Use of non-warfarin oral anticoagulants instead of warfarin during left atrial appendage closure with the Watchman device.

BACKGROUND: In the stroke prevention trials of left atrial appendage closure with the Watchman device (Boston Scientific), a postimplantation antithrombotic regimen of 6 weeks of warfarin was used. OBJECTIVE: Given the clinical complexity of warfarin use, the purpose of this study was to study the relative feasibility and safety of using non-warfarin oral anticoagulants (NOACs) instead of warfarin during the peri- and initial postimplantation periods after Watchman implantation. METHODS: This was a retrospective multicenter study of consecutive patients undergoing Watchman implantation and receiving peri- and postprocedural NOACs or warfarin. Transesophageal echocardiography or chest computed tomography was performed between 6 weeks and 4 months postimplant to assess for device-related thrombosis. Bleeding and thromboembolic events also were evaluated at the time of follow-up. RESULTS: In 5 centers, 214 patients received NOACs (46% apixaban, 46% rivaroxaban, 7% dabigatran, and 1% edoxaban) in either an uninterrupted (82%) or a single-held-dose (16%) fashion. Compared to a control group receiving uninterrupted warfarin (n = 212), the rates of periprocedural complications, including bleeding events, were similar (2.8% vs 2.4%, P = 1). At follow-up, the rates of device-related thrombosis (0.9% vs 0.5%, P = 1), composite of thromboembolism or device-related thrombosis (1.4% vs 0.9%, P = 1), and postprocedure bleeding events (0.5% vs 0.9%, P = .6) also were comparable between the NOAC and warfarin groups. CONCLUSION: NOACs proved to be a feasible peri- and postprocedural alternative regimen to warfarin for preventing device-related thrombosis and thromboembolic complications expected early after appendage closure with the Watchman device, without increasing the risk of bleeding.

Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects.

The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 (p=0.004) and VKORC1 (p=0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses (p=0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 (p=0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders.

Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU.

AIM: To determine if copy number variants contribute to warfarin dose requirements, we investigated CYP2C9, VKORC1, CYP4F2, GGCX and CALU for deletions and duplications in a multiethnic patient population treated with therapeutic doses of warfarin. PATIENTS & METHODS: DNA samples from 178 patients were subjected to copy number analyses by multiplex ligation-dependent probe amplification or quantitative PCR assays. Additionally, the CYP2C9 exon 8 insertion/deletion polymorphism (rs71668942) was examined among the patient cohort and 1750 additional multiethnic healthy individuals. RESULTS: All patients carried two copies of CYP2C9 by multiplex ligation-dependent probe amplification and no exon 8 deletion carriers were detected. Similarly, quantitative PCR assays for VKORC1, CYP4F2, GGCX and CALU identified two copies in all populations. CONCLUSION: These data indicate that copy number variants in the principal genes involved in warfarin dose variability (CYP2C9, VKORC1), including genes with lesser effect (CYP4F2, GGCX), and those that may be more relevant among certain racial groups (CALU), are rare in multiethnic populations, including African-Americans.

Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.

Thoracic aortic aneurysms (TAA) often represent the final manifestation of hereditary or degenerative disease processes. TAA are primarily caused by age-related degenerative changes. In this article, the authors highlight the most common pathophysiologic mechanisms responsible for TAA formation and review the paucity of evidence supporting the spectrum of medical therapies for TAA other than renin-angiotensin inhibition. More clinical trials on TAA are required before medical therapies such as beta-blockers, statins, and macrolide antibiotics can be recommended.

Anticoagulation for mechanical heart valves in patients with and without atrial fibrillation.

Surgical replacement of a native valve with a biological or mechanical prosthesis is the definitive treatment for many forms of advanced valvular heart disease. Mechanical heart valves are less prone to structural deterioration compared with bioprostheses, but require chronic oral anticoagulation to prevent thromboembolic events. Thromboembolic risk varies based on patient-related risk factors, including atrial fibrillation, advanced age, low ejection fraction, and hypercoagulability. Other important correlates of high thromboembolic risk include valve design, valve position, anticoagulation variability, and time from surgery. Clinical management is further complicated when antithrombotics may need to be interrupted or altered during surgery or pregnancy. At present, vitamin K antagonists are the only approved agents for thromboprophylaxis but are limited because of a narrow therapeutic window and requirement for frequent monitoring. Novel anticoagulants, including inhibitors of factor IIa and Xa, are currently being evaluated and may emerge as alternatives to vitamin K antagonists.

Cardiovascular risk factors in patients with chronic kidney disease.

Patients with chronic kidney disease have a higher burden of cardiovascular disease, which increases in a dose-dependent fashion with worsening kidney function. Traditional cardiovascular risk factors, including advanced age, diabetes mellitus, hypertension and dyslipidemia, have an important role in the progression of cardiovascular disease in patients who have a reduced glomerular filtration rate, especially in those with mild-to-moderate kidney disease. In patients with severe kidney disease, nontraditional or 'novel' risk factors, including inflammation, oxidative stress, vascular calcification, a prothrombotic milieu, and anemia, seem to confer additional risk. In this Review, we highlight factors that increase cardiovascular risk in patients with a reduced estimated glomerular filtration rate. In addition, we discuss therapeutic strategies for reducing cardiovascular risk in patients with kidney disease, whose unique atherosclerotic phenotype might require an approach that differs from traditional models developed in populations with normal kidney function. Therapeutic paradigms for patients with chronic kidney disease and cardiovascular risk factors must be evaluated in randomized trials, from which such patients have often been excluded.

Evolving anatomic, functional, and molecular imaging in the early detection and prognosis of hypertrophic cardiomyopathy.

Evolving imaging modalities in hypertrophic cardiomyopathy (HCM), such as tissue Doppler, speckle tracking, measures of myocardial blood flow, and cardiac magnetic resonance with gadolinium enhancement, have advanced our understanding of the pathogenesis of myocardial dysfunction in hypertrophic cardiomyopathy. These modalities have the potential to differentiate HCM from other causes of left ventricular hypertrophy when there is uncertainty about the diagnosis and to identify affected individuals in the pre-clinical phase of the disease process. Furthermore, preliminary data suggests that functional imaging techniques may add incremental value to conventional risk stratification tools to identify individuals at high risk for sudden death or progression to congestive heart failure.