Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06152562 |
| Other study ID # |
EK Nr: 2460/2020 |
| Secondary ID |
2021-004921-62 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 6, 2021 |
| Est. completion date |
November 28, 2023 |
Study information
| Verified date |
November 2023 |
| Source |
Medical University of Vienna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The aim of this study is to evaluate the incidence of any hemocompatibility related adverse
event (HRAE) after LVAD placement in patients responsive to a standard aspirin dose using
point-of-care platelet inhibition monitoring compared with initial non-responders who were
then up-titrated to achieve a therapeutic response using individualized acetylsalicylic acid
(ASA) therapy. Second, to investigate whether patients exhibit temporal changes in ASA
sensitivity during LVAD support.
Description:
Left Ventricular Assist Device (LVAD) therapy has become a well-established treatment option
for end stage heart-failure either as a bridge to transplant or destination therapy. As
previously reported, mechanical circulatory support (MCS) has continued to improve patient
survival and quality of life due to improvements in device design as well as implantation
technique.
However, HRAEs such as stroke, bleeding, and thrombosis, which are consequences of adverse
interactions between the pump and circulating blood elements, are associated with the use of
LVADs. Despite excellent clinical outcomes of continuous flow LVADs with one-year survival of
83%, the balance of pump thrombosis (PT) and bleeding continues to present a major treatment
challenge. Recent reports indicate, that only 80% of the patients supported with the
HeartMate 3 (Abbott Inc.) LVAD had a one-year freedom from gastrointestinal bleeding, and
freedom from any neurological adverse event. PT is described in up to 8 % of the HeartWare
HVAD (Medtronic Inc.) patients and in 1.4% of HeartMate 3 patients.
Therefore, during long-term treatment, oral anticoagulation with vitamin K antagonists (VKA),
such as warfarin or phenprocoumon, is essential to reduce HRAEs in LVAD patients. Most recent
guidelines of the International Society for Heart and Lung Transplantation (ISHLT) recommend
for centrifugal rotary blood pumps (such as the HeartMate 3 and HVAD) to start oral
anticoagulation and antiplatelet therapy on post-operative day (POD) 2 or 3, after removal of
the chest tubes and an intended target INR of 2.0-3.0. Furthermore, the ISHLT guidelines
recommend 81 - 325 mg daily antiplatelet therapy with ASA in addition to warfarin to decrease
thrombotic risk. Specifically for HeartMate 3 patients, the manufacturer recommends 81 -
100mg ASA daily therapy which should start 2 or 3 days after implantation. The manufacturer
recommended long term oral anticoagulation regimen for the HVAD pump is a combination of
warfarin and ASA. In general, ASA should be started at a doses >81mg per day (e.g.
moderate-dose ASA of 162mg or high-dose of 325mg per day) within 24 hours after implant if
there are no postoperative bleeding complications.
The relevance of these ASA daily dose recommendations for LVAD patients are supported by the
results of several recent clinical studies: Najjar et al. identified an ASA daily dose ≤ 81
mg as independent risk factor for HVAD PT; in addition, Teuteberg et al. also identified
daily ASA doses ≤ 81 mg as significant risk factor for ischemic and hemorrhagic
cerebrovascular accidents. Uriel et al. analyzed HRAEs at 6 months in the Momentum 3 trial
(comparing HeartMate II and 3) with antithrombotic management including anticoagulation with
warfarin and ASA therapy (81-325 mg daily). Absence of ASA at 30 days was independently
associated with development of HRAE or death at 6 months after implantation. Based on these
recommendations and recent publications, current best practice at the Medical University of
Vienna includes oral anticoagulation with phenprocoumon (INR target of 2.0-2.5) and without
contraindication, on POD 3, the antiplatelet therapy with ASA is initiated. ASA daily
standard doses vary device-specific from 100 mg (HeartMate 3) to 200 mg (HVAD).
In addition, the optimal antithrombotic regimen remains uncertain, and the frequency of
antiplatelet therapy monitoring differs among clinicians.
Several factors contributing to platelet dysfunction may be related to the propensity for
bleeding and thrombosis in patients with LVADs. Shear stress may play a role in platelet
dysfunction and increase the potential for PT. Acquired von Willebrand factor syndrome may
contribute to the bleeding probability in LVAD patients. Other factors that may increase the
may increase the risk of LVAD PT include inadequate antithrombotic or anticoagulant therapy,
coagulopathy, or platelet disorders. Aspirin resistance is defined as the inability of
aspirin to platelet thromboxane A2 production and thus platelet thromboxane A2 and thus
reduce platelet activation and aggregation. Thromboxane A2 is synthesized from achidonic acid
in several steps. Cyclooxygenase is a key enzyme for this metabolism. ASA inhibits this
enzyme, so the platelets are not able to produce Thromboxane A2 anymore. As the platelets
have no cell nucleus, they are incapable to resynthesize the Cyclooxygenase so the inhibition
lasts their whole life span (approximately seven days).
Numerous studies have shown that aspirin resistance in patients with cardiovascular disease
is associated with poor outcomes. Patients with inadequate response to their antiplatelet
medications may have a significantly higher risk of myocardial infarction, stent thrombosis,
and death. Patients with an excessive response to their antiplatelet agents are at increased
risk for bleeding. Recent literature suggests that 30 to 40% of patients on antiplatelet
medications may not receive the expected platelet inhibiting effect. Numerous factors may
cause inadequate response including: drug interactions (e.g. proton pump inhibitors), genetic
differences, pre-existing health conditions (e.g. diabetes) and non-compliance.
Although e.g. the HVAD manufacturer recommends, if ASA alone is the medication chosen for
antiplatelet therapy, a check for ASA resistance with a reliable test (e.g., VerifyNow) is
recommended to establish the dose or to select an alternative medication, literature
comparing outcomes of LVAD patients with standard aspirin therapy (SAT) and dose-adjusted
individualized treatment based on platelet inhibition is lacking. Additionally, little is
known about etiology, risk factors and outcomes of initial non-responders to ASA therapy
after LVAD implantation. To date, there is no standard platelet function test for use in LVAD
patients. Karimi et al. adjusted antiplatelet treatment in HeartMate II patients based on
thromboelastography, with an aim to achieve normal maximum amplitude. Although light
transmission aggregometry (LTA) is considered by many as gold standard for assessing platelet
function, ASA responsiveness can be determined by a turbidimetric based optical based assay
test (VerifyNow, Accriva Diagnostics).
The main advantage of VerifyNow is its availability as point-of-care testing at any time of
the day. No processing of the blood or specialist laboratorian assistant is needed. Several
studies covering different topics have shown the benefit of point-of-care testing with the
VerifyNow system. Platelet function testing leading to a customized treatment could reduce
thrombotic complications in pediatric patients after heart surgery as well as in
LVAD-patients or to identify ASA usage before an emergency surgery.
With the VerifyNow ASA responsiveness test, the unprocessed whole blood is automatically
transferred in four chambers containing platelet agonists (for example ADP or arachidonic
acid) and fibrinogen-coated beads to trigger the activation of the platelets. As the
platelets aggregate, the light transmitting through the chambers will increase because the
blood sample gets clearer. The device measures the changes in optical signals over a period
of a few minutes. The blood of an adequate platelet-inhibited patient forms fewer aggregates
allowing less light to pass through in comparison to a blood sample of an inadequate or
non-inhibited patient. Results can be expressed in Aspirin reaction units (ARU), which is
calculated as a function of the rate and extend of platelet aggregation. Higher ARU reflect a
greater arachidonic acid-induced platelet reactivity. The manufacturer defines an ARU ≤ 549
as an evidence of adequate platelet-dysfunction due to aspirin. ARU ≥ 550 indicates no
evidence of aspirin-induced platelet dysfunction. Additionally, the platelet activation via
P2Y12-receptors can be evaluated with the VerifyNow system. The results are then expressed in
P2Y12 Reaction Units (PRU). Values less than 194 PRU are an evidence of a P2Y12-inhibitor
effect.
Furthermore, ASA responsiveness not only varies between patients, but it may significantly
change within individual LVAD patients also over time. DeNino et al. described two cases,
where the patients had been reported to be sensitive to ASA when discharged on POD 10, but
during rehospitalization and a repeated test had shown no evidence of aspirin-induced
platelet dysfunction. This is in line with a recent study from Morgan et al., were the
resistance to ASA increased from 7% at baseline to 32% three months post-implant.
In conclusion, although ASA therapy is routinely recommended in LVAD patients with continuous
flow pumps to prevent HRAEs, the substantial number of events despite improved pump designs
may call into question the utility of standard ASA doses for all patients and that assessment
of individual response to ASA could further improve outcomes and guide therapy in LVAD
patients.
