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Use of D-dimer testing to determine duration of anticoagulation, risk of cardiovascular events and occult cancer after a first episode of idiopathic venous thromboembolism: the extended follow-up of the PROLONG study

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Abstract

Background The PROLONG study showed that D-dimer (D-d) testing could help tailor the duration of anticoagulation after idiopathic venous thromboembolism (VTE). In this report the initial 18 month study follow-up was extended for 1 year. Materials and Methods D-d was measured 1 month after anticoagulation withdrawal for a first episode of idiopathic VTE. Patients with a normal D-d did not resume anticoagulation, while patients with an abnormal D-d were randomized to either resume or not resume treatment. The primary outcome was the composite of recurrent VTE and major bleeding. Secondary end-points were cardiovascular events, newly diagnosed cancers and deaths. Results D-d was abnormal in 222/608 (36.5%) patients. Average follow-up was 2.55 years. Twenty-eight events occurred in the 121 patients who stopped anticoagulation (23.1%, 9.6% person-years) and five in the 101 patients who resumed anticoagulation (5.0%, 2.0% person-years, adjusted hazard ratio-HR = 3.76; P = 0.008). Recurrence rate was higher in patients with abnormal D-d who stopped anticoagulation than in patients with normal D-d (51 events in 386 patients −13.2%; 5% person-years; adjusted HR 1.70; P = 0.045). The adjusted HR ratio associated with normal D-d versus abnormal D-d in patients who resumed anticoagulation was 2.7 (P = 0.042). An abnormal D-d was associated with a non significant higher risk of cardiovascular events and newly diagnosed cancers vs normal D-d. Conclusions Patients with an abnormal D-d at 1 month after withdrawal of VKA have a significant risk of recurrence over a 2.55 year follow-up and they benefit from resuming anticoagulation.

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Acknowledgments

The study was supported by the Italian Federation of Anticoagulation Clinics (FCSA) and by the Department of Angiology and Blood Coagulation of the University Hospital S. Orsola-Malpighi of Bologna (Coordinating Center), Italy. The Instrumentation Laboratory company (Milan) provided the kits for D-dimer measurement (Clearview Simplify-D dimer test). Disclosure: Drs. Palareti, Cosmi, Legnani, Pengo, Testa, and Tripodi report having been paid lecture fees by the Instrumentation Laboratory company, Milan Italy.

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Authors and Affiliations

  1. Department Angiology and Blood Coagulation “Marino Golinelli”, S. Orsola-Malpighi University Hospital, Via Albertoni, 15, Bologna, Italy

    Benilde Cosmi, Cristina Legnani & Gualtiero Palareti

  2. Department of Hematology, S. Bortolo Hospital, Vicenza, Italy

    Alberto Tosetto

  3. Department Clinical and Experimental Medicine, Division of Clinical Cardiology, University Hospital, Padua, Italy

    Vittorio Pengo

  4. Department Internal Medicine I, Angiology, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy

    Angelo Ghirarduzzi

  5. Haemostasis and Thrombosis Center, General Hospital, Cremona, Italy

    Adriano Alatri

  6. Centro Trombosi, A.O. di Careggi, Università di Firenze, Firenze, Italy

    Domenico Prisco & Daniela Poli

  7. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department Internal Medicine, University and IRCCS Maggiore Hospital, Milan, Italy

    Armando Tripodi

Authors
  1. Benilde Cosmi
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  2. Cristina Legnani
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  3. Alberto Tosetto
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  4. Vittorio Pengo
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  5. Angelo Ghirarduzzi
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  6. Adriano Alatri
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  7. Domenico Prisco
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  8. Daniela Poli
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  9. Armando Tripodi
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  10. Gualtiero Palareti
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Corresponding author

Correspondence to Benilde Cosmi.

Additional information

All the authors are for the PROLONG Investigators (on behalf of FCSA, Italian Federation of Anticoagulation Clinics). The PROLONG investigators are listed in the Appendix. ClinicalTrials.gov: NCT00264277.

Appendix

Appendix

Study sites and investigators (all the participating centers are affiliated in the Italian Federation of Anticoagulation Clinics –FCSA; numbers in parentheses are the numbers of patients who underwent randomization):

Investigators: U.O. Angiologia e Malattie della Coagulazione “Marino Golinelli”, Policlinico S.Orsola-Malpighi, Bologna—G. Palareti, B. Cosmi, C. Legnani, C. Brusi (148); A.O. Istituti Ospitalieri, Cremona—S. Testa, A. Alatri (79); I° Div. Di Medicina Interna—Centro Emostasi e Trombosi, Arcispedale Santa Maria Nuova, Reggio-Emilia—A. Ghirarduzzi, A. Iorio (68); Centro Regionale Malattie Emorragiche e Trombotiche—Div. Ematologia, Ospedale S. Bortolo, Vicenza—A. Tosetto (36); Servizio di Prevenzione e Terapia della Trombosi, Ospedale “Ex Busonera”, Padova—V. Pengo, C. Pegoraro, S. Iliceto (27); Unita’ delle Malattie Tromboemboliche ed Emorragiche, Azienda Policlinico Universitario di Palermo—S. Siragusa (27); Centro Trombosi, A.O. di Careggi Universita’ di Firenze—D. Prisco, D. Poli (26); Modulo Trombosi ed Emostasi—Divisione di Ematologia Talamona, Ospedale Ca’ Granda Niguarda, Milano—F. Baudo (25); Centro Senese Sorveglianza Anticoagulati—Ist. Di Medicina Interna e Geriatria, Policlinico “Le Scotte”, Siena—R. Cappelli (20); Sezione Trasfusionale, Ospedale San Leopoldo Mandic, Merate—N. Erba (18); Centro Trasfusionale e Ambulatorio Emostasi e Trombosi, Ente Ospedaliero di Vimercate Usl 28, Vimercate—L. La Rosa (16); Centro Emostasi, Ospedale Regionale, Parma—C. Pattacini, R. Quintavalla (15); Centro Sorveglinza Anticoagulati—Malattie della Coagulazione e Angiologia Medica—Div. Di Med. Interna, Ospedale “S. Cuore di Gesù”, Gallipoli—L. Ria (14); Laboratorio Analisi—Ambulatorio per il Controllo della Terapia Anticoagulante Orale, Presidio Ospedaliero di Faenza—E. Bucherini (12); Laboratorio Analisi—Divisione di Cardiologia, Ospedale di Bentivoglio—E. Cerè (11); Centro Emostasi e Trombosi, Ospedale dell’Annunziata, Cosenza—V. Rossi (9); Centro Emostasi e Trombosi, Ospedale degli Infermi, Rimini—E. Tiraferri (9); Servizio Trasfusionale, Azienda Ospedaliera Bolognini, Seriate—C. Agazzi, Coffetti (9); Laboratorio di Patologia Clinica, Presidio Ospedaliero S.Maria Incoronata dell’Olmo, Cava dei Tirreni—C. Villani (8); Laboratorio Analisi—Centro Sorveglianza Anticoagulanti, Ospedale Valduce, Como—L. Frigerio (7); Dip.Scienze Biomediche e Terapie Avanzate, Arcispedale S.Anna, Ferrara—G. Scapoli (7); U.O. Medicina Interna, Policlinico Universitario Messina—A. Trifiletti (6); Servizio di Immunoematologia, Ospedale Maria Vittoria, Torino—M. Molinatti (6); Centro Trasfusionale e di Ematologia, Azienda Ospedaliera “Ospedale Treviglio—Caravaggio”, Treviglio—P. Dori Faccini (5); Laboratorio e Serv. Di Coagulazione—Serv. Trasfusionale, Azienda Opedaliera SS. Antonio e Biagio, Alessandria—R. Santi (5); Divisione di Cardiologia, Ospedale Regionale di Treviso—Scannapieco (4); Servizio di Fisiopatologia Vascolare, Casa Di Cura Villa Serena, Citta’ S.Angelo—G. Lessiani (3); Laboratorio Patologia Diagnostica Clinica, Ospedale “G. Iazzolino”, Vibo Valentia—V. Scarmozzino (3); Serv. Di Analisi—Sett. Emostasi, Presidio Ospedaliero S. Leonardo, Castellamare di Stabia—V. Imbimbo (2); Centro per lo Studio delle Coagulopatie a Rischio Trombotico, Osp. Galliera, Genova—A. Schenone (2).

Executive Committee: G. Palareti, B. Cosmi, C. Legnani (Bologna), A. Tosetto (Vicenza), A. Tripodi (Milan), A. Iorio (Reggio Emilia), S. Testa (Cremona).

Adjudication Committee: A. Ghirarduzzi (Reggio Emilia), C. Pattacini (Parma), V. Pengo (Padua).

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Cosmi, B., Legnani, C., Tosetto, A. et al. Use of D-dimer testing to determine duration of anticoagulation, risk of cardiovascular events and occult cancer after a first episode of idiopathic venous thromboembolism: the extended follow-up of the PROLONG study. J Thromb Thrombolysis 28, 381–388 (2009). https://doi.org/10.1007/s11239-009-0315-5

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