Efficacy and safety analysis of using a lower platelet threshold for warfarin initiation in patients with heparin-induced thrombocytopenia

Corresponding Author:

Anastasiya Plagova
Department of Pharmacy, WellStar Kennestone Hospital
677 Church Street, Marietta, GA 30060
E-mail: Anastasiya.plagova@gmail.com

Abstract

Objectives: To determine efficacy and safety of warfarin initiation in patients with confirmed heparin-induced thrombocytopenia (HIT) at a lower platelet threshold (less than 150x109/L) versus 150x109/L platelet threshold. Methods: This is a multi-center, retrospective, cohort study. Patients were divided into two groups based on platelet threshold at warfarin initiation in order to evaluate efficacy and safety of using a lower platelet threshold for transitioning patients from parenteral anticoagulation to warfarin. The primary outcome was the incidence of a new symptomatic thrombosis following warfarin initiation. Safety outcomes included major bleeding and incidence of thrombosis. Results: None of the patients in either group had a VTE within 30 days of warfarin. Hospital length of stay was shorter in the lower platelet threshold group at 21 days compared to 25 days in the latter group (P-value: 0.413). Transitioning to warfarin sooner was associated with an increase in major bleeding: 4 patients (33%) compared to 1 patient (6%), (P-value=0.133), respectively. Conclusion: The data suggests that initiating warfarin at a lower platelet threshold does not affect rate of thrombosis or mortality, but may be associated with an increased risk in major bleeding. Patients with HIT should be transitioned to warfarin when the platelet count is at least 150 x109/L

Keywords

Heparin-induced thrombocytopenia, warfarin, parenteral anticoagulation to warfarin, heparininduced thrombocytopenia treatment, lower platelet threshold

Introduction

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse effect of heparin exposure, which may lead to lifethreatening complications. Thromboembolic complications develop in approximately 50% of patients with confirmed HIT. High frequencies of HIT are especially common in surgical patients receiving prolonged perioperative anticoagulation [1].

HIT diagnosis is an integration of clinical features and laboratory testing. In clinical practice, a presumptive diagnosis of HIT is often made purely on clinical findings and platelet counts until the confirmatory laboratory tests are available. Clinical features may include a platelet count of less than 150×10⁹/L or a 50% decline from baseline, time of onset within five to ten days of heparin exposure, and presence of a venous or arterial thrombosis. When HIT is suspected, a 4T score is helpful in quantifying the clinical findings. The 4T score evaluates for thrombocytopenia, timing of platelet count fall, thrombosis, and other causes of thrombocytopenia.

In addition to clinical findings, laboratory tests include an initial enzyme-linked immunosorbent assay (ELISA) and the confirmatory serotonin release assay (SRA). ELISA is not a definitive diagnosis of HIT, but is usually obtained first as it is readily available. The SRA has a much greater diagnostic specificity than ELISA and is the gold standard per the 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. However, the SRA is more costly and rarely available on site [2].

When HIT diagnosis is presumed, it is important to discontinue all sources of heparin. HIT antibodies activate platelets and can cause catastrophic arterial and venous thrombosis [3]. Alternative parenteral anticoagulants, such as argatroban or fondaparinux, should be initiated for anticoagulation in order to provide therapeutic-dose anticoagulation until the thrombosis risk has returned to baseline. Therapy should be tailored to patient-specific factors, such as renal and hepatic function, urgency for therapeutic anticoagulation, as well as potential need for rapid anticoagulation reversal. Warfarin is used for anticoagulation once stable anticoagulation with another non-heparin agent has been established and an adequate platelet count has been reached. The CHEST Guidelines recommend initiating warfarin after the platelet count has recovered to at least 150 x10⁹/L to reduce the risk of venous limb gangrene and limb loss. Warfarin therapy is warranted because HIT antibodies can persist for as long as three months. The CHEST Guidelines recommend warfarin therapy for at least four weeks or up to three months if a thrombotic event has occurred.

Anecdotal evidence suggests that some patients may not achieve this platelet level or may have a slower platelet recovery. There is minimal guidance with this patient population. Currently at the study institution, determination of platelet recovery varies amongst providers and initiation of warfarin therapy is per physician discretion. One recent study demonstrated safety and efficacy with transitioning from parenteral anticoagulation to warfarin after two or more rising platelet counts in HIT patients [4]. The researchers suggest this method may lead to a decreased length of hospital stay as well as cost savings while ensuring safe patient care. Further research is needed to evaluate outcomes when initiating warfarin at a lower platelet threshold. The purpose of this study was to determine efficacy and safety of warfarin initiation in patients with confirmed HIT at a lower platelet threshold (less than 150 x10⁹/L) versus the recommended platelet threshold (150 x10⁹/L).

Methods

This safety and efficacy analysis was a multi-center, retrospective, cohort study. Chart review was performed from January 1, 2014 to August 31, 2017 at four hospitals within the health system. The data source was the health system’s electronic medical chart and data warehouse.

Patients were included if they were 18 years of age with a suspected or confirmed diagnosis of HIT. The criteria for diagnosis of HIT was comprised of a calculated 4T score of four or higher as well as positive ELISA and SRA results. Patients were excluded if they were pregnant, hospice patients, anyone with a contraindication to warfarin, or prescribed warfarin for another indication at the time of HIT diagnosis. Once the inclusion and exclusion criteria were met, patients were divided into two groups based on the platelet count at warfarin initiation of less than 150 x10⁹/L (Group A) and 150 x10⁹/L (Group B).

The primary endpoint was incidence of a new symptomatic thrombosis following warfarin initiation. Secondary endpoints were hospital length of stay, estimate of potential cost savings when transitioned to warfarin at a lower platelet threshold, as well as in-hospital mortality. Safety endpoints included major bleeding and incidence of thrombosis within 30 days following warfarin initiation. Major bleeding was defined as hemoglobin drop of at least 2 g/dL, requirement of two units of packed red blood cells, bleeding in body cavity, or a bleed that necessitated anticoagulation withdrawal, which is consistent with the CHEST Guidelines. Incidence of thrombosis included skin necrosis at subcutaneous heparin injection site, venous limb gangrene, and all-cause limb amputation. For statistical analysis, a two-tailed t-test was performed to determine statistical significance in hospital length of stay. Additionally, Fisher’s Exact Test was used to evaluate statistical significance in all-cause mortality and hospital readmissions within 30 days of warfarin initiation.

Results

A total of 42 patients were identified and 14 patients were excluded. Patients were excluded primrily for never initiating warfarin therapy, taking warfarin for another indication at the time of HIT diagnosis, or being transitioned to novel oral anticoagulant agents (NOACs). A total of 28 patients were included in the analysis. Group A consisted of 12 patients, whereas Group B had 16 patients. Baseline demographics were similar in both groups and are provided in TABLE 1. There were more females in Group A, eight patients (67%), as compared to six patients (38%) in Group B. Additionally, Group A consisted of 11 medical patients (92%), while Group B had nine medical patients (56%). The mean calculated 4Ts score was five in both groups. Group A had three patients (25%) with a new VTE within 14 days of heparin exposure compared to five patients (31%) in Group B. The mean platelet count at nadir and HIT anticoagulation treatment initiation was similar in both groups (61 x10⁹/L and 60x10⁹/L, respectively). As expected, mean platelet count at warfarin initiation was lower in Group A at 120 x10⁹/L compared to 172 x10⁹/L in Group B. Similarly, platelet count at discharge was 185 x10⁹/L in Group A and 294 x10⁹/L in Group B.

Table 1: Patient demographics.

The majority of the patients in both groups were treated with argatroban prior to warfarin initiation. As described in TABLE 2, the mean total dose of argatroban received was 186 mg in Group A compared to 224 mg in Group B. Two patients received fondaparinux in Group A, whereas four patients received fondaparinux in Group B. The mean total dose of fondaparinux was 18 mg and 21 mg, respectively. None of the patients were treated with bivalirudin.

Table 2: HIT treatment.

TABLE 3 highlights the primary outcomes. No patient developed a new venous thromboembolism (VTE) within 30 days of warfarin initiation in either group. As expected, the hospital length of stay was shorter in Group A at 21 days compared to 25 days in Group B. Because this study only consisted of 28 patients, it was heavily underpowered and this difference did not reach statistical significance (P-value=0.413). Additionally, the estimated cost of alternative HIT treatment anticoagulant prior to transitioning to warfarin was lower in Group A at $1,035 compared to $1,234 in Group B. No patient died secondary to anticoagulation related adverse events in the study. However, all-cause mortality occurred in one patient (8%) in Group A compared to two patients (13%) in group B (P-value=1). Diagnoses included respiratory failure and metastatic cancers. Hospital readmissions within 30 days of warfarin initiation occurred in one patient in each group (8% compared to 6%, P-value=1).

Table 3: Primary and secondary endpoints.

Safety endpoints are described in TABLE 4. Four patients (33%) experienced major bleeding in Group A compared to one patient (6%) in Group B (P-value= 0.133). The major bleeds consisted of upper and lower gastrointestinal bleeds as well as internal bleeds that required at least two units of packed red blood cells. Three of the major bleeds in Group A were severe enough to require long-term anticoagulation withdrawal. Patients did not develop skin necrosis, venous limb gangrene, or undergo limb amputation in either group.

Table 4: Safety endpoints.

Discussion

Although the sample size was small, occurrence of VTE within 30 days of warfarin initiation was similar in both groups. As expected, hospital length of stay was shorter and anticoagulant treatment was less costly for patients who were transitioned to warfarin at a lower platelet threshold. Additionally, transitioning to warfarin sooner did not have an effect on mortality secondary to anticoagulation, but was associated with an increase in major bleeding. Major bleeding in the study included patients with bleeding for which anticoagulation was stopped and a requirement of at least two units of packed red blood cells. There was no observed difference in hospital readmission rates between the two groups. Additionally, there were at least two incidents of patients with diagnosed HIT being transitioned to NOACs. NOACs have not been approved for an indication of HIT treatment and there is currently limited literature to support this off-label use.

All of the included patients in the study had a positive SRA result. This was beneficial because the SRA is considered to be the gold standard among diagnostic tests for HIT due to its high sensitivity and specificity. Thus, a positive SRA result limited over-diagnosis of HIT, which is common in studies evaluating patients with a diagnosis of HIT. There were few baseline imbalances. Because the groups had similar characteristics at baseline, the differences between the groups could therefore be attributed to initiating warfarin at a lower threshold and not due to random chance.

There were multiple limitations in this study. Foremost, this was a retrospective study with a small sample size of 28 patients. The final number of patients identified for analysis with sufficient retrievable data limited the power necessary to achieve statistical significance. In addition, repeat HIT testing was not done in patients with a platelet count of less than 150×10⁹/L to differentiate between thrombocytopenia due to HIT and other reasons. Lastly, there is a lack of prior research studies on the topic. More studies with larger sample sizes are needed in order to assess the safety and efficacy of using a lower platelet threshold count when initiating warfarin in patients with HIT.

The data suggests that initiating warfarin at a lower platelet threshold does not affect the rate of thrombosis or mortality, but may shorten overall hospital length of stay and associated costs. However, transitioning patients to warfarin at a lower platelet threshold may be associated with an increased risk in major bleeding. This study highlights the importance of initiating warfarin when the platelet count is at least 150×10⁹/L, as recommended by the CHEST Guidelines. Pharmacists play a vital role in this step by monitoring platelets daily. Patients who are transitioned to warfarin at a platelet count of less than 150 x109/L should be monitored closely for signs of bleeding, new VTEs, skin necrosis, and venous limb gangrene when transitioning from alternative HIT anticoagulation to warfarin.

Acknowledgments

I sincerely thank Deepa Patel, Pharm.D., BCPS, BCCCP and Joy Peterson, Pharm.D., BCPS for their guidance and encouragement in carrying out this project work.

Disclosures

Anastasiya Plagova, Pharm.D., Deepa Patel, Pharm.D., BCPS, BCCCP, and Joy Peterson, Pharm.D., BCPS have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this research paper.

References

1. https://www.nejm.org/doi/10.1056/NEJMcp1411910
2. Warkentin T, Greniacher A, Koster A, et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 8th Edition., 340-380 (2012)..
3. Warkentin TE, Greinacher A. Management of Heparin-Induced Thrombocytopenia. Curr. Opin. Hematol.23(5), 462-470 (2016).
4. Chen L, Roberts J, Dager W. Safety and Efficacy of Starting Warfarin After Two Consecutive Platelet Count Rises in Heparin-Induced Thrombocytopenia. Thromb. Res. 144, 229-233 (2016).