Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05669313 |
| Other study ID # |
Hypoth.Acidosis.Rivarox.ROTEM |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 4, 2022 |
| Est. completion date |
November 10, 2022 |
Study information
| Verified date |
February 2023 |
| Source |
Region Skane |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Rivaroxaban, a non-vitamin K oral anticoagulants, is increasingly used to prevent stroke in
patients with atrium fibrillation. It has previously been demonstrated that a point-of-care
coagulation instrument (ROTEM) can detect the effects of rivaroxaban. Further, the ROTEM
instrument can also detect the effects of hypothermia and acidosis. Given that trauma induced
coagulopathy is enhanced by both hypothermia, acidosis and rivaroxaban, the investigators
want to investigate any synergistic effects between hypothermia or acidosis and rivaroxaban.
In an attempt to do so the investigators designed the current experimental study with the
purpose to investigate the effects of rivaroxaban together with hypothermia or acidosis using
the ROTEM assay EXTEM. The hypothesis is that a synergistic prolongation of hypothermia or
acidosis and rivaroxaban can be detected in the initiation of clot formation demonstrated in
the primary outcome variable, clotting time of the ROTEM assay EXTEM. Secondary outcome
variables include direct effect on clotting time and direct and synergistic effects on clot
formation time and alfa angle of hypothermia and acidosis detected in the ROTEM assay EXTEM.
Description:
Non-vitamin K oral anticoagulants (NOACs) are widely used as prophylaxis against ischaemic
stroke in patients with atrial fibrillation and have replaced vitamin K antagonists (VKA) in
many case. Compared to the latter they have demonstrated reduced incidence of stroke,
all-cause mortality, and a reduced risk of bleeding, except for gastrointestinal bleeding.
According to guidelines from the European Society of Cardiology it is recommended that
patients with atrial fibrillation (AF) and adequate CHA¬2DS2-VASc score (2 for men and 3 for
women) preferentially are treated with NOAC rather than VKA, except in cases with significant
mitral stenosis or mechanical heart valves. Both the prevalence of patients with AF and of
patients treated with NOAC have increased in the last decade.
The NOACs available in clinical practice include one thrombin inhibitor (dabigatran) and
three factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) [3]. These drugs drive a
patient's blood further from clotting toward bleeding, and managing this tendency is
important for clinicians during haemorrhage or coagulopathy, which both occur e.g., in the
setting of trauma.
Trauma is a significant cause of mortality worldwide and among patients suffering from
traumatic injuries the leading cause of preventable death is uncontrolled bleeding.
Coagulopathy has been shown to contribute to bleeding in as many as one third of trauma
cases, predicting organ failure and mortality. This trauma induced coagulopathy (TIC) is
associated with hypothermia and acidosis. To prevent further coagulopathy current trauma
guidelines recommend that both body temperature and pH are kept within normal reference
range. Coagulopathy, hypothermia, and acidosis have collectively come to be known as the
'lethal triad'.
For trauma patients, hypothermia is associated with larger usage of blood products and
increased mortality/morbidity. How hypothermia affects haemostasis and blood loss has been
investigated in several studies. Hypothermia has been shown to worsen the function of
secondary haemostasis through temporary reduction of fibrinogen synthesis and inhibition of
the initiation phase of thrombin generation.
Hypothermia and acidosis often coexist and body temperatures of less than 35 degrees Celsius
have been shown to correlate with acidosis. The effects of hypothermia and acidosis on whole
blood coagulation in vitro, have previously been studied using Rotational thromboelastometry
(ROTEM). For hypothermia, a significant increase in coagulation time (CT) and clot formation
time (CFT) was observed, while acidosis alone did not produce these significant effects.
Interestingly however, combining acidosis with hypothermia worsened the effects of the
latter, providing increases in CT and CFT at higher temperatures, and a synergistic effect
between acidosis and hypothermia could be demonstrated.
The ROTEM assay EXTEM has previously been shown to be more sensitive to elevated
concentrations of NOAC in blood compared with other ROTEM assays, with a demonstrated linear
relationship between increasing concentrations of NOAC and prolonged clotting time (CT).
In summary, the EXTEM-assay can detect the effect of rivaroxaban as well as effects of
acidosis and hypothermia. However, to the best of the investigators knowledge the possibility
of any synergistic effects of acidosis or hypothermia together with NOACs on the EXTEM-assay
has never been explored. Given the increased prevalence of patients treated with NOAC and the
importance of acidosis and hypothermia in critical bleeding the investigators designed the
current experimental study with the purpose to investigate the effects of Rivaroxaban
together with hypothermia or acidosis using the ROTEM assay EXTEM. The hypothesis is that a
synergistic prolongation of hypothermia or acidosis and rivaroxaban can be detected in the
initiation of clot formation demonstrated in the primary outcome variable, CT of the ROTEM
assay EXTEM. Secondary outcome variables include direct effect on CT and direct and
synergistic effects on CFT and AA of hypothermia and acidosis detected in the ROTEM assay
EXTEM.
Methods Adult patients >18 years of age, reporting to the emergency department during office
hours at Skåne University Hospital Lund, Sweden that are planned for rivaroxaban treatment
will be included. Baseline blood samples will be taken prior to the first dose of rivaroxaban
(15 mg) and a second set of blood samples will be taken at a follow up visit the next day
after two doses of rivaroxaban had been taken, the later dose being taken by the patient the
morning of the follow up visit and thus ensuring sampling within one half-life of
rivaroxaban. On both occasions venous blood will be drawn in 2.7 ml tubes containing 0.109 M
citrate (BD Vacutainer Systems, Plymouth, UK) from an antecubital vein.
At the follow up visit all patients will be asked for compliance to the rivaroxaban
medication and were excluded if rivaroxaban had not been taken as prescribed. Upon the second
visit a blood sample for analysis of rivaroxaban concentration wil be taken (ref. range peak
value: 20 - 540 µg/L). All laboratory samples will be analysed at the accredited laboratories
at Skåne University Hospital Lund or Malmö.
Immediately after blood sampling, citrate blood will be transferred to 1.5 ml plastic test
tubes (Sarstedt, Micro tube 1.5 ml, Sarstedt AG & Co. KG, Nümbrecht, Germany) and divided in
one temperature group and one acidosis group, each consisting of four vials.
The temperature group vials will be incubated for 20 minutes at their target goal
temperatures of 28, 33, 37, and 40 degrees Celsius. The acidosis group will be incubated at
37 degrees Celsius and mixed with 15 µl of hydrochloric acid (HCl) at concentrations of 0.15
µM, 0.10 µM, 0.05 µM, or sterile water. Titration with the different concentrations of HCl
will be tested prior to the current study using blood from healthy volunteers, with the goal
of reaching the clinically relevant, pre-defined pH levels of 6.80, 7.00, and 7.20. After the
addition of hydrochloric acid and sterile water the pH in each tube was measured using a
pH-meter (Testo, Testo 230 pH/Temperature Meter, Testo SE & Co. KGaA, Lenzkirch, Germany).
All tests were performed within four hours of drawing blood.
After incubation at different temperatures and the addition of HCl/sterile water, all tests
will be analysed using one of two machines: the acidosis group using ROTEM using the EXTEM
assay. Clotting time (CT), Alpha angle (AA), and Clot formation time (CFT) will be
registered.
