Safety and Efficacy of Therapeutic Anticoagulation with Subcutaneous Unfractionated Heparin in Patients with Renal Failure

Therapeutic anticoagulation poses a significant challenge in patients with renal failure, particularly those with more advanced disease requiring renal replacement therapy. Although there are several therapeutic options, it is still unclear which is the safest and most effective, as available evidence is heterogeneous.[1] [2] Patients with renal impairment are at increased risk of both bleeding and thrombosis; hence, anticoagulation is often associated with unfavorable patient outcomes. A recent review focusing on patients with renal failure and pulmonary embolism (PE) showed an overall mortality rate of 30% in individuals with an estimated glomerular filtration rate (eGFR) <30 mL/min, compared with 10% in those with normal eGFR.[3] In a comprehensive multicenter cohort study evaluating the validity of bleeding scores in PE patients, an eGFR below 60 mL/min emerged as a predictor of early major bleeding in multivariate analysis.[4] Of the included patients, over half were treated with low-molecular-weight heparin (LMWH), whereas the remaining group was divided equally between unfractionated heparin (UFH) and direct oral anticoagulation (DOAC). A minority of patients received thrombolysis or invasive clot retrieval. Another study, involving 2,784 cases, examined the prognostic significance of renal function in acute PE, revealing a higher prevalence of bleeding within 30 days in patients with impaired renal function (8%) compared with those without (5%). Of these bleeding events 1.1% were fatal bleeding in patients with eGFR <30 mL/min compared with 0.3% without renal impairment.[5]

Intravenous unfractionated heparin (IVUFH) is frequently deployed for immediate parenteral anticoagulation in subjects with advanced renal impairment, especially when acutely ill. UFH is a mixture of negatively charged glycosaminoglycans, which bind to antithrombin and increase exponentially its inhibition of factors IIa, Xa, IXa, XIa, and XIIa. UFH also interacts with heparin cofactor II, induces tissue factor pathway inhibitor release from endothelium and inhibits platelet function.[6] UFH clearance is predominantly via the reticuloendothelial system and the endothelium. However, there is also partial renal clearance, especially at doses >100 U/kg, as seen in animals and healthy volunteers.[7] [8] Renal patients can show significantly increased heparin half-life.[9] These dose-dependent pharmacokinetics, which also fluctuate due to plasma protein binding, make monitoring of UFH infusions essential in all patients, but perhaps more so in those with renal dysfunction.[10] [11]

UFH can be monitored via different laboratory tests such as activated partial thromboplastin time (or its ratio against normal; APTTR), anti-factor Xa (anti-Xa) level, or activated clotting time. In addition, the half-life of UFH (60–90 minutes) is relatively short when compared with LMWH. This makes IVUFH an attractive choice in patients with impaired renal function or when rapid adjustment of anticoagulation may be necessary. However, the intense monitoring required is frequently challenging outside high-dependency units, which can adversely lead to over or underanticoagulation.[12] [13]

A weight-adjusted fixed therapeutic dose regimen[14] of subcutaneous unfractionated heparin (SCUFH) has been proven effective compared with LMWH.[15] In a 2017 systematic review, no difference in venous thromboembolism (VTE) recurrence, major bleeding and overall mortality was found between patients receiving IVUFH versus SCUFH for the initial treatment of VTE. However, the absence of blinding in these studies is recognized as a limiting factor and overall quality of evidence remains low.[16]

The advantages of using SCUFH include the absence of monitoring requirements, twice-daily subcutaneous injections instead of continuous infusion, and the potential for administration in an ambulatory setting.

In this retrospective single-center cohort study, we report the outcomes of inpatients who have received SCUFH for therapeutic anticoagulation.

A retrospective pharmacy database search was conducted to identify patients who received therapeutic SCUFH between August 2020 and September 2021. The encounters were then further selected for a creatinine clearance (CrCL) <50 mL/min, to a total of 45 patients.

Clinical data collected included demographics, comorbidities, medications, indication for anticoagulation, duration of treatment, bleeding episodes, breakthrough thrombosis, anticoagulant prescribed at discharge, and survival outcomes up to December 2021. Laboratory parameters recorded included baseline platelet count, CrCL, and fibrinogen levels.

Major and nonmajor clinically significant bleeding were defined as per International Society on Thrombosis and Haemostasis recommendations.[17] [18]

Statistical analysis was descriptive. To identify clinical–laboratory features associated with higher bleeding risk, we used Mann–Whitney test.

The study was approved by the local institutional board as an audit of local practice following introduction of therapeutic SCUFH in the local trust VTE treatment guidelines.

A total of 45 patients received therapeutic SCUFH from August 1, 2020 to August 31, 2021 and 48.8% (22/45) were men. This cohort was overall made up of elderly patients with a median age of 76 years (range: 39.6–102). Just over 70% of these subjects had two or more comorbidities recorded in their past medical history. All patients had a degree of renal impairment, with a median CrCL of 15 mL/min (range: 4–48) and 13 were established on dialysis. Some patients had already been on antiplatelet medications (n = 15) and/or on anticoagulation (n = 20) at the time of admission to hospital.

The main indications for anticoagulation while inpatient were atrial fibrillation (AF) (38%) and treatment of suspected/confirmed acute VTE (40%).

The confirmed acute VTE events included PE (n = 4), deep vein thrombosis (n = 7), both (n = 2), renal vein thrombosis (n = 1), portal and mesenteric vein thrombosis (n = 1). One patient in this cohort had arterial thrombosis involving renal and mesenteric artery during admission. Two patients had empirical treatment for suspected PE, but UFH was stopped after a negative computed tomography pulmonary angiogram.

Four patients had SCUFH while having subtherapeutic international normalized ratio on warfarin in view of high-risk background (two with thrombophilia, one recent VTE, one metallic heart valve). The remaining six patients required therapeutic anticoagulation as part of perioperative bridging protocol.

At time of SCUFH initiation, median platelet count was 199 × 10⁹/L (range: 69–763), whereas median fibrinogen was 4 g/L (range: 2.15–9.64). The median time of exposure to SCUFH was 3 days (range: 1–65).

While on SCUFH, there was no breakthrough thrombosis. Two patients were able to receive treatment in an outpatient setting while on SCUFH, before later switching to vitamin K antagonist (VKA). All discharged patients that met the need for ongoing anticoagulation proceeded to receive either a VKA (n = 23) or a DOAC (n = 11).

Seven patients (15%) experienced clinically significant bleeding while on SCUFH. Notably, three had major bleeding which was the presumed cause of death in two cases. The remaining patients had nonmajor bleeding, including four large hematomas (one from a below-knee amputation stump, one postfistula surgery, one from femoral venous catheter, and one at heparin injection site). Clinical–laboratory characteristics are summarized in [Table 1].

Table 1 Clinical–laboratory characteristics and outcomes

Clinical–laboratory characteristics and outcomes
Patients N = 45	Median (range)	%
Age, y	75.85 (39.6–102.1)
Gender
Male	22	49
Female	23	51
Comorbidities
One or less	13	28.8
Two or more	32	71.2
Antiplatelet treatment	15	33.3
Dialysis	13	28.9
Indications for anticoagulation
VTE	18	40
AF	17	37.8
Perioperative management	6	13.3
Other	4	8.8
Days of exposure to SCUFH	3 (1–65)
Creatinine clearance, mL/min	15 (4–48)
Fibrinogen, g/L	4 (2.15–9.64)
Platelets, N  × 109/L	199 (69–763)
Bleeding while on SCUFH	7	15.5
Major	3	6.7
Nonmajor	4	8.9
Thrombosis while on SCUFH	0	0
Discharged on oral anticoagulation	34	75.5
VKA	23	67.6
DOAC	11	32.4
Deceased	18	40

Abbreviations: AF, atrial fibrillation; DOAC, direct oral anticoagulation; SCUFH, subcutaneous unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

The three major bleeding events involved the gastrointestinal (GI) tract. In the two oldest patients (80 and 84 years of age, respectively), GI bleeding was the presumed primary cause of death. All three had multiple comorbidities. Two patients started anticoagulation for PE, whereas one had inferior vena cava thrombosis involving common femoral and renal vein. Although they were initially commenced on IVUFH, the clinical team changed to SCUFH due to either difficulty in monitoring (cases 2 and 3) or struggling to achieve therapeutic anti-Xa levels (case 1), after consulting the hematology team. The three cases are summarized in [Table 2].

Table 2 Summary of three cases of major gastrointestinal bleeding

Summary of three major gastrointestinal bleeding cases
	Case 1	Case 2	Case 3
Age, y	80	65	84
Gender	Male	Male	Female
Comorbidities	Chronic kidney disease on dialysis, type 2 diabetes, nephrectomy	Cholangiocarcinoma/bladder cancer on chemotherapy, chronic kidney disease not on dialysis, hypertension	Endometrial cancer, type 2 diabetes, hypertension
Reason for admission	Clostridium difficile-positive severe colitis, pneumonia, acute kidney injury	Chest pain, then confirmed pulmonary embolism	Pneumonia, acute, kidney injury, and cancer recurrence
Type of thrombosis	Distal inferior vena cava, common femoral vein, and renal vein thrombosis	Pulmonary embolism	Pulmonary embolism
Baseline blood results prior SCUFH	CrCL 32 mL/min Platelets 265 × 109/L Fibrinogen/PT/APTT not performed	CrCL 27 mL/min Platelets 226 × 109/L Fibrinogen 7.21 g/L APTT 47.3 s PT 29.7 s	CrCL 11 mL/min Platelets 496 × 109/L Fibrinogen 4.73 g/L APTT 35.9 s PT 15.5 s
Reason for choosing SCUFH	Difficulty in achieving therapeutic anti-Xa levels	Challenge of monitoring	Challenge of monitoring
Type of bleeding	Suspected lower gastrointestinal due to colitis, rapid hemoglobin drop and deterioration—not stable enough for further investigations	Lower gastrointestinal (per-rectum bleeding)	Upper gastrointestinal (hematemesis)

Abbreviations: APTT, activated partial thromboplastin time; CrCL, creatinine clearance; PT, prothrombin time; SCUFH, subcutaneous unfractionated heparin.

^a APTT normal range: 25–35 seconds; PT normal range: 12.8–17.4 seconds; fibrinogen normal range: 1.9–4.3 g/L.

We investigated whether there were any significant differences between bleeding and nonbleeding subjects. We found no difference in age, sex, dialysis status, number of comorbidities, CrCL, platelet count, fibrinogen levels, concomitant antiplatelet treatment, and days of exposure to SCUFH between these two groups.

Most recent trials report a major bleeding risk of <3% in patients treated with UFH for acute VTE.[19] [20] The 15% risk of bleeding is relatively high in our cohort, but comparable to similarly ill patients receiving monitored UFH infusions, as reported in a 358-patient cohort receiving therapeutic UFH during the coronavirus disease 2019 (COVID-19) surge, where major bleeding rate in COVID19-positive patients was 10.3% compared with 3.1% for COVID19-negative patients.[21]

Although the local trust guidelines indicated therapeutic SCUFH for acute inpatient VTE treatment only, several patients received it for interim stroke prevention in AF while being bridged to an oral anticoagulant or for perioperative cover. In all cases, clinicians individualized the anticoagulation plan in consultation with the hematology team.

Choice of anticoagulant in patients with renal failure remains challenging. Several studies have explored the use of DOAC in these patients.[22] [23] [24] [25] A large study of 604 patients with chronic kidney disease stage 4 (eGFR < 30 mL/min) and 5 (eGFR < 15 mL/min), including 194 on hemodialysis, treated with apixaban for VTE, showed no increase in bleeding rates at 3 months compared with warfarin and highlighted a higher bleeding incidence for patients remaining on warfarin at 6 and 12 months.[24] However, the use of DOACs in clinical practice is still controversial and warrants more studies, especially focusing on patients with end-stage renal failure, often excluded from trials.[1] [2] In the United Kingdom, DOACs are contraindicated when CrCL is <15 mL/min.[26] When considering anticoagulation reversal, andexanet alfa, the only available reversal agent for anti-Xa DOACs,[27] is exclusively licensed for apixaban and rivaroxaban in cases of refractory upper GI bleeding (England), whereas in Scotland it is approved for all uncontrolled life-threatening bleeding. VKAs are considered a safe and efficacious option,[2] but where immediate anticoagulation is needed, interim parenteral anticoagulation is required. Dose-adjusted LMWH can be used with caution; nonetheless, monitoring with anti-Xa levels is recommended[28] and is not suitable when rapid adjustment or reversal may be needed.

This study highlights many of the challenges that clinicians face when managing complex patients with renal impairment. A common theme was difficult venous access impeding anti-Xa monitoring while on IVUFH, prompting consideration of the weight-adjusted subcutaneous anticoagulation approach. It is important to also mention that this study coincided with the COVID-19 pandemic and there was a local and national effort to treat patients in an ambulatory setting where possible, which was the case for two patients successfully treated as outpatient with SCUFH, while being bridged to oral anticoagulation.

The main limitations of this study are absence of a matched control group of patients with renal dysfunction treated with IVUFH, small sample size, and its retrospective nature. Despite analyzing a large number of patients treated with IVUFH during the same period, these were not comparable to our SCUFH cohort due different clinical backgrounds, degree of renal impairment, indication for anticoagulation, and length of exposure to IVUFH. Second, several patients in this group received SCUFH for stroke prevention in the presence of AF, as bridge to anticoagulation or perioperatively, which was outside local guidelines.

In conclusion, the experience at our center illustrates the effectiveness of SCUFH as an anticoagulant strategy for the acute treatment of VTE. Additionally, SCUFH was utilized for stroke prevention in patients with AF, demonstrating a lack of breakthrough events. However, it is important to note that a significant proportion of patients experienced clinically relevant bleeding complications, including three cases of major GI bleeding. Further large-scale studies are necessary to optimize anticoagulant strategies in patients with renal failure, particularly those with end-stage disease. Managing these patients is complicated due to their often highly comorbid background, which poses simultaneous thrombotic and bleeding risks.

Author Contributions

G.S. conceived the study, performed data collection/analysis/interpretation, prepared the first draft, and edited the manuscript. M.L. and D.J.A. conceived the study, interpreted the data, reviewed, and edited the manuscript. F.A. identified the patient population for the study from pharmacy database and reviewed the manuscript. R.S. analyzed the data and reviewed the manuscript. All authors reviewed and approved the final version of the manuscript.

Publication History

Article published online:
23 August 2023

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