D-dimer prognostic role in thromboembolism recurrence

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Risk calculators and risk factors for D-dimer prognostic role in thromboembolism recurrence

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Overview

The recurrence rate within the first few months following a first episode of VTE is not negligeable. In fact, it is estimated to be around 6% at 6 months following the first episode.[1] Hence, the duration of treatment with oral anticoagulation therapy must be enough to decrease the risk of recurrence and at the same time not too long to cause bleeding complications. The duration of treatment of oral anticoagulation is most problematic in the category of patients suffering from their first episode of unprovoked VTE; therefore, a marker of risk of recurrence of VTE in this population in particular is needed in order to tailor the duration of their treatment.

An association between changes in D-dimer levels during and following discontinuation of oral anticoagulation was suggested more than a decade ago[2] and the prognostic role of D-dimer in predicting the rate of recurrence of VTE has been extensively studied.[3] The different studies seem to be consistent as their findings revealed an association between elevated D-dimer levels and higher rates of recurrence of VTE; hence, they suggest a possible role for D-dimer in predicting recurrence of thromboembolism and tailoring the duration of treatment of oral anticoagulation following VTE.[4]

Recurrence of Thromboembolism

  • The predictive value of D-dimer in predicting recurrence of VTE was investigated by Palareti and colleagues in a study involving 396 patients treated with oral anticoagulant therapy after a first episode of VTE. Patients were followed up for 21 months after discontinuation of oral anticoagulation. The negative predictive value of D-dimer 3 months after the discontinuation of oral anticoagulation was reported to be 95.6% (CI=95%).[5] Palareti et al conducted a prospective cohort study of 610 patients who suffered from their first spontaneous episode of VTE. Patients who had a D-dimer level less than 250 ng/ml had 60% less relative risk of recurrence of VTE compared to patients having higher D-dimer levels (RR=0.4; CI=95%). The 610 patients were followed up and their D-dimer levels were measured after the discontinuation of their treatment with oral anticoagulation which had lasted for at least 3 months. The follow up period was done at a 3 months interval for the first year and at a 6 months interval for 10 years.[6] Palareti et al also investigated the predictive role of D-dimer in recuurent VTE after the discontinuation of oral anticoagulant in patients with idiopathic thromboembolic events and in patients with inherited thrombophilia. The results of this study revealed that the D-dimer measured one month after discontinuation of oral anticoagulant has a high predictive balue for recurrence of VTE in subjects with and without inherited thrombophilia.[7] Palareti et al not only proved the role of D-dimer as a prognostic factor for recurrence of VTE, but also further investigated the use of D-dimer to tailor the duration of oral anticoagulation to minimize the risk of recurrence.[8][9] This point is further emphasized in a different study conducted by the same team, where poor anticoagulation quality, objectively assessed by an INR level less than 1.5 during the 3 months treatment period, was associated with higher D-dimer levels after discontinuation of the oral anticoagulation and with increased risk of recurrence of VTE.[10]. In addition, a higher hazard ratio for recurrence is reported to be associated when D-dimer levels are taken into consideration with inherited hypercoagulation disorders and not with residual venous obstruction.[11]
  • According to the PROLONG study, abnormal levels of D-dimer 1 month following discontinuation of anticoagulation were associated with an elevated risk of thromboembolism recurrence whereas normal levels of D-dimer 1 month following discontinuation of anticoagulation were associated with a lower risk of thromboembolism recurrence(4.4% patient-years). In addition, f[8] In addition, gender and age seems to influence the predictive value of D-dimer; in fact, a very low risk of VTE recurrence is reported in female subjects whose age is less than 65 years and whose D-dimer level at month after discontinuation of therapy is normal.[12]
  • The PROLONG Study followed up 608 patients for an average of 1.4 years and reported at the end of the follow up period an adjusted hazard ratio of 2.27 (1.15 to 4.46; CI=95%; P=0.02)for recurrence of VTE in subjects with abnormal D-dimer level compared with subjects with normal D-dimer levels.[8]
  • An additional year extended follow up of the PROLONG Study further reinforced the previous findings by reporting an adjusted hazard ratio of 2.7 (P = 0.042) for recurrence of VTE in subjects with abnormal D-dimer level compared with subjects with normal D-dimer levels.[13] In the additional extended follow up, PROLONG investigators also investigated the role of comorbidities alone and in combination with D-dimer levels at one month after discontinuation of treatment as risk factors for recurrence of VTE in the context of a first episode of unprovoked VTE. Higher D-dimer levels were reported in subjects with pre-existing comorbidities; nevertheless, D-dimer was an independent risk factor for recurrence of VTE while the presence of comorbidities was not. A detailed summary on the rates of recurrences is as follows:
    • Normal D-dimer, with comorbidities: 14.3%
    • Normal D-dimer, without comorbidities: 10.8%
    • Abnormal D-dimer, with comorbidities: 24.6%
    • Abnormal D-dimer, with comorbidities: 21.3%[14]
  • While the PROLONG Study investigated the association of abnormal D-dimer level at one month following more than one month after anticoagulation suspension for unprovoked venous thromboembolism, PROLONG II Study investigated the course of change in D-dimer level more than a month following the discontinuation of therapy and the association between the levels of D-dimers thereafter with the risk of recurrence. PROLONG II Study is a prospective multicenter cohort study that enrolled 355 patients with a first episode of VTE who were followed up for 13 months. The results of the PROLONG II Study showed that patients who have high levels of D-dimer at 3 months after anticoagulation suspension have higher thromboembolism recurrences risks than patients who have normal levels of D-dimer. 68% of the enrolled patients had a normal D-dimer one month following discontinuation of the treatment; however, not all subjects maintained a normal level of D-dimer in the follow up period. Among subjects who initially had a normal D-dimer level one month after the discontinuation of the treatment, the risks of recurrence of VTE were 27% patient years (95% CI: 12-48) and 2.9% patient years( 95% CI: 1-7) in subjects whom D-dimer became elevated at 3 months and remained abnormal and in subjects whom D-dimer remained normal throughout the follow up period respectively.[15] These studies suggest that the measurement of D-dimer levels at several months intervals following anticoagulation suspension in patient suffering from a first episode of VTE might be beneficial in triaging patients and targeting their therapies.[16] It is important to note that the predictive value of D-dimer for recurrence of thromboembolic events depends on the time of discontinuation of oral anticoagulant as the oral anticoagulant affects D-dimer by decreasing its level; hence, the prognostic role of D-dimer is best at least a month following discontinuation of the oral anticoagulation therapy. For instance, in this same study the percentages of patients who had abnormal D-dimer levels were 15.6%, 40.3% and 40.6% at the time of therapy discontinuation, after one month and after three months respectively. In addition, the predictive value of D-dimer is valid in idiopathic cases of thromboembolism and not in the context of cancer or predisposing risk factors.[16]
  • As previously proved, the D-dimer level have both a positive predictive value and a negative predictive value for recurrence of VTE,[5][17] and it has been suggested that D-dimer is a good tool to stratify patients who had their first episode of idiopathic VTE and tailor the duration of treatment. However, it is important to evaluate whether the predictive value of D-dimer remains the same regardless of the timing of D-dimer testing, the modalitiy of testing and the age of the patient since the D-dimer level is known to increase with age. A patient-level metaanalysis involving 1881 patients with a first unprovoked VTE followed up for 26.9 months (SD=19.1) revealed that the predictive value of D-dimer is independant of the age of the patient, the timing of D-dimer testing and the cut off point of the assay used to measure D-dimer.[18]
  • Tosetto and colleagues evaluated the use of the DASH score in predicting the rate of recurrence of VTE in patients who recieved at least 3 months of anticoagulation following a first episode of VTE. The DASH score includes D-dimer, age and hormonal therapy. The recurrence rates were reported as follows:
    • Score ≤ 1: 3.1% (95% confidence interval, 2.3-3.9)
    • Score=2: 6.4% (95% CI, 4.8-7.9)
    • Score ≥ 3: 12.3% (95% CI, 9.9-14.7)[19]
  • The annual rates of recurrence of VTE in patients treated with anticoagulant after their first episode of VTE were reported to be 3.5% (CI, 2.7% to 4.3%) and 8.9% (95% CI, 5.8% to 11.9%) in patients with negative D-dimer and patients with positive D-dimer respectively. These results were based on a systematic analysis of 7 studies involving a total of 1888 patients who received oral anticoagualtion therapy for at least 3 months and were followed up for two years thereafter.[20]
  • Another study investigated the predictive value of D-dimer for recurrence of VTE by following up 204 patients diagnosed with their first episode of VTE. Follow up was done after 3 months, 6 months, 12 months and then yearly. D-dimer was found to have a high negative predictive value of 94.2% and 92.2% in all studied patients and in patients with unprovoked VTE respectively. D-dimer was an independent predictor of recurrent VTE especially in the population of patients with unprovoked VTE (Hazard ratio=4.61; CI=95%; p=0.001).[21]
  • A study conducted in Bologna evaluated the predictive value for recurrence of VTE of D-dimer in combination with residual venous obstruction (RVO) assessed by compression ultrasound in 400 patients 30 days (+/- 10 days) following after the discontinuation of oral anticoagulation. Elevated levels of D-dimer more than 500 ng/ml were found to be an independent risk factor for the recurrence of VTE. The detailed results about the recurrence rates were as follows:
    • Normal D-dimer without RVO: 5.7% (95% CI:2-13%)
    • Normal D-dimer with RVO: 10.4% (95% CI:6-18%)
    • Abnormal D-dimer without RVO: 22.9% (95% CI: 14-33%)
    • Abnormal D-dimer with RVO: 25.9% (95% CI: 18-35%)[22]
  • D-dimer levels were evaluated in 152 patients following oral anticoagulation treatment for VTE. D-dimer levels were measured at the time of discontinuation of the treatment, after one week, after one month and after 3 months. The D-dimer levels were elevated at the time of discontinuation in 70% of the subjects, 80% of which sustained a high D-dimer after a week. The percentage of subjects with elevated D-dimer decreased to 30% after a month and to 13% after 3 months. Seven out of the 152 subjects developed recurrent VTE and all of them has a persistently high D-dimer levels.[23]
  • Further studies evaluated the prognostic role of D-dimer and factor VIII coagulant in the recurrence of VTE and lead to results consistent with previous studies. In fact, the Prevention of Recurrent Venous Thromboembolism trial evaluated 508 subjects who received anticoagulation therapy for at least three months following idiopathic VTE and followed them up for any VTE recurrence for more than 2 years. The results of this study revealed an association between recurrence of VTE and elevated level of D-dimer (>500ng/ml), and not elevated levels of factor VIII coagulant (> or = 150 IU dL). The hazard ratio of recurrent VTE with elevated D-dimer was reported to be 2.0 (1.2-3.4; CI=95%). This association was significant among subjects having their first episode of VTE. The annual rates of recurrence of VTE are summarized as follows:
    • Elevated level of D-dimer: 10.9%
    • Normal level of D-dimer: 2.9%[24]
  • Some have noted that a substantial change in risk between populations is needed before D-dimer can be used as a clinically significant prognostic tool and have suggested increased specificity in the grouping of populations at risk for recurrent VTE.[25]

References

  1. ↑ White RH (2003). "The epidemiology of venous thromboembolism". Circulation. 107 (23 Suppl 1): I4–8. doi:10.1161/01.CIR.0000078468.11849.66. PMID 12814979.
  2. ↑ Kévorkian JP, Halimi C, Segrestaa JM, Drouet L, Soria C (1998). "Monitoring of patients with deep-vein thrombosis during and after anticoagulation with D-dimer". Lancet. 351 (9102): 571–2. doi:10.1016/S0140-6736(05)78559-7. PMID 9492784.
  3. ↑ Wu C, Bates SM (2009). "Should D-dimer testing be used to predict the risk of recurrence after discontinuation of anticoagulant therapy for a first unprovoked episode of venous thromboembolism?". Pol Arch Med Wewn. 119 (4): 225–30. PMID 19413181.
  4. ↑ Zhu T, Martinez I, Emmerich J (2009). "Venous thromboembolism: risk factors for recurrence". Arterioscler Thromb Vasc Biol. 29 (3): 298–310. doi:10.1161/ATVBAHA.108.182428. PMID 19228602.
  5. ↑ 5.0 5.1 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S (2002). "Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped". Thromb Haemost. 87 (1): 7–12. PMID 11848459.
  6. ↑ Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B; et al. (2003). "D-dimer levels and risk of recurrent venous thromboembolism". JAMA. 290 (8): 1071–4. doi:10.1001/jama.290.8.1071. PMID 12941680. Review in: ACP J Club. 2004 Mar-Apr;140(2):50 Review in: J Fam Pract. 2004 Jan;53(1):20, 23
  7. ↑ Palareti G, Legnani C, Cosmi B, Valdré L, Lunghi B, Bernardi F; et al. (2003). "Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia". Circulation. 108 (3): 313–8. doi:10.1161/01.CIR.0000079162.69615.0F. PMID 12847064.
  8. ↑ 8.0 8.1 8.2 Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A; et al. (2006). "D-dimer testing to determine the duration of anticoagulation therapy". N Engl J Med. 355 (17): 1780–9. doi:10.1056/NEJMoa054444. PMID 17065639. Review in: ACP J Club. 2007 Mar-Apr;146(2):29 Review in: Evid Based Med. 2007 Apr;12(2):45
  9. ↑ Palareti G, Cosmi B, Legnani C (2007). "D-dimer testing to determine the duration of anticoagulant therapy". Curr Opin Pulm Med. 13 (5): 393–7. doi:10.1097/MCP.0b013e3282058b94. PMID 17940483.
  10. ↑ Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S (2005). "Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence". J Thromb Haemost. 3 (5): 955–61. doi:10.1111/j.1538-7836.2005.01330.x. PMID 15869591.
  11. ↑ Cosmi B, Palareti G (2005). "D-dimer, oral anticoagulation, and venous thromboembolism recurrence". Semin Vasc Med. 5 (4): 365–70. doi:10.1055/s-2005-922481. PMID 16302157.
  12. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Sex, age and normal post-anticoagulation D-dimer as risk factors for recurrence after idiopathic venous thromboembolism in the Prolong study extension". J Thromb Haemost. 8 (9): 1933–42. doi:10.1111/j.1538-7836.2010.03955.x. PMID 20553388.
  13. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Alatri A; et al. (2009). "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 (4): 381–8. doi:10.1007/s11239-009-0315-5. PMID 19288181.
  14. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Comorbidities, alone and in combination with D-dimer, as risk factors for recurrence after a first episode of unprovoked venous thromboembolism in the extended follow-up of the PROLONG study". Thromb Haemost. 103 (6): 1152–60. doi:10.1160/TH09-11-0759. PMID 20352167.
  15. ↑ Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S; et al. (2010). "Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study". Blood. 115 (3): 481–8. doi:10.1182/blood-2009-08-237354. PMID 19965693.
  16. ↑ 16.0 16.1 Stein PD, Janjua M, Matta F, Alrifai A, Jaweesh F, Chughtai HL (2011). "Prognostic value of D-dimer in stable patients with pulmonary embolism". Clin Appl Thromb Hemost. 17 (6): E183–5. doi:10.1177/1076029610395129. PMID 21288930.
  17. ↑ Fattorini A, Crippa L, Vigano' D'Angelo S, Pattarini E, D'Angelo A (2002). "Risk of deep vein thrombosis recurrence: high negative predictive value of D-dimer performed during oral anticoagulation". Thromb Haemost. 88 (1): 162–3. PMID 12152661.
  18. ↑ Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S; et al. (2010). "Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism". Ann Intern Med. 153 (8): 523–31. doi:10.7326/0003-4819-153-8-201010190-00009. PMID 20956709.
  19. ↑ Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S; et al. (2012). "Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH)". J Thromb Haemost. 10 (6): 1019–25. doi:10.1111/j.1538-7836.2012.04735.x. PMID 22489957.
  20. ↑ Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T; et al. (2008). "Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism". Ann Intern Med. 149 (7): 481–90, W94. PMID 18838728. Review in: Evid Based Med. 2009 Apr;14(2):59 Review in: Ann Intern Med. 2009 Feb 17;150(4):JC2-14
  21. ↑ Wang Y, Liu ZH, Zhang HL, Luo Q, Zhao ZH, Zhao Q (2011). "Predictive value of D-dimer test for recurrent venous thromboembolism at hospital discharge in patients with acute pulmonary embolism". J Thromb Thrombolysis. 32 (4): 410–6. doi:10.1007/s11239-011-0625-2. PMID 21847593.
  22. ↑ Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2005). "D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis". Thromb Haemost. 94 (5): 969–74. doi:10.1160/TH05-02-0095. PMID 16363238.
  23. ↑ Kuruvilla J, Wells PS, Morrow B, MacKinnon K, Keeney M, Kovacs MJ (2003). "Prospective assessment of the natural history of positive D-dimer results in persons with acute venous thromboembolism (DVT or PE)". Thromb Haemost. 89 (2): 284–7. doi:10.1267/THRO03020284. PMID 12574808.
  24. ↑ Shrivastava S, Ridker PM, Glynn RJ, Goldhaber SZ, Moll S, Bounameaux H; et al. (2006). "D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism". J Thromb Haemost. 4 (6): 1208–14. doi:10.1111/j.1538-7836.2006.01935.x. PMID 16706961.
  25. ↑ Garcia DA (2009). "Review: D-dimer concentrations predict risk of recurrent VTE after anticoagulant therapy is stopped". Evid Based Med. 14 (2): 59. doi:10.1136/ebm.14.2.59. PMID 19332615.

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