International Journal of Cardiology 169 (2013) e77–e78

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International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Stroke and urosepsis after discontinuation of rivaroxaban☆
Claudia Stöllberger a,⁎,1, Josef Finsterer b,1
a
b

2nd Medical Dept., Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria
Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria

a r t i c l e

i n f o

Article history:
Received 1 July 2013
Received in revised form 27 July 2013
Accepted 3 August 2013
Available online 14 August 2013
Keywords:
Rivaroxaban
Atrial fibrillation
Stroke
Infection
Epilepsy

Rivaroxaban, a factor Xa inhibitor, is a new oral anticoagulant
(NOAC) which has been shown to be non-inferior to the vitamin-Kantagonist (VKA) warfarin for prevention of stroke or embolism in
patients with atrial fibrillation (AF) in the ROCKET-AF trial [1]. It is
unknown if this pretended advantage of rivaroxaban is also present
outside clinical trials. Furthermore, concerns are emerging about an
increase of thromboembolism when rivaroxaban is discontinued [1–3].
Additionally, there are indications that rivaroxaban might increase the
risk of infection [4–6]. We report a patient with stroke shortly after discontinuation of rivaroxaban with a complicated course.
An 80-year old Caucasian man contacted his general practitioner in
November 2012 because of increasing dyspnea and leg edema. He had
a history of arterial hypertension, hyperlipidemia and benign prostatic
hyperplasia necessitating transurethral resection of the prostate in
2008. AF was diagnosed for the first time in November 2012 and anticoagulant therapy with rivaroxaban 20 mg/d was initiated since it seemed
more convenient for the patient in the eyes of the treating physician
compared with VKA. The additional medication was furosemide,
enalapril, allopurinol, hydrochlorothiazide, bisoprolol, simvastatin
and amlodipine. In January 2013 he suffered from diarrhoea. Assuming
that the diarrhoea was a side effect of rivaroxaban, the patient stopped
the intake of rivaroxaban.

☆ No grant support.
⁎ Corresponding author at: Steingasse 31/18, A-1030 Wien, Austria. Tel.: +43 676 403
11 87.
URL: claudia.stoellberger@chello.at (C. Stöllberger).
1
This author takes responsibility for all aspects of the reliability and freedom from bias
of the data presented and their discussed interpretation.
0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd.
http://dx.doi.org/10.1016/j.ijcard.2013.08.025

Five days later he was hospitalized because of an acute stroke. Clinical
neurologic examination showed aphasia and a right-sided hemiparesis,
and computed tomography a corresponding large ischemic lesion in
the territory of the left cerebral medial artery. Duplex sonography
showed no stenoses of the extracranial arteries. Under physiotherapy
his symptoms improved, and after 4 weeks, rivaroxaban 20 mg/d was
re-started since computed tomography did not show hemorrhagic
transformation.
Because of his prostatic problems spontaneous micturition was
not possible and he needed an indwelling catheter. Eight days after
restarting rivaroxaban, a new catheter was inserted. After this procedure
he developed fever, leukocytosis and Pseudomonas aeruginosa grew in
the urine culture. Despite antibiotic therapy with ciprofloxacin he developed a right-sided epididymitis necessitating a scrotal semicastratio after
4 days. He was transferred to a rehabilitation clinic.
Two months later, during change of the urinary catheter, a generalized seizure occurred for the first time. He was rehospitalized and an
anticonvulsive therapy with carbamezepine 600 mg/d was started.
Additionally, he suffered from urosepsis with Proteus mirabilis growing in urine and blood cultures. During antibiotic therapy with
ceftazidime, signs of inflammation regressed. However, two weeks
after cessation of antibiotic therapy, Pseudomonas aeruginosa and
Enterococcus faecalis grew again in his urine culture. The neurological
abnormalities remained unchanged and he was seizure-free under
the antiepileptic treatment. Despite physiotherapeutic efforts his
condition did not improve and he was transferred to a nursery
home 5 months after stroke onset.
The story of the presented patient raises the question whether
rivaroxaban might have contributed to the disastrous course.
Rivaroxaban—in contrast to VKA—has a short half-life of 11–13 h,
why discontinuation of the drug may lead to complete loss of
antithrombotic efficacy within a short time [7]. An increased risk of
stroke and non-CNS embolism was also observed in rivaroxabantreated patients compared with warfarin-treated patients after the
end of the ROCKET-AF-trial [2]. An in-vitro study has shown a rebound effect of rivaroxaban [3]. Although we have no evidence by
laboratory testing of a rebound effect in our patient, this might
have played a role. Additionally, dehydration due to fluid loss from
the diarrhoea and intake of two different diuretic drugs might additionally have increased his thromboembolic risk.
Poststroke infections are frequent, and urinary tract infections are
the most common infections among acute stroke patients. Urinary
tract infections have been shown to be an independent predictor of
poor functional outcome and death at discharge [8]. Epididymitis necessitating semicastration, however, has so far not been reported in stroke

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C. Stöllberger, J. Finsterer / International Journal of Cardiology 169 (2013) e77–e78

patients. Of interest, the patient had an indwelling urinary catheter since
the admission whereas the urinary tract infection only started after
5 weeks.
It remains speculative if rivaroxaban might have contributed to
the development of the infection. It is known from orthopaedic series that rivaroxaban, given for prevention of venous thromboembolism, leads to an increase in wound infections [4–6]. Thrombin is not
only important for blood coagulation but also for defense against infections [9]. Theoretically, long-term delay in thrombin-generation
by rivaroxaban could impair the immune system and mitigate the response to infections. So far it is unknown if rivaroxaban also favours
infections in patients with atrial fibrillation. There are indications
that thrombin is also involved in the pathogenesis of seizures in
the brain, however the role of rivaroxaban in this situation has not
been investigated [10].
We conclude from the presented case that there is a need for
more research about a rebound effect of rivaroxaban. As long as
these uncertainties exist, patients should be educated not to discontinue rivaroxaban without consulting their physicians since the risk
of thromboembolism might be high due to the short half-life of the
drug. Tapering down the dosage of rivaroxaban might prevent a potential rebound effect. There is a need to investigate the role of
rivaroxaban and other thrombin generation inhibitors on the occurrence of infections as well as epileptic seizures in patients with atrial
fibrillation.

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