Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.     

Underutilization of warfarin in older persons with chronic nonvalvular atrial fibrillation at high risk for developing stroke

OBJECTIVE: To investigate the prevalence of the use of warfarin to maintain an international normalized ratio (INR) between 2.0 and 3.0 in older persons with chronic nonvalvular atrial fibrillation (AF), and without contraindications to warfarin, who are at high risk for developing new thromboembolic (TE) stroke. DESIGN: A retrospective analysis of charts from all older persons seen during 1997 at an academic hospital-based geriatrics practice. SETTING: An academic hospital-based geriatrics practice staffed by fellows in a geriatrics training program and full-time faculty geriatricians. PATIENTS: Three hundred eighty men and 1183 women, mean age 80+/-8 years (range 59 to 103 years), were included in the study. MEASUREMENTS AND MAIN RESULTS: Of 1563 persons studied, 141 (9%) had chronic nonvalvular AF. Of 141 persons with AF, 127 (90%) were at high risk for developing TE stroke because they had either a previous thromboembolism, congestive heart failure, or echocardiographic evidence of abnormal left ventricular systolic function; a systolic blood pressure >160 mm Hg; or they were women older than 75 years of age. Of the 127 persons with AF at high risk for developing TE stroke, three (2%) had contraindications to warfarin. Of the 124 persons with AF at high risk for developing TE stroke and no contraindications to warfarin, 61 (49%) were treated with warfarin to maintain an INR between 2.0 and 3.0, and 45 (36%) were treated with 325 mg aspirin daily. Of 14 persons with AF at low risk for developing TE stroke, one (7%) was treated with warfarin to maintain an INR between 2.0 and 3.0, and six (43%) were treated with 325 mg aspirin daily. CONCLUSIONS: Warfarin is underutilized as a treatment to maintain an INR between 2.0 and 3.0 in older persons with chronic nonvalvular AF at high risk for developing TE stroke.     

Genotoxicity of hydrazino-phtalazine antihypertensive drugs assessed by an in vitro micronucleus assay

Oral anticoagulant therapy is effective antithrombotic treatment for several indications. The results of prothrombin time monitoring should be reported as the International Normalized Ratio (INR). An INR of 2 to 3 is the recommended therapeutic range for all indications except for the prevention of systemic embolism in patients with mechanical heart valves and for the long-term treatment of patients with myocardial infarction, for whom an INR range of 2.5 to 3.5 is recommended. Oral anticoagulant therapy with warfarin sodium is the preferred approach for preventing stroke in most patients with atrial fibrillation. The available data suggest that warfarin is more effective than aspirin. Aspirin, 325 mg/d, is indicated for patients in whom warfarin is contraindicated or in patients less than 75 years of age who are at low risk for stroke because risk factors are absent. In patients 75 years of age or more, close monitoring of warfarin treatment is prudent to avoid major bleeding due to poor anticoagulant control. In selected patients, patient-self-monitoring and adjustment of warfarin treatment using a portable prothrombin time monitor may be effective and safe.     

Combined warfarin and antiplatelet therapy after St. Jude Medical valve replacement for mitral valve disease

OBJECTIVES: The clinical effect of combined warfarin and antiplatelet therapy on the incidence of stroke and postoperative complications after mitral (plus aortic) valve replacement was studied and compared with that observed with warfarin therapy alone. BACKGROUND: It has been reported that combined warfarin and antiplatelet therapy may be effective but may be associated with an increased hemorrhagic risk. Therefore, definite benefits of the treatment in patients with an implanted prosthetic valve have not been clearly documented. METHODS: Between January 1980 and December 1992, 195 patients with a St. Jude Medical valve at the mitral (plus aortic) position were assigned to receive treatment with either warfarin alone (125 patients) or warfarin plus antiplatelet agents (70 patients), such as dipyridamole (150 or 300 mg daily, 14 patients) or ticlopidine (200 or 400 mg daily, 56 patients). A minimal dose of aspirin (10 to 40 mg) was added (29 patients) if the maximal platelet aggregation rate by collagen was not reduced. The target thrombotest level was 10% to 20%. RESULTS: The two treatment groups were similar with regard to gender and age distribution. The number of patients with atrial fibrillation, left atrial thrombus, history of previous stroke, simultaneous aortic valve operation and previously performed valve procedures were comparable in the two groups. Actuarial survival rate at 10 years was 98.3 +/- 1.7% (mean +/- SD) in the warfarin plus antiplatelet group and 90.3 +/- 3.2% in the warfarin group (p < 0.05 at 1 and 9 to 12 years). The actuarial stroke-free rate at 10 years was 95.3 +/- 3.4% and 84.3 +/- 3.8%, respectively (p < 0.05 by the generalized Wilcoxon test). The actuarial complication-free rate at 10 years was 89.4 +/- 4.3% and 67.9 +/- 4.8%, respectively (p < 0.05 by the generalized Wilcoxon test). No hemorrhagic complications were seen in the warfarin plus antiplatelet group. CONCLUSIONS: The results strongly indicate the effectiveness and safety of combined warfarin plus antiplatelet treatment after St. Jude Medical valve replacement for mitral (plus aortic) valve disease.     

The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life

BACKGROUND: Because most strokes cause neurological impairment rather than death, stroke prophylaxis may improve quality of life more than length of life. Thus, an understanding of how stroke and stroke prophylaxis affect quality of life is central to clinical decision making for many patients. METHODS: We elicited quality-of-life estimates, known as utilities, for 3 degrees of severity of anticipated stroke-mild, moderate, and major- and for stroke prophylaxis with either warfarin sodium or aspirin therapy. We used the time tradeoff and standard gamble methods to elicit these utilities from 83 patients who had atrial fibrillation. RESULTS: Seventy patients completed the interview successfully. Their utilities for stroke ranged from worse than death (< 0) to as good as current health (1.0). The median utilities for mild, moderate, and major stroke were 0.94, 0.07, and 0.0, respectively. Although the median utilities decreased with increasing severity of stroke (P < .001), there was high interpatient variability within each degree of stroke severity. For example, 7 subjects (10%) rated a major stroke above 0.5, while 58 subjects (83%) rated it as equal to or worse than death. In contrast to the stroke utilities, the median utilities for warfarin and aspirin therapy were high-0.997 and 1.0, respectively. However, the interpatient variability for warfarin therapy was also important: 11 patients (16%) with atrial fibrillation rated the utility of warfarin therapy so low that their quality-adjusted life expectancy would be greater with aspirin. CONCLUSION: Patients' utilities for stroke prophylaxis and anticipated stroke vary substantially. Many patients view the quality of life with major stroke as tantamount to or worse than death. These findings highlight the relevance of incorporating patient preferences when choosing stroke prophylaxis.     

Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators

The Stroke Prevention in Atrial Fibrillation II study compared the efficacy and safety of aspirin and warfarin in patients with atrial fibrillation. Three neurologists, blinded to patient therapy, categorized the pathophysiology of ischemic strokes that occurred in the trial based on predetermined clinical criteria. Upon analyzing the patients being treated with these two drugs, warfarin proved significantly more effective than aspirin in preventing cardioembolic strokes (p = 0.005) and strokes of uncertain pathophysiology (p = 0.01). There was no significant difference in the efficacy for prevention of noncardioembolic strokes.     

Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment

OBJECTIVE: To determine whether chronic atrial fibrillation is associated with abnormalities in plasma fibrinogen, von Willebrand factor (vWF) (a marker of endothelial disturbance), or fibrin D- dimer (a measure of fibrin turnover); and if so, whether such levels are related to haemodynamic disturbance (enlarged left atrium, poor left ventricular function) or existing treatment with warfarin or aspirin. To investigate the effects of introducing warfarin in patients with atrial fibrillation on fibrinogen and D- dimer levels. DESIGN: Cross sectional population sample controlled study and longitudinal study of patients undergoing anticoagulation. SETTING: District general hospital. SUBJECTS: 87 patients (44 men and 43 women of mean (SEM) age 63.0 (1.0)) with chronic atrial fibrillation. At the time of the study, 37 were taking no antithrombotic medication (group 1), 31 were taking warfarin (including two on warfarin and aspirin) (group 2) and 19 were taking aspirin alone (group 3). They were compared with 158 population controls from a random population sample (the second Glasgow monitoring trends and determinants in cardiovascular disease study). As part of clinical treatment warfarin was introduced in 20 patients with chronic atrial fibrillation (14 men and six women of mean (SEM) (range) age 63.9 (2.35 (32-74) years). RESULTS: Plasma fibrinogen remained significantly increased in patients of group 1 (no antithrombotic medication) compared with that of the population controls (median difference 1.23 g/l; 95% confidence interval (CI) 0.88 to 1.62, P < 0.0001). There was also a significant increase in plasma D-dimer levels (median difference 77 ng/ml; 95% CI 38 to 122, P < 0.01) and vWF (median difference 63 IU/dl; 95% CI 38 to 89, P < 0.0001). There was no significant difference in plasma fibrinogen (median difference 0.14 g/l; 95% CI -0.44 to 0.77, P = 0.65) or vWF (median difference 3.5 IU/dl; 95% CI - 41 to 41, P = not significant in patients of group 2 (warfarin treatment) compared with that of patients in group 1. Levels of D-dimer were significantly lower in group 2 (median difference 90 ng/ml, 95% CI 39 to 150, P < 0.0001) than in group 1. There were no significant differences in plasma fibrinogen (median difference 0.08 g/l; 95% CI - 0.52 to 0.77, P = 0.73), D-dimer (median difference - 34 ng/ml; 95% CI - 114 to 21.0, P = 0.25), or vWF (median difference 2%; 95% CI - 35 to 41, P = not significant) levels between patients of groups 1 and 3. There were no significant correlations between the coagulation indices and left atrial volume or ventricular function. There was a significant positive correlation between plasma fibrin D-dimer and vWF levels in patients of groups 1 and 3 (r = 0.52, P < 0.001). There was a significant reduction in median plasma fibrin D-dimer levels at 2 months after the introduction of warfarin (181 ng/ml v 80 ng/ml, P < 0.001), but no effect on plasma fibrinogen. CONCLUSIONS: Increased median plasma fibrinogen and vWF levels were found in patients with chronic atrial fibrillation. Plasma D-dimer levels were also increased in patients with chronic atrial fibrillation not receiving warfarin, suggesting increased intravascular thrombogenesis in such patients. Introduction of warfarin normalised circulating fibrin D- dimer levels, suggesting that warfarin treatment was effective in preventing excessive fibrin turnover, consistent with the antithrombotic effects of warfarin. These results suggest three possible thrombotic markers to assess patients with atrial fibrillation who are at high risk of thrombogenesis; D-dimer also merits assessment as a measure of reduction in thrombotic risk in patients receiving warfarin.     

Incidence and characteristics of fall-related emergency department visits

BACKGROUND: Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies. METHODS AND RESULTS: In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004). CONCLUSIONS: Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.     

Cost-effectiveness of preference-based antithrombotic therapy for patients with nonvalvular atrial fibrillation

BACKGROUND AND PURPOSE: Recent atrial fibrillation guidelines recommend the incorporation of patient preferences into the selection of antithrombotic therapy. However, no trial has examined how incorporating such preferences would affect quality-adjusted survival or medical expenditure. We compared 10-year projections of quality-adjusted survival and medical expenditure associated with two atrial fibrillation treatment strategies: warfarin-for-all therapy versus preference-based therapy. The preference-based strategy prescribed whichever antithrombotic therapy, warfarin or aspirin, had the greater projected quality-adjusted survival. METHODS: We used decision analysis stratified by the number of stroke risk factors (history of stroke, transient ischemic attack, hypertension, diabetes, or heart disease). The base case focused on compliant 65-year-old patients who had nonvalvular atrial fibrillation and no contraindications to antithrombotic therapy. RESULTS: In patients whose only risk factor for stroke was atrial fibrillation, preference-based therapy improved projected quality-adjusted survival by 0.05 quality-adjusted life year (QALY) and saved $670. For patients who had atrial fibrillation and one additional risk factor for stroke, preference-based therapy improved quality-adjusted survival by 0.02 QALY and saved $90. In patients who had atrial fibrillation and multiple additional risk factors for stroke, preference-based therapy increased medical expenditures and did not improve quality-adjusted survival substantially. The benefits of preference-flexible therapy arose from the minority of patients who would have had a longer quality-adjusted survival if they had been prescribed aspirin rather than warfarin. CONCLUSIONS: As do risks of stroke and of hemorrhage, patients' preferences help to determine which antithrombotic therapy is optimal. Preference-based treatment should improve quality-adjusted survival and reduce medical expenditure in patients who have nonvalvular atrial fibrillation and not more than one additional risk factor for stroke.     

Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin

BACKGROUND: Patients receiving long-term warfarin frequently develop asymptomatic excessive prolongation of their international normalized ratio (INR) results. The most appropriate management strategy in these patients is unknown. This prospective cohort study was designed to address whether 1 mg of oral vitamin K effectively reduces the INR value of such patients. METHODS: A prospective cohort study was performed in two tertiary care teaching hospitals, in which 62 patients receiving warfarin who had INR values between 4.5 and 10.0 received 1 mg of oral vitamin K. All patients had daily INR values and clinical assessments performed. RESULTS: The mean INR value at presentation was 5.79 (95% confidence interval (CI) 5.48 to 6.09, range 4.5 to 9.5). Sixteen hours after receiving the 1 mg of oral vitamin K, the mean INR was 2.86 (95% CI 2.50 to 3.23). On the second and third days after vitamin K, the mean INR values were 2.20 (1.93 to 2.47) and 2.14 (1.85 to 2.44), respectively. No adverse events or bleeding complications were observed. In three patients (6%) the INR value rose between the time of vitamin K administration and the next INR determination; two patients received a further 2 mg dose of subcutaneous vitamin K. CONCLUSIONS: In patients receiving warfarin who have asymptomatic excessive prolongations in their INR results, 1 mg of oral vitamin K reliably reduces the INR to the therapeutic range within 24 h. This therapy is more convenient, less expensive, and might be safer than parenteral vitamin K. Thus, it should be considered in all non-bleeding patients receiving warfarin, who present with INR results of 4.5 to 9.5.     

Warfarin, aspirin and microembolic signals in the acute phase of stroke in a patient with mechanical heart valves

We report the case of a 54-year-old woman, with atrial fibrillation and mechanical heart valves, who suffered a left-hemispheric stroke while she was under warfarin. Daily bilateral simultaneous transcranial Doppler monitoring of the middle cerebral arteries showed the presence of microembolic signals (MES), whose number remained unchanged after adding aspirin 100 mg daily. We conclude that anticoagulant plus antiplatelet therapy does not influence the number of MES in the acute phase of stroke in patients with prosthetic heart valves, suggesting the gaseous origin of MES in these patients.     

The appropriate lower limit for the percent free prostate-specific antigen reflex range

Currently available protocols for induction of warfarin anticoagulation employ initial doses of 10 mg and are best suited to in-patient use. However, with the increasing number of elderly patients with atrial fibrillation requiring anticoagulation, there is a need for a less intense regimen which could be used for out-patients. We have established such a regimen and report on its prospective evaluation in 3 7 patients referred for out-patient initiation of warfarin, and a non-randomized comparison with 37 in-patients, with similar diagnoses, commenced on a traditional warfarin protocol. After exclusion of five patients on amiodarone, all of whom experienced supratherapeutic International Normalized Ratio (INR) results, the new out-patient regimen, employing an initial 5 mg dose, resulted in a lower maximum INR during the first 21 d therapy (median 2.9 v 4.0; P = 0.0001) and fewer INRs >4.5 (2/36 v 9/33) compared to the traditional 10 mg regimen. Time to reach stable anticoagulation was similar with each regimen; however, the 5 mg regimen gave a more accurate prediction of maintenance dose (correlation coefficient for predicted versus actual maintenance dose, r = 0.985). In comparison to a traditional 10 mg protocol, the proposed 5 mg warfarin induction regimen proved both safer and more reliable for initiation of prophylactic anticoagulation in patients with atrial fibrillation.     

The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines

The English-language literature was systematically reviewed to clarify the role of combination antithrombotic therapy with warfarin and acetylsalicylic acid (ASA) versus monotherapy with either agent, including data from several recently published trials. Sixteen published studies with evaluable efficacy and/or safety data were identified. For patients with prosthetic heart valves at high risk of thromboembolism, combined warfarin and ASA therapy may be beneficial compared with warfarin alone. Combination therapy may also be used for primary prevention in patients at high risk for ischemic heart disease, although the expected benefits are small. Evidence does not support the use of combined antithrombotic therapy in patients with established ischemic heart disease, ischemic stroke, coronary artery bypass grafts or atrial fibrillation. Combination therapy is associated with an increased risk of minor and major bleeding. The highest dose of ASA that can be recommended in combination with warfarin is 100 mg daily.     

Allergic rhinitis and asthma as probable clinical manifestations of the same process

Acetylsalicylic acid (ASA) alone (at least 30 mg per day) in post-cerebral ischaemia patients reduces the relative risk of further vascular events by 13% compared with placebo. A meta-analysis of all studies shows that the combination of ASA with dipyridamole reduces the relative risk by 16% (95% confidence interval: 5-26%) compared with ASA alone, but confirmation by a major trial appears desirable, because of discrepant results of a recent trial and 4 previous ones. Clopidogrel might reduce the risk by 7% compared with ASA alone, but this drug is expected to be expensive. Anticoagulation therapy with an international normalized ratio (INR) of 2.0-4.0 is particularly efficacious for secondary prevention in patients with atrial fibrillation, but anticoagulation therapy with an INR of 3.0-4.5 is not safe in secondary prevention of cerebral ischaemia of presumed arterial origin. Finally, not all atherosclerotic vascular diseases are identical from the therapeutic point of view; the effect of treatment depends in part on the clinical manifestation form.     

Cost-effectiveness of therapies for patients with nonvalvular atrial fibrillation

BACKGROUND: The most appropriate treatment(s) for patients with atrial fibrillation remains uncertain. OBJECTIVE: To examine the cost-effectiveness of anti-thrombotic and antiarrhythmic treatment strategies for atrial fibrillation. METHODS: We performed decision and cost-effectiveness analyses using a Markov state transition model. We gathered data from the English-language literature using MEDLINE searches and bibliographies from selected articles. We obtained financial data from nationwide physician-fee references, a medical center's cost accounting system, and one of New England's larger managed care organizations. We examined strategies that included combinations of cardioversion, antiarrhythmic therapy with quinidine, sotalol hydrochloride, or amiodarone, and anticoagulant or antiplatelet therapy. RESULTS: For a 65-year-old man with nonvalvular atrial fibrillation, any intervention results in a significant gain in quality-adjusted life years (QALYs) compared with no specific therapy. Use of aspirin results in the largest incremental gain (1.2 QALYs). Cardioversion followed by the use of amiodarone and warfarin together is the most effective strategy, yielding a gain of 2.3 QALYs compared with no specific therapy. The marginal cost-effectiveness ratios of cardioversion followed by aspirin, with or without amiodarone, are $33800 per QALY and $10800 per QALY, respectively. Cardioversion followed by amiodarone and warfarin has a marginal cost-effectiveness ratio of $92400 per QALY compared with amiodarone and aspirin. Strategies that include cardioversion followed by either quinidine or sotalol are both more expensive and less effective than competing strategies. CONCLUSIONS: Cardioversion of patients with nonvalvular atrial fibrillation followed by the use of aspirin alone or with amiodarone has a reasonable marginal cost-effectiveness ratio. While cardioversion followed by the use of amiodarone and warfarin results in the greatest gain in quality-adjusted life expectancy, it is expensive (ie, has a high marginal cost-effectiveness ratio) compared with aspirin and amiodarone. Finally, for patients who are bothered little by symptoms of atrial fibrillation, cardioversion followed by either aspirin or warfarin without subsequent antiarrhythmic therapy is the treatment of choice.     

Neuropathology in the neurosciences. A system in transition

BACKGROUND: Despite the use of warfarin, major systemic embolism remains an important complication in patients with heart-valve replacement. Although the addition of antiplatelet agents has the potential to reduce this complication, their efficacy and safety when given in combination with warfarin are uncertain. METHODS: In a randomized, double-blind, placebo-controlled trial, we assessed the efficacy and safety of adding aspirin (100 mg per day) to warfarin treatment (target international normalized ratio, 3.0 to 4.5) in 370 patients with mechanical heart valves or with tissue valves plus atrial fibrillation or a history of thromboembolism. RESULTS: A total of 186 patients were randomly assigned to aspirin and 184 to placebo, and they were followed for up to 4 years (average, 2.5). Major systemic embolism or death from vascular causes occurred in 6 aspirin-treated patients (1.9 percent per year) and 24 placebo-treated patients (8.5 percent per year) (risk reduction with aspirin, 77 percent; 95 percent confidence interval, 44 to 91 percent; P < 0.001). Major systemic embolism, nonfatal intracranial hemorrhage, or death from hemorrhage or vascular causes occurred in 12 patients assigned to aspirin (3.9 percent per year) and 28 patients assigned to placebo (9.9 percent per year) (risk reduction, 61 per cent; 95 percent confidence interval, 24 to 80 percent; P = 0.005); major systemic embolism or death from any cause occurred in 13 patients (4.2 percent) and 33 patients (11.7 percent), respectively (risk reduction, 65 percent; 95 percent confidence interval, 33 to 82 percent; P < 0.001); and death from all causes occurred in 9 patients (2.8 percent) and 22 patients (7.4 percent), respectively (risk reduction, 63 percent; 95 percent confidence interval, 19 to 83 percent; P = 0.01). Bleeding occurred in 71 patients in the aspirin group (35.0 percent), as compared with 49 patients in the placebo group (22.0 percent) (increase in risk, 55 percent; 95 percent confidence interval, 8 to 124 percent; P = 0.02); major bleeding occurred in 24 and 19 patients, respectively (increase in risk, 27 percent; 95 percent confidence interval, -30 to 132 percent; P = 0.43). CONCLUSIONS: In patients with mechanical heart valves and high-risk patients with prosthetic tissue valves, the addition of aspirin to warfarin therapy reduced mortality, particularly mortality from vascular causes, together with major systemic embolism. Although there was some increase in bleeding, the risk of the combined treatment was more than offset by the considerable benefit.     

Oncocytic cancers of the thyroid. Hürthle cell cancers

Nonvalvular atrial fibrillation is a frequent finding in elderly patients; the risk of thromboembolic complications is comparable to that reported in patients with rheumatic atrial fibrillation. Recently, 6 multicenter clinical trials (5 primary prevention, 1 secondary prevention trail) have been published which demonstrate equivocally that oral anticoagulation therapy significantly reduces the embolic risk in patients with nonvalvular atrial fibrillation by about 67% to 87%. The target INR of anticoagulation with warfarin in 2 of these trials was 1.4 to 2.8 ("low-dose" warfarin); interestingly, the magnitude of risk reduction was similar to these 2 studies with "low-dose" warfarin as it has been reported by the others using full-dose warfarin with an INR target between 2.0 and 4.5. Side effects of oral anticoagulation (severe bleeding complications) were low in these trials. Thus, the benefit-risk ratio in these 6 clinical trials encourage the use of oral anticoagulation in patients with nonvalvular atrial fibrillation. It will be a challenge to transfer these results to clinical practice, and to define in more detail the risk-benefit ratios for subgroups of patients with atrial fibrillation, e.g. patients > 75 years of age, or patients with "lone" or paroxysmal atrial fibrillation. It is well established that patients with chronic atrial fibrillation undergoing medical or DC-cardioversion are at risk for thromboembolic complications. In previous studies, this risk appears to be in the range of 2% without concomitant anticoagulation, but only 0.33% in those patients with concomitant anticoagulation. Thus, it is widely accepted that patients should be anticoagulated for at least 2 weeks prior and after planned cardioversion. Recently, an alternative concept has been proposed omitting anticoagulation before cardioversion; instead, transesophageal echocardiography is used to exclude intracardiac thrombi. Because it is known that mechanical function of the left atrium and appendage is still impaired after cardioversion, this concept of echocardiographic-guided cardioversion does not assign the necessity of anticoagulation at the day of cardioversion, and 2 weeks afterwards. The safety aspects of this concept of echocardiographic-guided cardioversion is under current investigation.     

Antithrombotic therapy prescribed for patients with non-rheumatic atrial fibrillation

Patients with non-rheumatic atrial fibrillation have a fivefold increased risk of stroke. Warfarin reduces this risk by approximately two thirds, but evidence for benefit from aspirin is less compelling. We assessed whether our current practice reflects the message of the trials. In a retrospective case record study we reviewed notes of 131 patients with atrial fibrillation (AF), mean age 79 (range 53-95) years, admitted to a medical unit (72) or geriatric assessment unit (59). Thirty-two patients had paroxysmal AF. Of 115 patients with nonrheumatic AF, 36 (31%) had one or more recorded contraindication to anti-coagulation. Although 79 patients (69%) had no recorded contraindication to warfarin, only 2 took warfarin and 15 aspirin prior to admission. Ten patients commenced warfarin and 8 aspirin before discharge. Thirty-nine patients (53%) without contraindication, were discharged without antithrombotic therapy. Despite evidence to support anticoagulating patients with non-rheumatic AF, this rarely occurs.