Ignite Creation Date:
2024-05-06 @ 7:49 PM
Last Modification Date:
2024-10-26 @ 3:15 PM
Study NCT ID:
NCT06152562
Status:
COMPLETED
Last Update Posted:
2023-11-30
First Post:
2021-12-10
Brief Title:
Evaluation of Platelet Therapy Response in Left Ventricular Assist Device Patients
Sponsor:
Medical University of Vienna
Organization:
Medical University of Vienna
Study Overview
Official Title:
Evaluation of Platelet Therapy Response in Left Ventricular Assist Device Patients
Status:
COMPLETED
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
Detailed 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 14 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 20-30 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 eg 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 20-25 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 eg proton pump inhibitors genetic differences pre-existing health conditions eg diabetes and non-compliance
Although eg the HVAD manufacturer recommends if ASA alone is the medication chosen for antiplatelet therapy a check for ASA resistance with a reliable test eg 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
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 14 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 20-30 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 eg 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 20-25 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 eg proton pump inhibitors genetic differences pre-existing health conditions eg diabetes and non-compliance
Although eg the HVAD manufacturer recommends if ASA alone is the medication chosen for antiplatelet therapy a check for ASA resistance with a reliable test eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2021-004921-62 | EUDRACT_NUMBER | None | None |