warfarin and Atherosclerosis

Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease. It is caused by atherosclerosis; that is, the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem.. To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes.. We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, two other databases, and three trials registers from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials.. We included all randomised controlled trials (RCTs), irrespective of publication status and language, comparing a pharmacological intervention to placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis.. We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third author resolved disagreements when necessary. We assessed the evidence certainty for key outcomes using GRADE.. We included 34 RCTs with 11,571 participants. Data for meta-analysis were available from only 22 studies with 6887 participants. The mean follow-up period was 2.5 years. None of the 34 included studies assessed neurological impairment and quality of life. Antiplatelet agent (acetylsalicylic acid) versus placebo Acetylsalicylic acid (1 study, 372 participants) may result in little to no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47 to 2.47), stroke-related mortality (RR 1.40, 95% CI 0.54 to 3.59), progression of carotid stenosis (RR 1.16, 95% CI 0.79 to 1.71), and adverse events (RR 0.81, 95% CI 0.41 to 1.59), compared to placebo (all low-certainty evidence). The effect of acetylsalicylic acid on major bleeding is very uncertain (RR 0.98, 95% CI 0.06 to 15.53; very low-certainty evidence). The study did not measure neurological impairment or quality of life. Antihypertensive agents (metoprolol and chlorthalidone) versus placebo The antihypertensive agent, metoprolol, may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95% CI 0.02 to1.16; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95% CI 0.17 to 1.94; 1 study, 793 participants) compared to placebo (both low-certainty evidence). However, chlorthalidone may slow the progression of carotid stenosis (RR 0.45, 95% CI 0.23 to 0.91; 1 study, 129 participants; low-certainty evidence) compared to placebo. Neither study measured neurological impairment, major bleeding, adverse events, or quality of life. Anticoagulant agent (warfarin) versus placebo The evidence is very uncertain about the effects of warfarin (1 study, 919 participants) on major bleeding (RR 1.19, 95% CI 0.97 to 1.46; very low-certainty evidence), but it may reduce adverse events (RR 0.89, 95% CI 0.81 to 0.99; low-certainty evidence) compared to placebo. The study did not measure neurological impairment, ipsilateral major or disabling stroke, stroke-related mortality, progression of carotid stenosis, or quality of life. Lipid-lowering agents (atorvastatin, fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin) versus placebo or no treatment Lipid-lowering agents may result in little to no difference in ipsilateral major or disabling stroke (atorvastatin, lovastatin, pravastatin, and rosuvastatin; RR 0.36, 95% CI 0.09 to 1.53; 5 studies, 2235 participants) stroke-related mortality (lovastatin and pravastatin; RR 0.25, 95% CI 0.03. Although there is no high-certainty evidence to support pharmacological intervention, this does not mean that pharmacological treatments are ineffective in preventing ischaemic cerebral events, morbidity, and mortality. High-quality RCTs are needed to better inform the best medical treatment that may reduce the burden of carotid stenosis. In the interim, clinicians will have to use other sources of information.. پیشینه: تنگی شریان کاروتید عبارت است از باریک شدن شریان‌های کاروتید. تنگی کاروتید بدون نشانه زمانی است که این تنگی در افراد بدون سابقه یا نشانه‌های این بیماری رخ می‌دهد. این عارضه ناشی از آترواسکلروز (atherosclerosis) است؛ یعنی تجمع چربی، کلسترول و دیگر مواد داخل و روی دیواره‌های شریان. احتمال بروز آترواسکلروز در افرادی که عوامل خطر متعددی دارند، مانند دیابت، هیپرتانسیون، هیپرلیپیدمی و مصرف سیگار، بیشتر است. از آنجایی که این آسیب می‌تواند بدون نشانه ایجاد شود، اولین نشانه می‌تواند یک سکته مغزی کشنده یا ناتوان کننده باشد که به عنوان سکته مغزی ایسکمیک شناخته می‌شود. تنگی کاروتید منجر به وقوع سکته مغزی ایسکمیک در مردان بالای 70 سال شایع‌تر رخ می‌دهد. سکته مغزی ایسکمیک یک مشکل سلامت عمومی در سراسر جهان است. اهداف: ارزیابی تاثیرات مداخلات دارویی در درمان تنگی کاروتید بدون نشانه به منظور پیشگیری از بروز‌اختلالات نورولوژیکی، سکته مغزی ماژور یا ناتوان کننده یک طرفه (ipsilateral)، مرگ‌ومیر، خونریزی شدید، و دیگر پیامدها. روش‌های جست‌وجو: پایگاه ثبت کارآزمایی‌های گروه سکته مغزی (stroke) در کاکرین، CENTRAL؛ MEDLINE؛ Embase؛ دو بانک اطلاعاتی دیگر، و سه پایگاه ثبت کارآزمایی را از زمان شروع به کار تا 9 آگوست 2022 جست‌وجو کردیم. هم‌چنین فهرست منابع مرورهای سیستماتیک مرتبط را که شناسایی شدند، بررسی کرده و برای یافتن منابع بیشتر برای کارآزمایی‌ها با متخصصان این زمینه تماس گرفتیم. معیارهای انتخاب: همه کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) را بدون در نظر گرفتن وضعیت انتشار و زبان نگارش مقاله وارد کردیم، که به مقایسه یک مداخله دارویی با دارونما (placebo)، عدم درمان، یا مداخله دارویی دیگر در درمان تنگی کاروتید بدون نشانه پرداختند. گردآوری و تجزیه‌وتحلیل داده‌ها: از پروسیجرهای استاندارد روش‌شناسی (methodology) کاکرین استفاده کردیم. دو نویسنده مرور به‌طور مستقل از هم به استخراج داده‌ها و ارزیابی خطر سوگیری (bias) در کارآزمایی‌ها پرداختند. در صورت لزوم، نویسنده سوم اختلاف‌نظرات را حل‌وفصل کرد. قطعیت شواهد را برای پیامدهای کلیدی با استفاده از رویکرد درجه‌بندی توصیه، ارزیابی، توسعه و ارزشیابی (Grading of Recommendations Assessment, Development and Evaluation; GRADE) ارزیابی کردیم. نتایج اصلی: تعداد 34 RCT را با 11,571 شرکت‌کننده وارد کردیم. برای انجام متاآنالیز، داده‌هایی از فقط 22 مطالعه با 6887 شرکت‌کننده در دسترس بودند. میانگین دوره پیگیری 2.5 سال بود. هیچ یک از 34 مطالعه وارد شده اختلالات نورولوژیکی و کیفیت زندگی را ارزیابی نکردند. عامل ضد پلاکت (استیل‌سالیسیلیک اسید) در برابر دارونما استیل‌سالیسیلیک اسید (acetylsalicylic acid) در مقایسه با دارونما (1 مطالعه، 372 شرکت‌کننده) ممکن است تفاوتی اندک تا عدم تفاوت را در سکته مغزی ماژور یا ناتوان ک

Topics: Aspirin; Atherosclerosis; Atorvastatin; Carotid Stenosis; Chlorthalidone; Fluvastatin; Hemorrhage; Humans; Ischemic Stroke; Metoprolol; Pravastatin; Probucol; Rosuvastatin Calcium; Stroke; Warfarin

Adverse effects of drugs are one of the objective criteria used for choosing the most appropriate anticoagulant. It is worrying that warfarin may be involved in the progression of systemic atherosclerosis, as more and more articles suggest. Warfarin has been widely used in the past and has greater efficacy compared to dabigatran in patients with mechanical heart valves; there is an antidote to it and it is cheap. Unfortunately, warfarin inhibits the synthesis and activity of Matrix-Gla-Protein, which is the major vitamin K-dependent inhibitor of arterial calcification - an active process associated with atherosclerosis, stimulated by inflammatory mechanisms. Vitamin K antagonizes the NF-κB signaling mechanism and contributes to the prevention of arterial calcifications. Warfarin given in experimental animal models of atherosclerosis contributed to the occurrence of an increased number of aortic calcifications. Warfarin treatment used in clinical trials was associated with the progressive increase of coronary atheroma calcification. Younger patients are more sensitive to warfarin-related arterial calcifications compared to older patients, due to warfarin-induced cellular senescence changes. Non-vitamin K antagonist direct oral anticoagulants do not interact with vitamin K. Edoxaban reduces the inflammatory process in the vascular walls and the proliferation of smooth vascular muscle cells, so it is involved in the prevention of vascular maladaptive remodeling process. Apixaban is able to stabilize the coronary atherosclerotic process. Randomized clinical trials are needed to evaluate the impact of warfarin on plaque stability and cardiovascular evolution of patients.

Topics: Administration, Oral; Animals; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Humans; Stroke; Vitamin K; Warfarin

Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K-dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.

Topics: Animals; Anticoagulants; Arteries; Atherosclerosis; Dietary Supplements; Disease Models, Animal; Humans; Time Factors; Vascular Calcification; Vascular Stiffness; Vitamin K; Warfarin

The role of thrombin in vascular physiology and pathophysiology continues to impact our understanding of many cellular processes and systems including the function of platelets, endothelial cells, smooth muscle cells, leukocytes and the regulation of the coagulation cascade. Recent acute coronary syndrome clinical trial results that have compared the use of parenteral or oral anticoagulants versus or in combination with anti-platelet agents have forced a reexamination of the importance of thrombin activity in influencing patient outcomes, particularly in the area of secondary prevention. The debate of the need to include oral anticoagulation as a concomitant or replacement therapy to an antiplatelet regimen as a means to improve patient outcomes requires further examination and larger prospective clinical trials.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Atherosclerosis; Blood Coagulation; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Inflammation; Mice; Platelet Aggregation Inhibitors; Receptor, PAR-1; Receptors, Thrombin; Risk Factors; Secondary Prevention; Thrombin; Warfarin

As chronic kidney disease (CKD) is a contraindication to the use of the new anticoagulants, the vitamin K antagonists (VKA) are still valid in patients with CKD, though their use may be harmful. During overanticoagulation, some patients can develop acute kidney injury (AKI), especially those with CKD, by obstruction of the renal tubules and Bowman's spaces by erythrocytes. In addition, VKA increase atherogenesis through vitamin K deficiency, which is essential for the carboxylation of proteins that inhibit calcification of vessels. Eventually, hemodialysed patients under VKA have an increased risk of stroke, especially those over 75 years of age. Therefore anticoagulation with VKA in patients with CKD should be carefully implemented and its monitoring more frequent than in non-CKD patients.

Topics: 4-Hydroxycoumarins; Acute Kidney Injury; Anticoagulants; Atherosclerosis; Blood Coagulation Disorders; Cerebrovascular Disorders; Coumarins; Humans; Indenes; Renal Insufficiency, Chronic; Vitamin K; Warfarin

Atrial fibrillation and severe carotid artery stenosis are the most common causes of stroke. However, several patients recognize unusual cause for their cerebral ischemia. At the beginning of the last decade after the introduction of transesophageal echocardiography (TEE) and other imaging techniques, atheromatosis of the thoracic aorta has been recognized as an important source of stroke or systemic embolism. Formerly in the pre-TEE era, this entity was included into cryptogenic strokes. Notably, aortic atheromas are found in about one quarter of patients presenting with embolic events and their grading by TEE correlates with the risk of future embolism, especially if mobile lesions or superimposed thrombi are present. Unfortunately, the diagnosis of aortic atheroma is mostly established when an embolic event has already occurred. The aim of this paper is to review the current evidence for aortic atheroma as an important independent risk factor for stroke, and to discuss the potential therapeutic options. Unfortunately, randomized studies addressing the treatment of patients with severe aortic atheroma are not yet completed. Furthermore, although warfarin and statins look promising in several retrospective series, their results are by most controversial so far. In conclusion, although the diagnostic criteria and the negative prognostic significance of aortic atheroma are almost defined, its therapeutic options are far to be clear. Therefore, clinical trials addressing this relevant pathologic condition are urgently needed.

Topics: Anticoagulants; Aorta, Thoracic; Aortic Diseases; Aspirin; Atherosclerosis; Clopidogrel; Controlled Clinical Trials as Topic; Echocardiography, Transesophageal; Fibrinolytic Agents; Follow-Up Studies; Humans; Hypolipidemic Agents; Meta-Analysis as Topic; Odds Ratio; Platelet Aggregation Inhibitors; Prognosis; Recurrence; Risk Factors; Stroke; Ticlopidine; Time Factors; Warfarin

Aortic atheromatous disease is associated with stroke in both the ambulatory and perioperative setting. In addition to atheromatous deposits, a reduction in the compliance of the aorta takes place as elastin fibers are replaced by collagen fibers. Both of these distinct processes, termed atherosclerosis, can easily be measured using transesophageal echocardiography during cardiac surgery. A review of the literature demonstrates many studies supporting the benefit of transesophageal echocardiography examination of the aorta for reducing stroke following cardiac surgery, through modification of surgical techniques. There have also been attempts by surgeons to remove atheromatous lesions from the aorta during cardiac surgery. Unfortunately, these procedures currently have a high perioperative mortality. Finally, medical therapy such as warfarin or statins may help reduce the incidence of stroke following heart surgery.

Topics: Anticoagulants; Aorta; Aortic Diseases; Atherosclerosis; Cardiac Surgical Procedures; Clinical Trials as Topic; Endarterectomy; Humans; Risk Factors; Stroke; Ultrasonography; Warfarin

Aortic arch plaques are a risk factor for ischemic stroke. Although the stroke mechanism is conceivably thromboembolic, no randomized studies have evaluated the efficacy of antithrombotic therapies in preventing recurrent events.. The relationship between arch plaques and recurrent events was studied in 516 patients with ischemic stroke who were double-blindly randomized to treatment with warfarin or aspirin as part of the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), based on the Warfarin-Aspirin Recurrent Stroke Study (WARSS). Plaque thickness and morphology were evaluated by transesophageal echocardiography. End points were recurrent ischemic stroke or death over a 2-year follow-up. Large plaques (> or =4 mm) were present in 19.6% of patients; large complex plaques (those with ulcerations or mobile components) were seen in 8.5%. During follow-up, large plaques were associated with a significantly increased risk of events (adjusted hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.04 to 4.32), especially those with complex morphology (HR, 2.55; 95 CI, 1.10 to 5.89). The risk was highest among cryptogenic stroke patients, both for large plaques (HR, 6.42; 95% CI, 1.62 to 25.46) and large complex plaques (HR, 9.50; 95% CI, 1.92 to 47.10). Event rates were similar in the warfarin and aspirin groups in the overall study population (16.4% versus 15.8%; P=0.43).. In patients with stroke, especially cryptogenic stroke, large aortic plaques remain associated with an increased risk of recurrent stroke and death at 2 years despite treatment with warfarin or aspirin. Complex plaque morphology confers a slight additional increase in risk.

Topics: Adult; Aged; Aged, 80 and over; Aorta, Thoracic; Aortic Diseases; Aspirin; Atherosclerosis; Death; Double-Blind Method; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Risk; Secondary Prevention; Stroke; Treatment Outcome; Warfarin

There are limited data on the causes and severity of subsequent stroke in patients presenting initially with TIA or stroke attributed to intracranial arterial stenosis.. We evaluated the location, type (lacunar vs nonlacunar), cause, and severity of stroke in patients who had an ischemic stroke endpoint in the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial.. Of the 569 patients enrolled in the WASID trial, 106 patients (18.6%) had an ischemic stroke during a mean follow-up of 1.8 years. Stroke occurred in the territory of the symptomatic artery in 77 (73%) of 106 patients. Among the 77 strokes in the territory, 70 (91%) were nonlacunar and 34 (44%) were disabling. Stroke out of the territory of the symptomatic artery occurred in 29 (27%) of 106 patients. Among these 29 strokes, 24 (83%) were nonlacunar, 14 (48%) were attributed to previously asymptomatic intracranial stenosis, and 9 (31%) were disabling.. Most subsequent strokes in patients with symptomatic intracranial artery stenosis are in the same territory and nonlacunar, and nearly half of the strokes in the territory are disabling. The most commonly identified cause of stroke out of the territory was a previously asymptomatic intracranial stenosis. Penetrating artery disease was responsible for a low number of strokes.

Topics: Anticoagulants; Aspirin; Atherosclerosis; Brain Ischemia; Cerebral Arteries; Cerebrovascular Disorders; Constriction, Pathologic; Double-Blind Method; Embolism; Endpoint Determination; Humans; Platelet Aggregation Inhibitors; Recurrence; Stents; Stroke; Warfarin

Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infarction, stroke, and death from cardiovascular causes. Antiplatelet drugs reduce this risk, but the role of oral anticoagulant agents in the prevention of cardiovascular complications in patients with peripheral arterial disease is unclear.. We assigned patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant agent (target international normalized ratio [INR], 2.0 to 3.0) or to antiplatelet therapy alone. The first coprimary outcome was myocardial infarction, stroke, or death from cardiovascular causes; the second coprimary outcome was myocardial infarction, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular causes.. A total of 2161 patients were randomly assigned to therapy. The mean follow-up time was 35 months. Myocardial infarction, stroke, or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy (12.2%) and in 144 of 1081 patients receiving antiplatelet therapy alone (13.3%) (relative risk, 0.92; 95% confidence interval [CI], 0.73 to 1.16; P=0.48). Myocardial infarction, stroke, severe ischemia, or death from cardiovascular causes occurred in 172 patients receiving combination therapy (15.9%) as compared with 188 patients receiving antiplatelet therapy alone (17.4%) (relative risk, 0.91; 95% CI, 0.74 to 1.12; P=0.37). Life-threatening bleeding occurred in 43 patients receiving combination therapy (4.0%) as compared with 13 patients receiving antiplatelet therapy alone (1.2%) (relative risk, 3.41; 95% CI, 1.84 to 6.35; P<0.001).. In patients with peripheral arterial disease, the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding. (ClinicalTrials.gov number, NCT00125671 [ClinicalTrials.gov].).

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Aspirin; Atherosclerosis; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Ticlopidine; Warfarin

Antithrombotic/anticoagulation effects of direct oral anticoagulants (DOACs) are dose-dependent. However, recent observations suggest that administering lower dose DOACs may better protect against all-cause mortality. We investigated whether, in patients with established atherosclerosis, DOAC dose selection would affect the risk of all-cause mortality.. We performed a structured literature research for controlled trials allowing random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy in patients with established atherosclerosis. Pooled risk ratios (RRs) of all-cause mortality in lower and higher dose DOACs versus control therapy were estimated using a random-effect model.. Atherosclerosis manifested as acute coronary syndrome (n=17,220), stable coronary (CAD) and/or peripheral artery disease (PAD) (n=27,395) or CAD associated with atrial fibrillation (n=4,510). Antithrombotic doses of rivaroxaban (2.5 mg or 5.0 mg BID) or dabigatran (50 mg, 75 mg, 110 mg, or 150 mg, BID) were tested in three trials versus single or dual antiplatelet control therapy, whereas anticoagulation doses of edoxaban (30 mg or 60 OD) were tested versus warfarin in one trial. Compared to control, patients receiving lower dose (RR 0.80, 95% CI 0.73-0.89, p<0.0001, I²=0%), but not those receiving higher dose DOACs (RR 0.95, 95% CI 0.87-1.05, p=0.3074, I²=0%), had a significant reduction of all-cause mortality. Benefit from lower dose DOACs remained after sensitivity analysis or direct comparison with higher dose DOACs (RR 0.84, 95% CI 0.76-0.93, p=0.0009, I²=0%).. Within antithrombotic/anticoagulation regimens of DOAC administration, selection of lower dose appears to protect from all-cause mortality in patients with established atherosclerosis.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Stroke; Warfarin

Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.. Female Apoe. Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.. Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Topics: Animals; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Female; Humans; Mice; Vitamin K; Warfarin

Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown.. Apolipoprotein E knockout (ApoE. There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p < .001)). No difference in mRNA content of inflammatory cytokines in muscle tissue or spleen was detected between the three groups.. These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Topics: Animals; Anticoagulants; Atherosclerosis; Collateral Circulation; Disease Models, Animal; Factor Xa Inhibitors; Fibrosis; Hindlimb; Ischemia; Mice, Inbred C57BL; Mice, Knockout, ApoE; Muscle, Skeletal; Neovascularization, Physiologic; Plaque, Atherosclerotic; Pyridines; Thiazoles; Vascular Remodeling; Warfarin

Vascular calcification is commonly observed in atherosclerosis and diabetes. The renin-angiotensin II system is associated with the regulation of arterial stiffening. The aim of this study was to examine whether the angiotensin-converting enzyme inhibitors captopril attenuates artery calcification.. The rat model of arterial calcification was established by a combination of warfarin and vitamin K1. Two weeks after the induction of arterial calcification, captopril treatment was initiated. One week after captopril treatment, aortic arteries were examined to determine the calcification morphology and the connexin 43 expression. Matrix Gla protein (MGP), receptor activator of nuclear factor-κB ligand (RANKL) and extracellular regulated protein kinase (ERK) pathways were examined.. The morphology of the calcified arteries was significantly attenuated after captopril treatment. Consistently, captopril inhibited the increased connexin 43 expression and enhanced the decreased MGP expression in calcification arteries. Furthermore, captopril enhanced the decreased SM22 expression in calcified arteries by fluorescence assay. Finally, the calcification arteries increased the p38, p-ERK and RANKL expression, which were downregulated by captopril treatment.. We concluded that captopril attenuated the increased connexin 43 expression and enhanced the MGP and SM22 expression levels, which are associated with the inactivation of p-ERK, p38 and RANKL pathways in rat aortic arteries.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Atherosclerosis; Calcium-Binding Proteins; Captopril; Connexin 43; Down-Regulation; Extracellular Matrix Proteins; Extracellular Signal-Regulated MAP Kinases; Male; Matrix Gla Protein; Microfilament Proteins; Muscle Proteins; RANK Ligand; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Up-Regulation; Vascular Calcification; Vascular Stiffness; Vitamin K 1; Warfarin

Warfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized and compared warfarin and apixaban on progression of coronary atherosclerotic plaques measured by coronary computed tomographic angiography in 66 subjects with non-valvular atrial fibrillation over the period of one-year follow up. There was significant higher total, calcified and low attenuation plaque volume in the group randomized to warfarin as compared to apixaban (all P < .05). Greater volume of total (β

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Vascular Calcification; Warfarin

Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification.. To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice.. 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators.. We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.

Topics: Animals; Anticoagulants; Aortic Valve; Aortic Valve Stenosis; Atherosclerosis; Calcinosis; Cattle; Cells, Cultured; Cyclooxygenase 2; Disease Models, Animal; Disease Progression; Factor Xa Inhibitors; Female; Male; Mice, Knockout, ApoE; Risk Assessment; Rivaroxaban; Time Factors; Vascular Calcification; Warfarin

Warfarin, a vitamin K antagonist, is associated with systemic vascular calcification. We evaluated whether rivaroxaban (a direct oral factor Xa inhibitor with no interaction with vitamin K) will slow the progression in coronary plaque volumes compared with warfarin in patients with nonvalvular atrial fibrillation using coronary computed tomography angiography.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Rivaroxaban; Warfarin

Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE(-/-) model of atherosclerosis.. A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE(-/-) mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K(1) (VK(1), 1.5 mg/g) or vitamin K(1) and warfarin (VK(1)&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.. VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE(-/-) mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.

Topics: Aged; Animals; Apolipoproteins E; Atherosclerosis; Calcinosis; Coronary Artery Disease; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Phenotype; Plaque, Atherosclerotic; Risk; Thromboembolism; Vitamin K; Warfarin

Topics: Anticoagulants; Aortic Diseases; Aspirin; Atherosclerosis; Fibrinolytic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk; Secondary Prevention; Stroke; Warfarin

Patients with atrial fibrillation (AF) on treatment with oral anticoagulants may still suffer ischemic cerebrovascular events. The aim of this study was to evaluate the risk factors for cerebral ischemic events in warfarin-treated AF patients with an International Normalized Ratios (INR) above 1.8 on admission.. In a case-control study, cases were consecutive patients with AF who were on warfarin and who were admitted to four Italian hospitals after an acute cerebrovascular ischemic event (ischemic stroke or transient ischemic attack) with an INR above 1.8. Controls were selected from a single anticoagulation clinic and were patients with AF on adequate warfarin treatment who did not suffer cerebrovascular events.. Cases were identified among 4785 consecutive patients with an ischemic cerebral event. 148 cases (3.1%, 21 with transient ischemic events and 127 with ischemic strokes) had AF and were taking warfarin with an INR above 1.8 on admission. On multivariate analysis, diabetes (OR 3.8; 95% CI 1.09-13.82, p=0.025), hyperlipidemia (OR 4.5; 95% CI 1.11-18.23, p=0.035) and carotid/vertebral atherosclerosis on ultrasound (OR 3.0; 95% CI 1.13-8.41, p=0.028) were independent predictors for ischemic cerebral events. The use of statins was inversely correlated with an ischemic event (OR 0.1; 95% CI 0.06-0.47. p=0.001).. Carotid/vertebral atherosclerosis, diabetes and hyperlipidemia are associated with an increased risk for ischemic events in patients with AF on adequate warfarin treatment. Statins significantly reduce the risk of ischemic events.

Topics: Aged; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Brain Ischemia; Case-Control Studies; Female; Humans; Hyperlipidemias; Male; Middle Aged; Multivariate Analysis; Risk; Stroke; Warfarin

Topics: Aged; Anticoagulants; Atherosclerosis; Cystitis; Diagnosis, Differential; Embolism, Cholesterol; Female; Foreign-Body Reaction; Gastrointestinal Hemorrhage; Granuloma; Hematuria; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Ischemic Attack, Transient; Risk Factors; Syndrome; Tuberculosis, Urogenital; Urinary Bladder Neoplasms; Warfarin

Instrumentation of the aorta during cardiac catheterization, resulting in peripheral embolization, is an underdiagnosed clinical entity. Such an atheromatous embolization can present in a subtle way or could be catastrophic. Isolated splenic infarction as a complication of the procedure is extreme rare. We report a 59-year-old man with risk factors for atherosclerotic vascular disease who underwent percutaneous coronary intervention and presented 3 days later with isolated splenic infarction. He was managed conservatively with heparin. Further evaluation revealed a concomitant mural thrombus in an abdominal aortic aneurysm, which could be a contributing factor along with atheroembolization from advanced atherosclerosis. Our case highlights the importance of using a right brachial or radial approach in an individual with significant atherosclerotic vascular disease and with an abdominal aortic aneurysm.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Aortic Aneurysm, Abdominal; Aspirin; Atherosclerosis; Cardiac Catheterization; Clopidogrel; Coronary Stenosis; Embolism, Cholesterol; Heparin; Humans; Infarction; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Factors; Spleen; Thrombosis; Ticlopidine; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Topics: 1-Carboxyglutamic Acid; Anticoagulants; Atherosclerosis; Calcinosis; Humans; Immunohistochemistry; Vascular Diseases; Warfarin

Inappropriate prescribing encompasses acts of commission i.e. giving drugs that are contraindicated or unsuitable, and acts of omission i.e. failure to prescribe drugs when indicated due to ignorance of evidence base or other irrational basis e.g. ageism. There are considerable published data on the prevalence of inappropriate prescribing; however, there are no recent published data on the prevalence of acts of omission. The aim of this study was to calculate the prevalence of acts of prescribing omission in a population of consecutively hospitalised elderly people.. A screening tool (screening tool to alert doctors to the right treatment acronym, START), devised from evidence-based prescribing indicators and arranged according to physiological systems was prepared and validated for identifying prescribing omissions in older adults. Data on active medical problems and prescribed medicines were collected in 600 consecutive elderly patients admitted from the community with acute illness to a teaching hospital. On identification of an omitted medication, the patient's medical records were studied to look for a valid reason for the prescribing omission.. Using the START list, we found one or more prescribing omissions in 57.9% of patients. In order of prevalence, the most common prescribing omissions were: statins in atherosclerotic disease (26%), warfarin in chronic atrial fibrillation (9.5%), anti-platelet therapy in arterial disease (7.3%) and calcium/vitamin D supplementation in symptomatic osteoporosis (6%).. Failure to prescribe appropriate medicines is a highly prevalent problem among older people presenting to hospital with acute illness. A validated screening tool (START) is one method of systematically identifying appropriate omitted medicines in clinical practice.

Topics: Age Factors; Aged; Aged, 80 and over; Atherosclerosis; Atrial Fibrillation; Calcium; Dietary Supplements; Evidence-Based Medicine; Guideline Adherence; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mass Screening; Osteoporosis; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Prevalence; Vascular Diseases; Warfarin

To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 +/- 12 years), in 25 patients with inherited thrombophilia (mean age 40 +/- 10 years), and in 34 normal controls (mean age 38 +/- 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P = 0.01), at the bifurcation (P = 0.003), and at the internal carotid (P = 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.

Topics: Adult; Age Factors; Anticoagulants; Antiphospholipid Syndrome; Atherosclerosis; Carotid Arteries; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Risk Factors; Thrombophilia; Tunica Intima; Tunica Media; Ultrasonography; Warfarin