Evaluation of Platelet Therapy Response in Left Ventricular Assist Device Patients
Condition: End-stage Heart Failure; Cardiomyopathies; Mechanical Circulatory Support
MeSH terms: Cardiomyopathies
Study type: Observational

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 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.
    

Intervention name(s): VerifyNow antiplatelet therapy response test
Intervention type(s): Diagnostic Test
Intervention description(s): VerifyNow testing after minimum of 2 hours and at latest 24 hours after the first four dosis of ASA
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Study population will consist of HeartMate 3 LVAD or HVAD recipients implanted at the
        Medical University of Vienna. Based on the initial ASA response type (responder vs.
        non-responder) the primary and secondary outcomes will be assessed.
      
Keywords: Left ventricular assist device