In a recent issue of the Journal of Thrombosis and Hemostasis, we report that cancer patients with isolated distal deep vein thrombosis (IDDVT) have similar outcomes as cancer patients with proximal venous thromboembolism (VTE) with regard to the rate of VTE recurrence, overall survival, subsequent hospital admission, and the rate of major bleeding at 6 months [1]. These findings potentially impact clinical decision-making by cancer patients.
IDDVT includes the thrombosis of infrapopliteal veins in the calf and may account for up to half of all lower extremity deep vein thromboses [2]. Historically, there has been a dichotomy in treating IDDVT with anticoagulation versus serial monitoring as the risk of clot propagation to proximal veins or a risk of recurrence of DVT was considered lower in patients with an index IDDVT. Indeed, in one randomized placebo-controlled trial of the treatment of IDDVT, anticoagulation was not found to be superior to placebo in reducing the risk of proximal extension or VTE events [3]. However, the hypercoagulable state of cancer manifests differently. Two recent multicenter, long-term studies showed a high rate of VTE recurrence in cancer patients with IDDVT despite staying on active anticoagulants [4,5]. Indeed, in cancer patients, anticoagulation is recommended over serial monitoring of clots in the distal leg [6]. The current ACCP guideline suggests treating both proximal VTE and IDDVT with anticoagulants for 3 months or longer in cancer patients. Despite the uniformity of recommendations across consensus guidelines, there remains heterogeneity in clinical practice and IDDVT in cancer patients is still being treated on a case-by-case basis [7].
A retrospective cohort study found an incidence rate of recurrent VTE of 13.2 events per 100 patient‐years (95% CI: 9.9–17.6%) in cancer patients with IDDVT [4]. Similarly, another prospective cohort study (OPTIMEV) reported a higher risk of VTE recurrence in cancer patients with IDDVT vs proximal (11.5% per person-years [PY] vs 5.4% per PY; adjusted cause-specific hazard ratio [aCHR]: 1.8 [95% CI: 0.7–4.5]), and a similar risk of death and of major bleeding [5].
In our study, we compared the clinical outcomes of cancer patients with IDDVT (unmatched n=124, matched n=96) versus proximal VTE (unmatched n=178, matched n=96).
What were the findings? First, in cancer patients with IDDVT, the annual incidence of recurrent VTE was 6.5 per 100 patient-years. There was no difference in the rate of recurrent VTE between cancer patients with proximal VTE vs IDDVT, with or without matching (matched: HR: 0.77, 95% CI: 0.31–1.92, p=0.58; unmatched univariable analysis: HR: 0.66, 95% CI: 0.34–1.27, p=0.21; unmatched multivariable analysis: HR: 0.95, 95% CI: 0.42–2.11, p=0.89). Of note, half of the patients in the IDDVT cohort experienced proximal DVT or pulmonary embolism (PE) as recurrent events, whereas, the remaining half had clot propagation or recurrence in the distal veins. In both proximal VTE and IDDVT patient cohorts, 50% of patients experienced extension or new VTE within 30 days of the index VTE. Furthermore, we found no difference in overall survival (OS) between cancer patients with proximal VTE versus IDDVT with or without matching (matched: HR: 1.18, 95% CI: 0.77–1.82, p=0.45; unmatched univariable analysis: HR: 0.99, 95% CI: 0.69–1.42, p=0.95; unmatched multivariable analysis: HR: 1.31, 95% CI: 0.85–2.03, p=0.22). Finally, after propensity score matching, there was no difference in the rates of subsequent hospitalization, major bleeding within 6 months, or clinically relevant non-major bleeding within 6 months in patients with IDDVT vs proximal VTE.
What are the implications of this study?
1_These results add to the emerging understanding that the rate of recurrent VTE is high in cancer patients with IDDVT and is comparable to previous studies [4,5].
2_ Our findings suggest that cancer patients with IDDVT should be treated similarly to cancer patients with proximal DVT. Indeed, our analysis did not identify any difference in the rate of recurrent VTE in cancer patients with IDDVT vs proximal VTE, similar to the OPTIMEV study. Our study builds on the OPTIMEV data by including direct oral anticoagulant treatment, which is an emerging standard of practice [8]. OPTIMEV was conducted from the mid- to late- 2000s, and less than one-quarter of the patients in each of the IDDVT and proximal DVT arms were treated with low-molecular weight heparin with no data on direct oral anticoagulants.
3_ This study showed that there was no difference in OS in cancer patients with IDDVT vs proximal VTE suggesting that cancer patients with IDDVT do not have a more indolent course compared with their proximal counterparts.
4_ The rate of hospitalization in cancer patients with IDDVT was similar to the rate of hospitalization in cancer patients with proximal VTE suggesting similar healthcare resource utilization between the two cohorts [9].
5_this study underscores the safety outcome showing that there was no difference in the rate of major or clinically relevant non-major bleeding within 6 months in cancer patients treated with anticoagulation in the IDDVT arm vs the proximal VTE arm.
References
- Poudel, S. K. et al. Clinical outcomes of isolated distal deep vein thrombosis versus proximal venous thromboembolism in cancer patients: The Cleveland Clinic experience. J Thromb Haemost 2019.
- Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost 2012;10:11–19.
- Righini M, Galanaud JP, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol 2016;3:e556–e562.
- Dentali F, Pegoraro S, Barco S,et al. Clinical course of isolated distal deep vein thrombosis in patients with active cancer: a multicenter cohort study. J Thromb Haemost 2017;15:1757–1763.
- Galanaud JP, Sevestre MA, Pernod G, et al. Long-term outcomes of cancer-related isolated distal deep vein thrombosis: the OPTIMEV study. J Thromb Haemost 2017;15:907–916.
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315–352.
- Palareti G. How I treat isolated distal deep vein thrombosis (IDDVT). Blood 2014;123:1802–1809.
- Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020;38(5):496–520.
- Khorana AA, McCrae KR, Milentijevic D,et al. Healthcare resource utilization and costs associated with venous thromboembolism recurrence in patients with cancer. J Med Econ 2019;11:1–7.