During the 10th ICTHIC, Prof. Jeffrey Zwicker (Harvard Medical School, MA, USA) gave an overview of the evidence of the efficacy of thromboprophylaxis in hospitalized patients with cancer.
VTE incidence in the total medical population
A paper published in 2017 looked at the overall event rate of hospital versus nonhospital-related thromboses, not specifically in cancer patients, over the period 2005–2010, when thromboprophylaxis became more common [1]. The results show that the total number of nonhospital-related thrombotic events did not change during the considered period. More importantly, despite the increase in the use of thromboprophylaxis, hospital-related thrombosis still represented about 50% of all thrombotic events [1].
In the total medical population again, randomized trials suggest that thromboprophylaxis can prevent thrombosis. Clinical trials largely conducted in the 1980s and 1990s, looking at low-molecular-weight heparin (LMWH) versus placebo controls, demonstrated a 50% reduction in deep vein thrombosis (DVT) in patients who received LMWH and a 70% reduction in pulmonary embolism (PE) in hospitalized medical patients who received LMWH [2].
VTE incidence in cancer patients
It is known that cancer is associated with an increased risk of thrombosis and bleeding. The estimated incidence of venous thromboembolism (VTE) in patients with cancer during hospitalization is between 2% and 17%. For this reason, guidelines recommend VTE prophylaxis for hospitalized cancer patients [3].
The recent American Society of Hematology (ASH) guidelines suggest using thromboprophylaxis over no thromboprophylaxis for hospitalized medical patients with cancer without venous thromboembolism [4].
An older version of the ASCO guidelines in 2014, recommended thromboprophylaxis for most patients with active cancer throughout hospitalization. However, data were inadequate to support routine thromboprophylaxis in patients admitted for minor procedures or short chemotherapy infusion [5].
Similar indications were given in the updated version published in 2019. Hospitalized patients who have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding. However, routine pharmacological thromboprophylaxis should not be offered to patients admitted only for minor procedures, chemotherapy infusion or stem cell transplant [6].
Although guidelines recommend thromboprophylaxis for hospitalized patients with cancer, a systematic review and meta-analysis investigated the benefits of thromboprophylaxis in these patients. The analysis showed no clear benefit for using LMWH over no thromboprophylaxis in patients with cancer [7].
The meta-analysis identified three randomized studies that reported thrombosis rates specifically in the cancer population: the MEDENOX, PREVENT, and ARTEMIS [7].
In the MEDENOX study, the overall VTE event rate in patients with cancer receiving enoxaparin was 9.7% (19.5% in the placebo group). In the PREVENT, the overall event rate in cancer patients receiving dalteparin was 3.1% (8.3% in the placebo group). In the ARTEMIS trial, 17% of those receiving fondaparinux developed thrombosis (compared to 3.9% in the placebo group) [7].
Despite the thromboprophylaxis, in all three trials, the VTE rates are still quite high, although lower than in the equivalent placebo group in the MEDEBOX and PREVENT studies. Of note, the number of patients with cancer enrolled in these studies is low (72 for MEDENOX, 137 for PREVENT, and 98 for ARTEMIS) [7].
Performing a pooled analysis of the three studies, no clear benefit can be seen for using LMWH over no thromboprophylaxis in patients with cancer [7].
Other subsequent larger studies compared LMWH with DOACs. In the APEX trial, the VTE rate in cancer patients on betrixaban was 6.2% versus 5.7% on enoxaparin. In the MAGELLAN trial, the VTE rate with rivaroxaban was 7.4% versus 9.9% with enoxaparin. Once again, all the VTE rates found in these studies are high despite the use of thromboprophylaxis [3].
Two potential explanations may exist for the lack of reduction in VTE events with thromboprophylaxis: the dosage used is not effective, or the duration of the thromboprophylaxis is inadequate.
Increase in the thromboprophylaxis dosage
To test an increase in the thromboprophylaxis dosage, a pilot randomized clinical trial investigated the feasibility of enoxaparin administration at a weight-adjusted dose (compared to a fixed-dose) in hospitalized patients with cancer who had an additional risk factor by the Padua score (≥4) [8].
Patients blindly received either enoxaparin 40 mg or enoxaparin 1 mg/kg once a day for up to 14 days. After this time, the groups were unblinded. The patients who received enoxaparin 40 mg once a day underwent a compression ultrasound to test the true event rate in higher-risk cancer patients [8].
This pilot study randomized only 50 patients. However, no major hemorrhages were detected in the weight-adjusted group. In addition, the ultrasound test detected a couple of cases of DVT in patients who weighed much more than those who do not develop thrombosis. These results can corroborate the argument that weight-adjusted anticoagulation may benefit these high-risk cancer patients [8].
The pilot study concluded that weight-adjusted anticoagulation appears to be well tolerated with no increased risk of major bleeding, but larger randomized clinical trials are needed.
Weight-adjusted thromboprophylaxis in patients with COVID-19
In COVID-19 times, weight-adjusted thromboprophylaxis gained widespread discussion.
A pooled analysis of all the published studies that looked at different doses of thromboprophylaxis during hospitalization for COVID-19 patients showed that the VTE event rates in patients receiving standard dose (enoxaparin 40 mg per day or equivalent dosing of other anticoagulants) appeared to be much higher than those receiving either intermediate (weight-adjusted, double-dose prophylaxis, or any dosage that is greater than the standard dose and lower than the therapeutic-dose anticoagulants) or therapeutic anticoagulation (enoxaparin 1 mg/kg twice daily or 1.5 mg/kg once daily or equivalent doses of other anticoagulants) [9]. Also, the therapeutic dose did not seem to be more beneficial than the intermediate dose thromboprophylaxis [9].
In a pre-print study testing therapeutic anticoagulation versus standard-dose thromboprophylaxis in patients with COVID-19, therapeutic anticoagulation seemed to reduce the risk of thrombosis in patients critically ill compared to standard prophylaxis (5.77% compared to 10.3%). Additionally, in moderately ill patients, there was a significant reduction in VTE for therapeutic dosing compared to standard (1.9% vs 3.2%, respectively) [10].
Not unexpectedly, there seems to be a signal for increased bleeding. For example, in critically ill patients, there appeared to be a 50% increase in bleeding for therapeutic dosage compared to standard, and the same was true in moderately ill patients [10].
Extended thromboprophylaxis duration
A systematic review investigated extended thromboprophylaxis for medically ill patients with cancer [11].
The pooled analysis of those in the APEX, EXCLAIM, MAGELLAN and MARINER studies that had either a history of or active cancer showed similar rates of VTE between the extended-duration (28–42 days) and standard-duration (14 days) groups (odds ratio [OR], 0.85; 95% CI: 0.61–1.18; I2 = 0%) [11].
However, the extended duration prophylaxis group experienced significantly more major and clinically relevant nonmajor bleeding (OR, 2.10; 95% CI: 1.33–3.35; I2 = 8%) [11].
Conclusion
In conclusion, VTE is common in hospitalized cancer patients, but a lack of evidence exists about the efficacy of primary thromboprophylaxis.
No randomized primary thromboprophylaxis studies exist specifically conducted in hospitalized patients with cancer, and further studies are needed to assess the benefit of weight-adjusted anticoagulation.
References
1) Heit JA, Crusan DJ, Ashrani AA, Petterson TM, Bailey KR. Effect of a near-universal hospitalization-based prophylaxis regimen on annual number of venous thromboembolism events in the US. Blood. 2017;130(2):109-114.
2) Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(14):1476-1486.
3) Patell R, Zwicker JI. Inpatient prophylaxis in cancer patients: where is the evidence?. Thromb Res. 2020;191 Suppl 1:S85-S90.
4) Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927-974. Blood Adv. 2021;5(7):1953.
5) Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33(6):654-656.
6) 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.
7) Carrier M, Khorana AA, Moretto P, Le Gal G, Karp R, Zwicker JI. Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med. 2014;127(1):82-6.e1.
8) Zwicker JI, Roopkumar J, Puligandla M, et al. Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial. Blood Adv. 2020;4(10):2254-2260.
9) Patell R, Chiasakul T, Bauer E, Zwicker JI. Pharmacologic Thromboprophylaxis and Thrombosis in Hospitalized Patients with COVID-19: A Pooled Analysis. Thromb Haemost. 2021;121(1):76-85.
10) The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Ryan Zarychanski. Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. medRxiv 2021.03.10.21252749; doi: https://doi.org/10.1101/2021.03.10.21252749
11) Osataphan S, Patell R, Chiasakul T, Khorana AA, Zwicker JI. Extended thromboprophylaxis for medically ill patients with cancer: a systemic review and meta-analysis. Blood Adv. 2021;5(8):2055-2062.