This is a Prospective, Open-label Phase 2 Pilot Study With Independent Evaluation of All Outcomes and a Historical Control Group to Determine if Rivaroxaban (Xarelto) is Feasible and Safe for Prevention of Major Complications in Patients Undergoing a Mechanical Aortic Heart Valve Replacement.
This is a Prospective, Open-label Phase 2 Pilot Study With Independent Evaluation of All Outcomes and a Historical Control Group to Determine if Rivaroxaban (Xarelto) is Feasible and Safe for Prevention of Major Complications in Patients Undergoing a Mechanical Aortic Heart Valve Replacement.
Objectives
Primary objective:
To determine if rivaroxaban (Xarelto) is feasible and safe for prevention of major complications in patients undergoing a mechanical aortic heart valve replace-ment.
Secondary objectives:
To identify the value of molecular markers suitable for monitoring of anticoagulation effectiveness of rivaroxaban and its correlation with transcranial Doppler emboli count in patients undergoing a mechanical aortic heart valve replacement.
Design This is a prospective, open-label phase 2 pilot study with independent evaluation of all outcomes and a historical control group.
Number of patients 30 in experimental group (patients in the center's registry database serve as control group).
Main eligibility criteria All patients between 18 and 70 years old receiving a mechanical aortic valve replacement with a pre-operative left ventricular ejection fraction >/=35%.
Interventions Experimental: Rivaroxaban 20mg p.o., once daily, for six months Historical control: Phenprocoumon (Marcoumar) p.o., once daily Outcomes
Primary outcome:
Composite outcome of prosthetic thrombus requiring reoperation/intervention, major bleeding, visceral ischemia, stroke, pulmonary embolism, myocardial infarction or death from any cause 180 days after intervention.
Secondary outcomes:
Each component of the composite outcome plus serious adverse events. Prosthetic thrombus requiring reoperation/intervention plus non-clinically relevant thrombi will be used as an additional safety outcome.
Molecular markers suitable for monitoring the effectiveness of rivaroxaban.
Background
Although the overall incidence of complications associated with prosthetic cardiac valve implantation has decreased considerably since its introduction more than 3 decades ago, valvular thrombosis and systemic thromboembolism remain a major concern for cardiothoracic surgeons, cardiologists, and other practicing clinicians because of the well-known potential to cause devastating events including ischemic stroke and death.
Factors that contribute to the thrombogenicity of prosthetic heart valves include: altered blood flow and haemostatic activation caused by vessel-wall disruption during surgery or exposure of artificial surfaces to the circulating blood. Short-term parenteral anticoagulation with unfractionated heparin or low-molecular-weight heparin is often used until therapeutic concentrations of an oral vitamin K antagonist are reached. Vitamin K antagonists, alone or in combination with aspirin, are used for long-term management of these patients. However, Vitamin K antagonists are cumbersome to use, because of their multiple interactions with food and drugs, and they require frequent laboratory monitoring. Therefore, they are often not used, and when they are, rates of discontinuation are high. Many patients receiving Phenprocoumon still have inadequate anticoagulation. Thus, there is a need for new anticoagulant agents.
Patients who self-monitor therapy with vitamin K antagonists at home rather than in a laboratory are more often in the therapeutic range and have a lower incidence of complications and hospital admissions than those who do not. Meta-analyses of randomized trials have recently found that patient self-monitoring was associated with a 33% reduction of risk of death, a 55% reduction of risk of thromboembolism, and a slight decrease in major haemorrhage. Self-monitoring was also associated with improved quality of life and satisfaction. However, the number of INR values within the target range in self-monitored patients is still very poor, which is no more than 70% !, even taking in account a wide range of INR 2.5-4.5. Another main obstacle to widespread use of patient self-monitoring is cost. In the UK National Health Service, the estimated cost of patient self-monitoring is £122 000 per quality-adjusted life year (QALY) over 5 years and £63 000 over 10 years. This is not cost-effective considering the commonly accepted threshold of £30 000 per QALY. Costs are related to the portable INR-monitoring device, test strips, and patient education programs.
The oral direct thrombin inhibitor - dabigatran etexilate - and two oral direct factor Xa inhibitors - rivaroxaban and apixaban - are in advanced stages of clinical development and are expected to replace oral vitamin K antagonists for many indications.
There is a published phase 2, dose-validation study investigating the use of dabigatran in patients with mechanical heart valves (the RE-ALIGN trial). This trial was terminated prematurely because of an excess of thromboembolic and bleeding events among dabigatran-treated patients.
Does the RE-ALIGN trial preclude the investigation of rivaroxaban and other direct oral factor Xa inhibitors in patients with mechanical heart valves? Not necessarily! Coagulation develops in at least two subsequent waves of thrombin generation and fibrin deposition, with factor Xa playing a pivotal role for its amplification. In fact, since activation of 1 molecule of factor X results in the generation of 1000 molecules of thrombin, on a molar basis factor Xa is more thrombogenic than thrombin and several lines of research show that it requires less heparin to inhibit thrombosis prior thrombin formation than afterwards. Therefore, there is a sound rationale for hypothesizing that direct factor Xa inhibitors may be more efficient than dabigatran in preventing thromboembolic events among patients with mechanical heart valves.
Objective
Primary Objective: CATHAR is a pilot study to determine if rivaroxaban is feasible and safe for prevention of major complications in patients undergoing a mechanical aortic heart valve replacement.
Secondary objectives will be to identify the value of molecular markers suitable for monitoring of anticoagulation effectiveness of rivaroxaban and its correlation with transcranial Doppler emboli count in patients undergoing a mechanical aortic heart valve replacement.
Methods
CATHAR is a prospective, open-label, pilot, phase 2 study with independent evaluation of all outcomes. The trial is based on a Bayesian design by incorporating historical information for the control group for all analyses. All patients will receive an aortic valve replacement with a bileaflet mechanical valve. Rivaroxaban (Xarelto, Bayer) will be administered to all patients for prevention of complications. The dose of rivaroxaban is 20mg once daily. Continuous bood monitoring will be performed during hospitalisation and at follow up. Before hospital discharge and at 1, 3 and 6 months follow up all patients will receive an echocardiography. Trans-cranial Doppler will be performed in 10 random patients.
End of the study: Rivaroxaban patients will be switched to Phenprocoumon at 6 months follow up.
Inclusion Criteria:
Exclusion Criteria