Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves cared for in a tertiary care center. What have we learned?

BACKGROUND: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. OBJECTIVE: To determine the complications related to complementary anticoagulation therapy and the probability of risk. METHODS: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. RESULTS: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). CONCLUSIONS: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

ANTECEDENTES: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. OBJETIVO: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. MÉTODOS: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. RESULTADOS: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). CONCLUSIONES: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Calcification of Various Bioprosthetic Materials in Rats: Is It Really Different?

The causes of heart valve bioprosthetic calcification are still not clear. In this paper, we compared the calcification in the porcine aorta (Ao) and the bovine jugular vein (Ve) walls, as well as the bovine pericardium (Pe). Biomaterials were crosslinked with glutaraldehyde (GA) and diepoxide (DE), after which they were implanted subcutaneously in young rats for 10, 20, and 30 days. Collagen, elastin, and fibrillin were visualized in non-implanted samples. Atomic absorption spectroscopy, histological methods, scanning electron microscopy, and Fourier-transform infrared spectroscopy were used to study the dynamics of calcification. By the 30th day, calcium accumulated most intensively in the collagen fibers of the GA-Pe. In elastin-rich materials, calcium deposits were associated with elastin fibers and localized differences in the walls of Ao and Ve. The DE-Pe did not calcify at all for 30 days. Alkaline phosphatase does not affect calcification since it was not found in the implant tissue. Fibrillin surrounds elastin fibers in the Ao and Ve, but its involvement in calcification is questionable. In the subcutaneous space of young rats, which are used to model the implants' calcification, the content of phosphorus was five times higher than in aging animals. We hypothesize that the centers of calcium phosphate nucleation are the positively charged nitrogen of the pyridinium rings, which is the main one in fresh elastin and appears in collagen as a result of GA preservation. Nucleation can be significantly accelerated at high concentrations of phosphorus in biological fluids. The hypothesis needs further experimental confirmation.

A randomized clinical trial to evaluate the efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valve and atrial fibrillation or flutter: Rationale and design of the RIVER trial.

The efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valves and atrial fibrillation or flutter remain uncertain. DESIGN: RIVER was an academic-led, multicenter, open-label, randomized, non-inferiority trial with blinded outcome adjudication that enrolled 1005 patients from 49 sites in Brazil. Patients with a bioprosthetic mitral valve and atrial fibrillation or flutter were randomly assigned (1:1) to rivaroxaban 20 mg once daily (15 mg in those with creatinine clearance <50 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-30.); the follow-up period was 12 months. The primary outcome was a composite of all-cause mortality, stroke, transient ischemic attack, major bleeding, valve thrombosis, systemic embolism, or hospitalization for heart failure. Secondary outcomes included individual components of the primary composite outcome, bleeding events, and venous thromboembolism. SUMMARY: RIVER represents the largest trial specifically designed to assess the efficacy and safety of a direct oral anticoagulant in patients with bioprosthetic mitral valves and atrial fibrillation or flutter. The results of this trial can inform clinical practice and international guidelines.

Comparison of Different Anticoagulation Regimens Regarding Maternal and Fetal Outcomes in Pregnant Patients With Mechanical Prosthetic Heart Valves (from the Multicenter ANATOLIA-PREG Registry).

Mechanical prosthetic heart valves (MPHVs) are highly thrombogenic, and a pregnancy-induced procoagulant status increases the risk of MPHV thrombosis. Despite numerous case reports, 2 major registries and meta-analyses/systematic reviews, optimal anticoagulation therapy during pregnancy remains controversial. The goal of this study was to evaluate different anticoagulation regimens in pregnant patients with MPHVs. The outcomes of anticoagulation regimens were assessed retrospectively in pregnant women (110 women; 155 pregnancies) with MPHVs. The study population was divided into 5 groups according to anticoagulation regimens used; high-dose warfarin (>5 mg/d) throughout pregnancy (group 1), low-dose warfarin (≤5 mg/d) throughout pregnancy (group 2), low molecular weight heparin (LMWH) throughout pregnancy (group 3), first trimester LMWH, 2nd and 3rd trimester warfarin (group 4), first 2 trimester LMWH, and 3rd trimester warfarin (group 5). Of 155 pregnancies, 55 (35%) resulted in fetal loss; whereas 41 (27%) cases with abortion (miscarriage and therapeutic) and 14 (9%) stillbirths occurred. The comparison of the groups showed that the whole abortion rates including therapeutic abortion were significantly higher in Group 1, and lower in groups 3 and 5 (p <0.001). However, miscarriage rates were similar between the groups. A total of 53 pregnancies (34%) suffered from prosthetic valves thrombosis (PVT) during pregnancy or in the postpartum period. Group 2 had significantly lower rates of PVT than the other groups (p <0.001). In conclusion, the current data suggests that there is no optimal therapy, and that all managements have advantages and disadvantages. Low-dose warfarin (≤5 mg/day) regimen with therapeutic international normalized ratio levels may provide effective maternal protection throughout pregnancy with acceptable fetal outcomes.

Rivaroxaban and Dabigatran for Suppression of Mechanical Heart Valve-Induced Thrombin Generation.

BACKGROUND: Patients with mechanical heart valves (MHVs) require warfarin to prevent thromboembolism. Dabigatran was less effective than warfarin in patients with MHVs, which prompted a black box warning against the use of direct oral anticoagulants for this indication. However, rivaroxaban and apixaban, which inhibit factor Xa, have not been evaluated in patients with MHVs. To determine whether rivaroxaban and apixaban would be effective, we used MHV-induced thrombin generation assays to compare them with warfarin either alone or in combination with dabigatran. METHODS: Thrombin generation in the absence or presence of MHV leaflets or sewing ring segments (SRSs) was quantified. Studies were done in control plasma; plasma from patients on warfarin; plasma containing varying concentrations of rivaroxaban, apixaban, or dabigatran alone; or plasma containing rivaroxaban plus dabigatran. RESULTS: Mean endogenous thrombin potential (ETP) increased 1.2-fold, 1.5-fold, and 1.8-fold in the presence of leaflets, Teflon (Terumo Aortic (Sunrise, FL)) SRSs, or Dacron (Terumo Aortic (Sunrise, FL)) SRSs, respectively. Rivaroxaban and apixaban reduced ETP at concentrations above 50 ng/mL but were less effective than warfarin. When rivaroxaban and dabigatran were combined, they suppressed ETP in a more than additive manner. CONCLUSIONS: Whereas warfarin suppresses MHV-induced thrombin generation, MHVs induce the generation of factor Xa in concentrations that overwhelm clinically relevant concentrations of rivaroxaban or apixaban. When used in combination, rivaroxaban and dabigatran are more effective than either agent is alone, suggesting that concomitant inhibition of factor Xa and thrombin is better than inhibition of either clotting enzyme alone.

The novel use of oral antibiotic monotherapy in prosthetic valve endocarditis caused by Finegoldia magna: a case study.

BACKGROUND: Finegoldia magna, a Gram-positive anaerobic coccus, is part of the human normal microbiota as a commensal of mucocutaneous surfaces. However, it remains an uncommon pathogen in infective endocarditis, with only eight clinical cases previously reported in the literature. Currently, infective endocarditis is routinely treated with prolonged intravenous antibiotic therapy. However, recent research has found that switching patients to oral antibiotics is non-inferior to prolonged parenteral antibiotic treatment, challenging the current guidelines for the treatment of infective endocarditis. CASE PRESENTATION: This case report focuses on a 52-year-old gentleman, who presented with initially culture-negative infective endocarditis following bioprosthetic aortic valve replacement. Blood cultures later grew Finegoldia magna. Following initial intravenous antibiotic therapy and re-do surgical replacement of the prosthetic aortic valve, the patient was successfully switched to oral antibiotic monotherapy, an unusual strategy in the treatment of infective endocarditis inspired by the recent publication of the POET trial. He made excellent progress on an eight-week course of oral antibiotics and was successfully discharged from surgical follow-up. CONCLUSIONS: This case is the 9th reported case of Finegoldia magna infective endocarditis in the literature. Our case also raises the possibility of a more patient-friendly and cost-effective means of providing long-term antibiotic therapy in suitable patients with prosthetic valve endocarditis and suggests that the principles highlighted in the POET trial can also be applicable to post-operative patients after cardiac surgery.

Mechanical Prosthetic Heart Valve Thrombosis in a Patient Receiving Rivaroxaban.

Direct oral anticoagulants are not approved for use in patients with mechanical valves. When used to replace vitamin K antagonists, they may cause catastrophic consequences. The authors describe the case of a patient who, after discontinuation of warfarin and introduction of rivaroxaban, developed thrombosis of his mechanical mitral prosthesis.

Early failure of a bioprosthetic aortic valve due to thrombus formation while on rivaroxaban.

There is increasing evidence that bioprosthetic valve thrombosis (BPVT) is more common than previously thought. However, there are very few cases describing the occurrence of BPVT on therapeutic anticoagulation, and no previous cases are available stating the occurrence of BPVT on direct oral anticoagulant therapy. We describe the case of surgically managed aortic BPVT that was diagnosed while the patient was on rivaroxaban.

Transcatheter aortic valve replacement: relative safety and efficacy of the procedure with different devices.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is a well-established treatment for patients with severe aortic stenosis and intermediate-to-high surgical risk. The increasing clinical experience along with technical and design iterations of transcatheter valve systems have contributed to reducing adverse events and improving clinical outcomes. AREAS COVERED: Overview of the latest generation transcatheter heart valves (THVs), focusing on early safety and efficacy outcomes. EXPERT COMMENTARY: Improvements in valve repositionability, reducing the size of valve delivery systems, and antiparavalvular leak iterations have contributed to improving the safety and clinical outcomes following TAVR. However, while certain complications like major vascular events and residual paravalvular leaks have significantly decreased with the arrival of newer generation THVs, no major changes in thromboembolic events (particularly stroke) have been observed, whereas other complications like conduction disturbances requiring pacemaker implantation have slightly increased over time. Also, no major progress on device retrievability has been observed in the last years. The expansion of TAVR toward the treatment of younger and lower risk patients, as well as newer indications (e.g. asymptomatic patients) will likely require an extra-effort involving additional device iterations and complementary therapies (e.g. embolic protection, newer vascular closure devices) to further improve safety and clinical outcomes.

Evaluation of bleeding risk in patients on anticoagulation for mechanical cardiac valve operated for benign prostatic obstruction.

OBJECTIVE: To evaluate bleeding risk in patients on anticoagulation for mechanical cardiac valve operated for benign prostatic obstruction (BPO). MATERIAL AND METHOD: Fifty-eight patients operated between 1998 and 2014, in seven French departments of Urology were included. Forty-five patients were operated by conventional surgery (transurethral resection of the prostate 38, open simple prostatectomies 7), and 13 patients were operated by Greenlight™ photovaporization of the prostate (PVP). In order to assess bleeding risk, blood transfusion was considered as the primary outcome. RESULTS: Fifteen (26%) patients received blood transfusion in the postoperative period. Mean duration of hospitalization was 8.5 days. Secondary surgery was required in 12 cases (21%), including endoscopic clot removal under general anaesthesia in 10 patients, and suprapubic haemostasis in 3 patients. One patient died 72hours after transurethral resection of the prostate because of a massive pulmonary embolism. Two independent predictors of blood transfusion were identified: conventional surgery use versus PVP, and high preoperative PSA. Blood transfusion rate was significantly lower in the group of patients operated by PVP compared to conventional surgery (0% versus 33%, P=0.010). In addition, the laser surgery was associated with shorter duration of hospitalization (3.4 days versus 9.9 days, P=0.014). However, it was not found any significant difference between patients operated by PVP compared to conventional surgery in terms of secondary bleeding (3/13 vs 8/45, P=0.7), or second surgery (2/13 vs 10/45, P=0.5). CONCLUSION: Bleeding risk of BPO surgery in patients with mechanical cardiac valve is high. The PVP seems to decrease significantly the early haemorrhagic risk compared to classic surgical procedures for patients with mechanical cardiac valve. LEVEL OF EVIDENCE: 4.

Late Obstructive Transcatheter Heart Valve Thrombosis Resolved by Rivaroxaban.

BACKGROUND Although transcatheter aortic valve replacement (TAVR) has become a worldwide and generally accepted treatment of patients with aortic stenosis at high surgical risk, there is a rising concern and debate about the occurrence of transcatheter heart valve (THV) thrombosis and its impact on TAVR outcome. It seems that the incidence of THV thrombosis is higher than first anticipated, but uncertainty remains regarding how to prevent and how to treat it. Hence, there is an urgent need for understanding THV thrombosis and to communicate experiences within the field. CASE REPORT We present a unique case of late occurrence of THV thrombosis that was resolved by switching from clopidogrel to rivaroxaban treatment. CONCLUSIONS As a novel observation, our case demonstrates that THV thrombosis may develop even late after TAVR, and even in such cases may be completely reversed. It also underscores that THV dysfunction should evoke prompt investigation for possible thrombus formation, preferable by multidetector computed tomography. Finally, this case report suggests NOAC as an alternative to warfarin treatment in patients with THV thrombosis.

Successful treatment of mechanical mitral valve thrombosis without thrombolytic therapy or surgery.

Prosthetic valve thrombosis is an uncommon, life-threatening complication that often mandates urgent repeat surgery or thrombolytic therapy. We present an alternative approach in a patient with rheumatic heart disease who presented with subacute thrombosis of a recently implanted On-X mechanical mitral valve (On-X Life Technologies Inc, Austin, TX), diagnosed on echocardiography and valve fluoroscopy. The patient refused surgery, hence we elected to treat the patient with high-dose antithrombotic therapy alone. Echocardiographic monitoring demonstrated complete reabsorption of the thrombus within 6 months without any embolic complications. Endogenous fibrinolysis with appropriate antithrombotic therapy might be a suitable option for select, high-risk patients with mechanical mitral valve thrombosis.

Early bioprosthetic valve calcification with alfacalcidol supplementation.

We report a case of early bioprosthetic valve calcification in a 76 year-old woman who had received supplementation with alfacalcidol, an analogue of vitamin D, for 3 years after her initial valve replacement. She underwent aortic valve replacement at the age of 71 and subsequently complained of shortness of breath. Ultrasonic cardiography revealed severe aortic stenosis and we performed a second aortic valve replacement with a bioprosthesis. Histopathologic and x-ray examination showed calcification on the explanted valve. She had not presented with any known risk for early bioprosthetic calcification, suggesting that vitamin D supplementation may accelerate calcification of bioprosthetic valves.

Periprocedural anticoagulant management.

Approximately 6 million Americans are treated with chronic anticoagulation. Of these, 10% of patients will require temporary anticoagulation interruption for an invasive procedure each year. Anticoagulation management during this period requires a formal strategy in order to limit both bleeding and thromboembolic complications. This article will give health care providers a stepwise approach to this process. The first step is to determine whether warfarin discontinuation is necessary for the planned procedure. For procedures requiring warfarin discontinuation, the second step is to determine the appropriate timing. The third step is to identify the patient-specific thromboembolic risk in order to determine which patients require bridging therapy with parenteral anticoagulants. The fourth step is both the most complicated and most critical step in this management strategy. This decision-making step involves choosing the appropriate anticoagulant regimen, dose, and timing of reinitiation that is best tailored to a specific patient, as well as determining procedural variables, in order to limit bleeding and thrombotic complications.

Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model.

BACKGROUND: Mechanical heart valve replacement is an absolute indication for anticoagulation. We report our experience comparing dabigatran to warfarin as thromboembolic prophylaxis after mechanical mitral valve replacement in the swine model. METHODS: Nineteen swine underwent mitral valve replacement with a regulatory approved, 27 mm mechanical valve. Two control groups consisted of three animals receiving no anticoagulation and five animals receiving warfarin (5 mg once a day [QD], adjusted to maintain international normalized ratio [INR] from 2.0 to 2.5). The experimental group consisted of 11 animals receiving dabigatran (20 mg/kg twice a day [BID]). The study period was 90 days. The primary outcome was animal mortality; secondary outcomes included presence of thrombus and bleeding complications. RESULTS: The experimental group had four full-term survivors (40.0%); there were no full-term survivors in either control group. The average length of survival was 50.3 days in the experimental group compared with 18.7 and 15.6 days for the no anticoagulation and warfarin groups, respectively (p = .017). Valve thrombus was observed in all study groups. Hemorrhagic complications were present in 40% of the warfarin group and 27% of the dabigatran group. CONCLUSIONS: There was a significant mortality benefit to the use of dabigatran as thromboembolic prophylaxis when compared with warfarin in the setting of mechanical heart valve replacement in the swine model. There was also a decreased incidence of bleeding complications in the dabigatran group compared with the warfarin group. Valve thrombus was observed in all study groups. Any conclusions regarding the rate of thrombus formation are outside the scope of this study and merit further investigation.

A low-volume tester for the thrombogenic potential of mechanical heart valve prostheses.

BACKGROUND AND AIM OF THE STUDY: During the development of a mechanical heart valve prosthesis, many studies are conducted to guarantee its correct function. Currently, investigations into the thrombogenic potential of a valve after its replacement are conducted with expensive and time-consuming chronic animal trials. Hence, the study aim was to develop and test an alternative system to resolve such thrombogenic issues. METHODS: The Thrombosis Tester of the Helmholtz Institute Aachen (THIA II) has a reasonably small priming volume (220-270 ml) that allows analysis of the thrombogenic potential of two valves, using one human blood bottle. RESULTS: Hydrodynamic evaluation demonstrated an absolutely stable physiological pressure and flow progression at the aortic and pulmonary positions. A sinus geometry of the human aortic root is implemented downstream of the valve in order to guarantee physiological leaflet motion. The tester remained absolutely thrombus-free during several tests carried out with minimally anticoagulated porcine blood, while the valves showed reproducible thrombus formation in reasonable locations. Tests with fully heparinized porcine blood showed that a soft silicon fixture for the valve could reduce hemolysis in the THIA II. CONCLUSION: This in-vitro test protocol can enable the optimization of a valve design during the early stages of its research and development. The system can provide a unique and suitable supplement to animal trials for testing thrombogenic performance, under constant and reproducible boundary conditions, including considerable physiological and pathological circumstances such as the influence of valve position (aortic, pulmonic), and a comparison of different valve types.

Use of Ankaferd Blood Stopper as a hemostatic agent: a clinical experience.

AIM: To determine the efficacy of the topical application of Ankaferd Blood Stopper (ABS) on hemorrhagic diathesis following dental procedures under different conditions. BACKGROUND: Some patients have a tendency to bleed excessively after dental surgery for a variety of reasons, making oral surgical procedures more risky for these patients. Since hemorrhage can cause major morbidity and mortality, the identification of a novel, effective hemostatic agent could improve the management of excessive bleeding that occurs during dental procedures. CASE DESCRIPTIONS: Four patients (3 females, 1 male) aged 28-45 with bleeding tendencies due to different presurgical conditions such as von Willebrand Disease, chronic liver failure, and mitral valve replacement presented for tooth extraction. Hematological consultations were obtained prior to surgical intervention and their international normalized (INR) ratio values were adjusted to less than 1.5; none received clotting factor replacement. All the extractions were performed under local anesthesia with and without epinephrine. In the presence of postsurgical bleeding, the efficacy of the ampule form of topical ABS was observed. Sex, age, anamnesis, von Willebrand Factor, activated partial thromboplastin time, factor VIII, and platelet counts of patients were recorded prior to the extractions. CONCLUSIONS: ABS was found to be effective within 10 to 20 minutes in controlling bleeding in most of the patients after dental surgery. These observations suggest the use of ABS may be a beneficial hemostatic agent for use in patients with hemorrhagic diathesis following tooth extraction. Additional research is needed to clarify the role of this unique medicinal product in the surgical treatment of dental patients with bleeding tendency. CLINICAL SIGNIFICANCE: ABS has demonstrated potential for being an effective hemostatic agent for the treatment of excessive bleeding following dental surgery in four patients with hemorrhagic diathesis.

[Consensus document for the treatment of bacteremia and endocarditis caused by methicillin-resistent Staphylococcus aureus. Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica]. / Documento de consenso sobre el tratamiento de la bacteriemia y la endocarditis causada por Staphylococcus aureus resistente a la meticilina. Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.

Bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and clinically important. The rise in MRSA bacteremia and endocarditis is related with the increasing use of venous catheters and other vascular procedures. Glycopeptides have been the reference drugs for treating these infections. Unfortunately their activity is not completely satisfactory, particularly against MRSA strains with MICs > 1 microg/mL. The development of new antibiotics, such as linezolid and daptomycin, and the promise of future compounds (dalvabancin, ceftobiprole and telavancin) may change the expectatives in this field.The principal aim of this consensus document was to formulate several recommendations to improve the outcome of MRSA bacteremia and endocarditis, based on the latest reported scientific evidence. This document specifically analyzes the approach for three clinical situations: venous catheter-related bacteremia, persistent bacteremia, and infective endocarditis due to MRSA.