Was the DOAC to blame for the patient’s LVAD pump thrombosis?

[ad_1]

A 56-year-old woman with morbid obesity and stage D congestive heart failure presented to the emergency room, telling clinicians that for the previous 2 months she had been suffering from increasing fatigue and dullness of his urine to the point that it was now cola in color. She came to the hospital one day after receiving several low flow alarms from her HeartWare Left Ventricular Assist Device (LVAD), which had been implanted 2 years previously.

The patient’s medical history included class III obesity – her weight was 144 kg (317 lb) and her BMI was 44 – non-insulin dependent diabetes mellitus, stage IIIb chronic kidney disease with a filtration rate estimated glomerular count (eGFR) of 44, and obstructive sleep apnea. She had undergone a total abdominal hysterectomy for stage 1B endometrial cancer (with no evidence of active disease).

Since implantation of the LVAD, she has been taking daily high-dose aspirin (325 mg) and warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. Initially, a daily dose of 15 mg of warfarin was sufficient to maintain INR at therapeutic levels.

Five months after starting warfarin treatment, the patient developed a urinary tract infection (UTI). The clinicians prescribed a course of nitrofurantoin, which raised her INR to a supra-therapeutic level of 8. Warfarin was temporarily discontinued but then resumed at 15 mg daily when the UTI resolved.

Although no other drug changes were made, his INR remained below therapeutic levels despite adherence to treatment.

Antithrombin III level was found to be low at 62 (range 80-120); protein C and S levels were not monitored. Clinicians gradually increased his warfarin to 25 mg daily over the next 2 months, but the INR level did not meet treatment goals. Based on suspected warfarin resistance, the patient was changed from anticoagulant therapy to apixaban (Eliquis) 5 mg twice daily.

Apart from a brief period of upper gastrointestinal bleeding due to erosive gastropathy leading to discontinuation of apixaban for 2 days, treatment was continued for more than a year without serious adverse effects.

However, when the patient presented to the ER for consultation after a day of low flow alarms from her LVAD, she mentioned her dark urine and worsening fatigue that had begun 2 months previously. She told clinicians on admission that she did not experience any chest pain, palpitations, new pedal edema or shortness of breath.

Laboratory test results were significant for elevated lactate dehydrogenase of 606 (range: 140-280) – an increase of more than 50% – and plasma-free hemoglobin of 30 (range 5-15), while serum creatinine remained at baseline.

The decision was made to stop apixaban and the clinicians put the patient on a bivalirudin infusion. The LVAD polling evaluation indicated a reduced average flow rate of 0.5 L/min and a power output of 2.3 watts at a speed of 2500 rpm.

Computed tomography (CT) imaging of the chest showed no evidence of pulmonary embolism, definitive outflow cannula thrombosis, or significant stenosis. Because the medical team suspected thrombosis, the clinicians ordered a transesophageal echocardiogram, which revealed a lack of Doppler flow through the LVAD, confirming their presumed diagnosis of pump thrombosis.

The LVAD pump was changed, which restored excellent flow rates, and the patient was placed on a heparin infusion. The genetic test for the warfarin resistance gene mutation (VKORC1) was negative.

The clinicians speculated that the patient’s previous lack of response to warfarin was due to her consumption of a vitamin K-rich diet and decided to re-challenge the patient with warfarin while doing the bridge with heparin.

Within 3 days of starting warfarin therapy, the patient’s INR had returned to therapeutic levels. She was informed about the risks of drug interactions, as well as the need for proper diet and dietary restrictions. At follow-up 1 month later, she underwent a repeat echocardiogram and device interrogation, which indicated that her LVAD was working as expected. His INR had stabilized at a therapeutic level.

A one-year follow-up showed no major complications.

Discussion

Clinicians presenting this case of a patient with continuous flow LVAD diagnosed with pump thrombosis one year after switching from warfarin to apixaban said they believe this to be the first report of LVAD pump thrombosis occurring in a patient receiving apixaban after failure of warfarin therapy. The “case is a reminder that apixaban may be associated with an increased risk of thrombosis in patients with LVAD, despite the few case series supporting its use in warfarin-resistant patients,” the authors wrote.

In patients with severe heart failure who are not eligible for heart transplantation, providing long-lasting mechanical circulatory support with devices such as LVADs may improve outcomes compared to medical therapy, the group explained. .

However, the associated risks of adverse events, such as ischemic stroke and device thrombosis, necessitate the continued use of anticoagulant therapy, optimally with vitamin K antagonists and specific INR targets. to the device for best results, the authors noted, citing the International Society’s 2013 guidelines. heart and lung transplantation.

Although direct oral anticoagulants (DOACs) are preferred for long-term use “in the appropriate patient with venous thromboembolism, nonvalvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosage , lack of need for routine monitoring, and limited food and drug interactions,” the authors noted that warfarin remains the first choice for the prevention of thrombosis in patients with LVAD.

Other research has identified various causes of pharmacokinetic resistance due to reduced absorption or increased elimination of the drug. Hypoalbuminemia may increase the free fraction of warfarin, thereby increasing clearance rates and shortening plasma half-life; while paradoxically, hyperalbuminemia may also contribute to warfarin resistance via drug binding, these researchers noted.

Hyperlipidemia, primarily elevated triglycerides, may also play a role in warfarin resistance. The researchers cited increased sensitivity observed when high lipid levels are reduced and clinical diagnoses of resistance in patients receiving intravenous lipids with total parenteral nutritional reductions. This impact is thought to be related to a decrease in the vitamin K pool, part of which is related to triglycerides.

Case authors noted that it may be difficult to maintain therapeutic INR in patients receiving vitamin K antagonists, “and failure to do so may predispose patients to bleeding and thromboembolic complications,” they noted. note. A meta-analysis of patients anticoagulated with continuous flow LVADs noted a “time in therapeutic range (TTR) of only 46.6%”. Such challenges have increased the appeal of DOACs as an alternative option, the group noted, “due to their ease of use and limited food interactions, despite the lack of strong safety data in LVAD patients. “.

The patient’s HeartWare Ventricular Assist Device Instructions for Use from the case report advises taking aspirin, usually 325 mg daily, plus warfarin with an INR target of 2.0 to 3, 0 for long-term treatment, the group noted, since DOACs are not advised for primary anticoagulation in patients with LVADs due to a lack of safety data.

The case authors suggested that vitamin K antagonists (VKAs) might be preferable in patients with LVAD because thrombosis occurs primarily due to direct blood contact with the device, which “in turn, leads to the activation of the contact pathway (factors VII, IX, X and II), which are all inhibited by AVKs.” In contrast, in the context of atrial fibrillation, thrombosis is linked to stasis and endothelial dysfunction of the left atrial appendage, they noted.

The group explained that patients requiring more than 80 mg of warfarin per week to maintain a therapeutic INR level are considered warfarin resistant, with up to 30% dosage variance linked to VKORC1-specific gene mutations. . The patient reported here had the wild-type variant, which led to further investigation of possible non-genetic causes, such as food and drug interactions, and ultimately, upon review of her history of endometrial cancer, was succeeded in his new challenge. with warfarin. “VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in cancer patients,” the authors wrote. But warfarin was the treatment of choice, given the low risk that their patient’s localized, completely resected cancer contributed to her thrombosis.

They recognized that factors specific to the patient – in particular her obesity (BMI of 44) – could have increased her thrombotic risk. The 2016 recommendation from the International Society of Hemostasis and Thrombosis is to avoid using “direct oral anticoagulants in patients with a BMI >40 or weight >120 kg due to the lack of strong clinical data at the support”. Although these guidelines have not been revised to date, the authors noted that some data have emerged since then showing the safety of apixaban in obese patients, without any dose adjustment, and other publications advising the use of drug-specific peaks and valleys.

conclusion

The case authors concluded that, given the lack of strong data to support this use of apixaban, clinicians should be cautious and selective when using apixaban in patients with LVAD, and ideally avoid its use. in patients with morbid obesity (BMI > 40) or renal insufficiency. (eGFR <30), and in those taking medications known to interact with DOACs.

Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

The authors of the case reports noted no conflict of interest.

[ad_2]