Was DOAC to Blame for Patient’s LVAD Pump Thrombosis?

A 56-year-old woman with morbid obesity and stage D congestive heart failure presented to an emergency department, telling clinicians that for the previous 2 months she had increasing fatigue and darkening of her urine to the point where it was now cola-colored. She came to the hospital a day after receiving several low-flow alarms from her HeartWare left ventricular assist device (LVAD), which was implanted 2 years prior.

The patient’s medical history included class III obesity — her weight was 144 kg (317 lb), and BMI was 44 — non-insulin-dependent diabetes mellitus, stage IIIb chronic kidney disease with estimated glomerular filtration rate (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 the LVAD was implanted, she had 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 keep the INR at therapeutic levels.

Five months after beginning treatment with warfarin, the patient developed a urinary tract infection (UTI). Clinicians prescribed a course of nitrofurantoin, which caused her INR to increase to a supra-therapeutic level of 8. Warfarin was temporarily discontinued but subsequently resumed at 15 mg daily when the UTI resolved.

Although no other changes in medication were made, her 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 checked. Clinicians gradually increased her warfarin to up to 25 mg per day over the next 2 months, but the INR level failed to reach therapeutic goals. Based on suspected warfarin resistance, the patient’s anticoagulation therapy was switched to apixaban (Eliquis) 5 mg twice daily.

Aside from a brief period of upper gastrointestinal bleeding due to erosive gastropathy prompting apixaban to be halted for 2 days, treatment was continued for more than a year without any serious adverse effects.

However, when the patient presented to the emergency department for consultation after a day of low-flow alarms from her LVAD, she mentioned her darkened urine and worsening fatigue that had begun 2 months previously. She told clinicians at intake that she had not experienced any chest pain, palpitations, new pedal edema, or shortness of breath.

Lab test results were significant for elevated lactate dehydrogenase of 606 (range: 140–280) – a rise 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 clinicians started the patient on a bivalirudin drip. Assessment of the LVAD interrogation indicated reduced average flow of 0.5 L/min, and power of 2.3 watts at a speed of 2,500 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, 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 exchanged, which restored excellent flow rates, and the patient was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative.

Clinicians theorized that the patient’s previous lack of response to warfarin was due to her consuming a diet rich in vitamin K, and decided to re-challenge the patient with warfarin while bridging with heparin.

Within 3 days of beginning warfarin treatment, the patient’s INR had returned to therapeutic levels. She was advised about the risks of medication interactions, along with the need for appropriate diet and dietary restrictions. At follow-up 1 month later, she underwent a repeat echocardiogram and device interrogation, which indicated that her LVAD was functioning as expected. Her INR had stabilized at a therapeutic level.

One-year follow-up showed no major complications.

Discussion

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

In patients with severe heart failure who are not eligible for a heart transplant, provision of durable mechanical circulatory support with devices such as LVADs can improve outcomes compared with medical therapy, the group explained.

However, the associated risks of adverse events, such as ischemic stroke and device thrombosis, necessitate ongoing use of anticoagulation treatment, optimally with vitamin K antagonists and device-specific INR targets for best outcomes, authors noted, citing the 2013 guidelines of the International Society of Heart and Lung Transplantation.

While direct oral anticoagulants (DOAC) are preferred for long-term use “in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions,” the authors noted that warfarin remains the first choice for thrombosis prevention in patients with LVADs.

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, thus increasing rates of clearance and shortening plasma half-life; while paradoxically, hyperalbuminemia may also contribute to warfarin resistance via drug binding, those researchers noted.

Hyperlipidemia, primarily high triglycerides, may have a role in warfarin resistance as well. The researchers cited increased sensitivity observed when elevated lipid levels are reduced and clinical diagnoses of resistance in patients receiving intravenous lipids with total parenteral nutrition reductions. This impact is thought to be related to a decreased pool of vitamin K, some of which is bound to triglycerides.

Case authors noted that it can be difficult to maintain therapeutic INR in patients receiving vitamin K antagonists, “and failure to do so can predispose patients to bleeding and thromboembolic complications,” they noted. 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, “because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients.”

The case report patient’s HeartWare ventricular assist device instructions for use advise taking aspirin, generally at 325 mg daily, plus warfarin with an INR goal of 2.0 to 3.0 for long-term treatment, the group noted, given that DOACs are not advised for primary anticoagulation in patients with LVADs due to a lack of safety data.

Case authors suggested that vitamin K antagonists (VKA) may be preferable in LVAD patients because thrombosis occurs mainly due to direct blood contact with the device, which “in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA.” In contrast, in the setting of atrial fibrillation, thrombosis is related to stasis and endothelial dysfunction in 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% of dosing variance related to genetic mutations specific to VKORC1. The patient reported here had the wild-type variant, which led to a more extensive review of possible non-genetic causes, such as dietary and medication interactions, and ultimately, after consideration of her history of endometrial cancer, resulted in her being successfully rechallenged with warfarin. “VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer,” authors wrote. But warfarin was the preferred treatment, given the low risk that their patient’s localized and completely resected cancer had contributed to her thrombosis.

They acknowledged that patient-specific factors – in particular, her obesity (BMI of 44) – might have increased her thrombotic risk. The 2016 recommendation of International Society of Hemostasis and Thrombosis is to avoid using “direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data.” While these guidelines have not been revised to date, authors noted that some data have emerged since then showing safety of apixaban in obese patients, without any dose adjustments, and other literature advising use of drug-specific peak and trough levels.

Conclusions

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 LVADs, and ideally avoid its use in patients with morbid obesity (BMI >40) or poor renal function (eGFR <30), and in those taking drugs known to interact with DOACs.