, Italy
    2. 2Dipartimento di Angiologia, Ospedale SS. Filippo e Nicola, Avezzano, Italy
    3. 3SOD Malattie Aterotrombotiche, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
    4. 4Divisione di Ematologia, Ospedale San Bortolo, Vicenza, Italy
    5. 5Thrombosis Research Laboratory, Università di Padova, Padova, Italy
    6. 6Centro Emostasi e Trombosi A O Istituti Ospitalieri di Cremona, Cremona, Italy
    7. 7Dipartimento di Emergenza e Accettazione, Centro Trombosi ed Emostasi, Ospedale di Circolo, Università dell’Insubria, Varese, Italy
    1. Correspondence to Dr Gualtiero Palareti; gualtiero.palareti{at}


    Objective The proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.

    Design A prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed.

    Setting About 60 Italian anticoagulation and thrombosis centres participated in the observational START2-Register

    Participants 2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment.

    Interventions Patients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE.

    Outcomes measures Efficacy: rate of VTE recurrence (all thrombotic complications were also recorded). Safety: the rate of major and clinically relevant non-major bleeding events.

    Results Almost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was >180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14–4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, p<0.0001). All-cause mortality was higher in VKA-treated (5.9%) than in DOAC-treated patients (2.6%, p<0.001).

    Conclusion Italian centres treat most patients with VTE with DOACs and prefer VKA for those with more serious clinical conditions. Recurrences were significantly more frequent in DOAC-treated patients due to increased incidence after 180 days of treatment, probably due to reduced adherence to treatment. These results underline the importance of structured surveillance of DOAC-treated patients with VTE to strengthen treatment adherence during extended therapy.

    • anticoagulation
    • thromboembolism
    • vascular medicine

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    • Collaborators START2 Register Investigators: Daniela Poli, Rossella Marcucci, Niccolò Maggini, SOD Malattie Aterotrombotiche, Azienda Ospedaliero Universitaria-Careggi, Firenze; Sophie Testa, Oriana Paoletti, UO Laboratorio Analisi, Centro Emostasi e Trombosi A O Istituti Ospitalieri di Cremona, Cremona; Walter Ageno, Giovanna Colombo, UO. Medicina I, Ospedale di Circolo, Varese; Benilde Cosmi, Giuliana Guazzaloca, Ludovica Migliaccio, UO di Angiologia e Malattie Coagulazione, AOU S. Orsola-Malpighi, Bologna, Bologna; Anna Falanga, Teresa Lerede, Luca Barcella, USC SIMT, Centro Emostasi e Trombosi, Ospedale Papa Giovanni XXIII, Bergamo; Vittorio Pengo, Gentian Denas, Elisa Bison, Dipartimento di Scienze Cardio-Toraco-Vascolari, Centro Trombosi, AOU Padova, Padova; Lucia Ruocco, Paolo Chiarugi, Ambulatorio Antitrombosi per la sorveglianza dei pazienti in terapia anticoagulante orale, U.O. Analisi Chimico-Cliniche, Azienda Ospedaliero Universitaria Pisana, Pisa; Giuliana Martini, Centro Emostasi, Spedali Civili Di Brescia, Brescia; Simona Pedrini, Federica Bertola, Servizio di Laboratorio, Istituto Ospedaliero Fondazione Poliambulanza Brescia; Lucilla Masciocco, Pasquale Saracino, Angelo Benvenuto, UOC Medicina Interna, Centro Controllo Coagulazione, Presidio Ospedaliero Lastaria, Lucera (Foggia); Claudio Vasselli, Laboratorio Patologia Clinica, Policlinico Casilino, Roma; Marco Marzolo, UOC Medicina Interna, Ospedale di Rovigo; Daniela Mastroiacovo, UOSD Angiologia e Diagnostica Vascolare, Ospedale SS Filippo e Nicola, Avezzano (L’Aquila); Antonietta Piana, Francesco Cibecchini, Centro Prevenzione e Cura Malattie Tromboemboliche Azienda Ospedaliera Universitaria San Martino-IST, Genova; Andrea Toma, Pietro Barbera, UOC di Patologia Clinica, Ambulatorio Terapia Anticoagulante Orale, O.C. "L.Cazzavillan" Arzignano, (Vicenza); Antonio Insana, SC Patologia Clinica, Ospedale Santa Croce Moncalieri, Moncalieri (Torino); Carmelo Paparo, Patologia Clinica, Ospedale Maggiore Chieri (Torino); Elvira Grandone, Donatella Colaizzo, Centro Trombosi Casa del Sollievo e della Sofferenza, S.Giovanni Rotondo (Foggia); Domizio Serra, Centro Trombosi, Ospedale Evangelico Internazionale, Genova; Pasquale Pignatelli, Daniele Pastori, Centro Trombosi, Clinica Medica Policlinico Umberto I°, Roma; Serena Rupoli, Clinica Ematologica, AOU- Ospedali Riuniti Ancona, Ancona; Giuseppe Malcangi, Centro Emofilia e Trombosi, Policlinico di Bari, Bari; Maddalena Loredana Zighetti, SIMT- AO San Paolo, Milano; Giovanni Nante, UOS Geriatria ULSS 16 Padova, Padova; Alberto Tosetto Divisione di Ematologia, Ospedale San Bortolo, Vicenza; Rosella Sangiorgio, Centro Emostasi e Trombosi, Ospedale di Lecco, Lecco.

    • Contributors GP designed the study, interpreted data and drafted the manuscript. EA and CL analysed data. DM contributed to the data collection and revised the draft. DP contributed to the data collection and revised the draft. PP revised the draft of the manuscript critically for important intellectual content. AT revised the draft of the manuscript critically for important intellectual content. VP revised the draft. ST contributed to the data collection and revised the draft. WA revised the draft of the manuscript critically for important intellectual content and finally approved the submitted manuscript.

    • Funding Fondazione Arianna Anticoagulazione promotes and supports the START2-Register, including the present study. N/A award/grant number.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer-reviewed.

    • Data availability statement Data are available upon reasonable request. Anonymised study data can be made available to qualified investigators by contacting the first author.

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