Atrial fibrillation and anticoagulation in patients with permanent pacemakers: implications for stroke prevention

Several large prospective randomized trials have demonstrated that anticoagulation with warfarin reduces the risk of thromboembolic stroke in high risk patients with chronic AF by approximately 70%. Large numbers of patients with permanent pacemakers have AF, and anticoagulation rates in this population have not been described. In a prospective analysis of 110 consecutive patients attending the pacemaker clinic of a large university hospital we assessed the number of patients with AF and the proportion of these patients who were receiving anticoagulation to prevent thromboembolic stroke. Where necessary, temporary pacemaker reprogramming to low ventricular rates was utilized to facilitate the diagnosis of AF. Fifty-three of the 110 patients (48%) were diagnosed with AF, all of whom (100%) had accepted high risk factors for thromboembolic stroke. Only eight of the 53 (15%) had been anticoagulated with warfarin. Thirty-six of the 53 patients (68%) diagnosed with AF had no prior documented diagnosis of chronic AF, and the majority had no symptoms suggesting AF. A single lead II ECG was insufficient in 67 of the 110 patients (61%) to diagnose the underlying atrial rhythm; the remainder required 12-lead ECGs or temporary pacemaker reprogramming to low ventricular rates to diagnose the underlying atrial rhythm. AF is common in patients with permanent pacemakers. It is commonly asymptomatic, and anticoagulation is markedly underutilized in reducing stroke risk in these patients. Attention to the possibility of AF in paced patients should allow prompt diagnosis and allow both the initiation of anticoagulation in order to reduce thromboembolic stroke risk and consideration for cardioversion of AF to sinus rhythm.     

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.     

A counterdefensive strategy of plant viruses: suppression of posttranscriptional gene silencing

Anticoagulants have been used in patients with acute ischemic stroke to limit infarct volume and to prevent reinfarction and thrombotic complications like deep venous thrombosis. Three important randomized trials of anticoagulants have been reported recently. One trial showed that nadroparin reduced the percentage of patients with poor outcome at 6 months. One unblinded trial of subcutaneous unfractionated heparin showed that heparin reduced the rate of early recurrent stroke, but this benefit was offset by an increase in hemorrhages. A trial of the heparinoid ORG 10172 showed no efficacy overall at 3 months, although there was an increase in patients with very favorable outcomes at 7 days. The defibrinogenating agent ancrod has shown promise in a series of small clinical trials, but efficacy has not been established. There are no reliable data on the use of antithrombotic agents to prevent reocclusion after thrombolytic therapy. Anticoagulants are generally recommended in patients with cerebral venous thrombosis, but the recommendation is supported by only one small and methodologically limited trial.     

Quantitative SPECT uptake of 99mTc-dimercaptosuccinic acid by the kidneys in children

Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8% per year (95% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7% per year (95% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.     

Underutilization of antithrombotic therapy in elderly rural patients with atrial fibrillation

BACKGROUND: Antithrombotic agents are underutilized in elderly patients with atrial fibrillation. In a peer-review audit of antithrombotic use in Missouri, rural patients were given antithrombotic therapy less often than rural patients for unclear reasons. METHODS AND RESULTS: The charts of 597 hospitalized Medicare patients discharged between October 1, 1993, and December 31, 1994, from urban and rural hospitals in Missouri were reviewed. In addition to antithrombotic therapy prescribed at the time of discharge, patient and physician information, relative contraindications to antithrombotic therapy, and risk factors for stroke were identified. Rural and urban patients were similar in terms of age, sex, and risk factors for stroke. At least one stroke risk factor was noted in 87% of rural patients and in 84% of urban patients. Urban patients were more likely to have a relative contraindication to antithrombotic therapy compared with rural patients (66% vs 54%, P =.04) but received antithrombotic therapy more often (58% vs 47%, P =.02). Cardiologists prescribed antithrombotic therapy significantly more often than noncardiologists (69% vs 52%, P =.003). CONCLUSIONS: Elderly rural patients with atrial fibrillation receive antithrombotic therapy less frequently than urban patients despite having a similar high-risk profile and fewer relative contraindications. Primary care physicians prescribe antithrombotic therapy less often than cardiologists, which is one of the reasons for this underutilization.     

CD34+-enriched donor lymphocyte infusions in a case of pure red cell aplasia and late graft failure after major ABO-incompatible bone marrow transplantation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Increased life expectancy will result in a higher prevalence of AF. Treatment of AF constitutes a persistent medical dilemma. Different multicenter trials have confirmed that oral anticoagulant therapy is the best choice for the prevention of systemic embolism. It must be recognized, however, that the incidence of systemic embolism in patients with AF varies according to the presence and type of underlying heart disease. Advanced age increases the risk of emboli in patients with AF. At the same time, older patients have a higher risk of hemorrhage when treated with oral anticoagulants. Thus, careful titrated individual oral anticoagulant therapy targeted to a safe and effective INR must be considered in patients with AF. Another dilemma in AF patients is the convenience of restoring sinus rhythm and indicating permanent antiarrhythmic therapy versus the alternative of heart rate control plus oral anticoagulants. Several multicenter trials now in progress have addressed this issue and most likely will answer these questions. Identification of patients with paroxysmal AF and risk of systemic embolism constitutes another dilemma, since only a small proportion of these patients evolve to chronic arrhythmia. Advanced age, history of hypertension and left atrial enlargement in 2D Echo are well recognized risk factors for embolism in patients with non valvular paroxysmal AF. A history of previous embolism constitutes another risk factor and supports the hypothesis that AF may activate systemic coagulation factors and left atrial thrombus formation in some patients.     

Pretherapy dental status of patients with malignant conditions of the head and neck

Atrial fibrillation (AF) is a common arrhythmia in elderly persons and a common cause of embolic stroke. Most studies of the prevalence and correlates of AF have used selected, hospital-based populations. The Cardiovascular Health Study is a population-based, longitudinal study of risk factors for coronary artery disease and stroke in 5,201 men and women aged > or = 65 years. AF was diagnosed in 4.8% of women and in 6.2% of men at the baseline examination, and prevalence was strongly associated with advanced age in women. Prevalence of AF was 9.1% in men and women with clinical cardiovascular disease, 4.6% in patients with evidence of subclinical but no clinical cardiovascular disease, and only 1.6% in subjects with neither clinical nor subclinical cardiovascular disease. A history of congestive heart failure, valvular heart disease and stroke, echocardiographic evidence of enlarged left atrial dimension, abnormal mitral or aortic valve function, treated systemic hypertension, and advanced age were independently associated with the prevalence of AF. The low prevalence of AF in the absence of clinical and subclinical cardiovascular disease calls into question the existence and clinical usefulness of the concept of so-called "lone atrial fibrillation" in the elderly.     

Diagnosis and treatment of cerebrovascular accidents of cardioembolic origin

Compared to the normal population, patients with atrial fibrillation are at a significantly enhanced risk for cerebrovascular insults, in particular when the fibrillation is of recent occurrence, chronic rather than paroxysmal, and when it is associated with cardiopathy. Several studies have documented the efficacy of anticoagulation in prevention of cerebrovascular insults. Aspirin may be a valid alternative in young patients without cardiopathy; however, anticoagulation is more effective in patients which have experienced thromboembolism. In elderly patients (over 75 years) the situation is unclear, because the favorable effects of anticoagulation are offset by an increased risk for intracerebral hemorrhage. The treatment must thus be individualized by assessment of a risk/benefit ratio.     

Preventing stroke in atrial fibrillation

Atrial fibrillation, a common cardiac arrhythmia, is now recognized as a powerful risk factor for stroke. Previously, atrial fibrillation was thought to predispose persons to stroke only in the presence of rheumatic heart disease with mitral stenosis. The significant impact of nonvalvular atrial fibrillation on stroke incidence, recurrence and mortality was not fully appreciated. A series of clinical trials have confirmed that a five-fold increase in stroke incidence occurs in patients with atrial fibrillation, and that warfarin anticoagulation is efficacious in stroke prevention. This anticoagulation benefit was achieved with an acceptably low risk of serious hemorrhage.     

Auricular fibrillation, systemic embolism and anticoagulant treatment

The risk of arterial embolism, specially cerebral, in patients with mitral stenosis associated atrial fibrillation is seventeen fold greater than that of the general population and five fold greater than that of non rheumatic atrial fibrillation. The usefulness of oral anticoagulant therapy in patients with atrial fibrillation and mitral stenosis is clear. In patients with non rheumatic atrial fibrillation, the controversy about its usefulness has been cleared with five recent reports showing a significant benefit or oral anticoagulation. We believe that these results may be applied to the routine management of these patients provided an adequate patient selection, consideration of contraindications and the use of a low anticoagulation range. Aspirin effectiveness in these patients is unsettled. One study showed benefits of 375 mg/day in patients younger than 75 years. The embolic risk in patients with atrial fibrillation must be stratified. High risk patients require the use of oral anticoagulation with an INR range between 3 and 4.5; those with medium risk require an INR between 2 and 3 and in some, aspirin use may be an alternative. When electrical cardioversion is indicated, oral anticoagulation must be used when atrial fibrillation has lasted for more than two days. In these cases, it is advisable to postpone cardioversion for three weeks after oral coagulation has started and to maintain this treatment for 3 or 4 additional weeks after cardioversion.     

Cerebral embolism in elderly patients with atrial fibrillation

Novalvular (nonrheumatic) atrial fibrillation (NVAF) is the most common cardiac condition associated with presumed embolic stroke, accounting for approximately half of the cardiogenic embolic infarctions. Of autopsied stroke patients in the Tokyo Metropolitan Geriatric Hospital, cerebral infarction was found in 75%, intracranial hemorrhage in 19%, and coexisting cerebral hemorrhage and cerebral infarction in 6%. Twenty-eight percent of the cerebral infarctions were embolic infarctions of cardiac origin, 56% of which were caused by NVAF. The incidence of cardiogenic brain embolism ranged from 6 to 23% of the ischemic strokes, and NVAF is the most frequent substrate for brain embolism. Atrial fibrillation increases in its incidence with increasing age. Chronic AF was observed in 10%, and paroxysmal AF in 7% of the autopsied elderly patients. Most of them were nonrheumatic AF. Twenty-two percent of the AF patients had large cerebral infarction, and 15% had medium-sized cortical infarction at the autopsy. NVAF is a very important cause of fatal massive cerebral infarction in the elderly. Of 56 patients with fatal massive cerebral infarction who died within 2 weeks after the strokes, 25 (45%) had embolic stroke associated with NVAF. Anticoagulant therapy prevents recurrent cerebral embolism of cardiac origin. The proper time to initiate anticoagulant therapy following cardiac brain embolism is controversial. Immediate initiation of anticoagulant therapy can reduce the early recurrence, but can result in secondary brain hemorrhage or hemorrhatic transformation. Patients with NVAF may have a lower risk of recurrence during the first 2 to 4 weeks following the initial embolic stroke compared with other cardioembolic sources. Cerebral embolism with NVAF can recur during a long period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transesophageal echocardiography to assess embolic risk in patients with atrial fibrillation. ELAT Study Group. Embolism in Left Atrial Thrombi

BACKGROUND: Transesophageal echocardiography visualizes the left atrium and its appendage, thrombi, and spontaneous echocardiographic contrast. OBJECTIVE: To assess the association of transesophageal echocardiographic characteristics with stroke or embolism in atrial fibrillation. DESIGN: Multicenter observational follow-up study. SETTING: Hospitals in Austria and Slovakia. PATIENTS: 409 outpatients with nonrheumatic atrial fibrillation and without recent stroke. INTERVENTION: Patients with thrombi received anticoagulation, and patients without thrombi received aspirin. MEASUREMENTS: Primary events were stroke or embolism. Secondary events were death not caused by stroke or embolism and need for anticoagulation. RESULTS: In the left atrium or left atrial appendage, 10 patients (2.5%) had thrombi and 47 (12%) had spontaneous echocardiographic contrast. The appendage had a mean (+/- SD) length of 44+/-10 mm, a mean width of 23+/-6 mm, and a mean area of 5.8+/-2.5 cm2. Follow-up ranged from 1 to 74 months (mean, 58 months). Fifty patients had stroke or embolism, 53 died of a cause other than stroke or embolism, and 38 required anticoagulation. On univariate analysis, thrombi (risk ratio, 3.9 [95% CI, 1.4 to 10.1]; P = 0.009), length of the left atrial appendage (risk ratio, 1.6 [CI, 1.05 to 2.5]; P = 0.03), and width of the left atrial appendage (risk ratio, 2.4 [CI, 1.2 to 4.81; P = 0.01) were associated with stroke or embolism. Multivariate analysis identified hypertension (risk ratio, 3.6 [CI, 1.8 to 8.4]; P = 0.001), previous stroke (risk ratio, 3.7 [CI, 1.5 to 7.5]; P = 0.002), and age (risk ratio, 1.1 [CI, 1.0 to 1.11; P < 0.001) as risk factors for stroke or embolism and provided evidence of an association between thrombi and stroke or embolism (risk ratio, 2.4 [CI, 0.9 to 6.9]; P = 0.09). CONCLUSIONS: In outpatients with atrial fibrillation and without recent stroke, thrombi of the left atrium or left atrial appendage and length and width of the left atrial appendage were associated with stroke or embolism in univariate analysis. In a multivariate analysis, age, hypertension, and previous stroke were risk factors for stroke or embolism, and thrombi of the left atrium or left atrial appendage were possible risk factors. In these patients, history may be more useful than transesophageal echocardiography for the assessment of embolic risk.     

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.     

Therapy and prevention of cerebral ischemia

Two large randomized studies - NINDS and ECASS - have shown that fibrinolytics, when given early enough, reduce morbidity and mortality in acute stroke. The treatment has to be initiated within three hours after onset of symptoms. In middle cerebral artery stroke, fibrinolysis can be performed within six hours from onset, guided by computed tomography criteria. Thereafter, s.c. low-molecular-weight heparin can still improve the fate of the patient. Currently, the potential benefit or harm of unfractionated heparin and aspirin is not yet known. However, large-scale studies using standard heparin, aspirin of low-molecular-weight heparin are in progress with results expected soon. After the acute stage of stroke, risk factors have to be eliminated or modified, and anticoagulants, platelet inhibitors and, in selected cases, carotid endarterectomy are useful in preventing recurrent stroke or other vascular events.     

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.     

Design-enhanced breast reduction: an approach for very large, very ptotic breasts without a vertical incision

BACKGROUND: The impact of atrial fibrillation (AF) on mortality, stroke, and medical costs is unknown. METHODS: We conducted a prospective cohort study of hospitalized Medicare patients with AF and 1 other cardiovascular diagnosis (CVD) compared with a matched group without AF (n = 26,753), randomly selected in 6 age-sex strata from 1989 MedPAR files of more than 1 million patients diagnosed as having AF. Stroke rates were also determined in another cohort free of CVD (n = 14,267). Total medical costs after hospitalization were available from a 1991 cohort. Cumulative mortality, stroke rates, and costs following index admission were adjusted by multivariate and proportional hazard regression analyses. RESULTS: Mortality rates were high in individuals with CVD, ranging from 19.0% to 52.1% in 1 year. Adjusted relative mortality risk was approximately 20% higher in patients with AF in all age-sex strata during each of the 3 years studied (P < .05). Incidence of stroke was high in individuals with CVD, 6.2% to 15.4% in 1 year, with and without AF, and was at least 5-fold higher than in individuals without CVD. In those with CVD, stroke rates were approximately 25% higher in women with AF (P < .05) but only 10% higher in men. Adjusted total Medicare spending in 1 year was 8.6- to 22.6-fold greater in men, and 9.8- to 11.2-fold greater in women with AF (P < .05). Second- and third-year costs were increased as well. CONCLUSION: Prevention of AF and treatment of patients with AF and associated CVD may yield benefits in reduced mortality and stroke as well as reducing health care costs.     

Cytokines and bioincompatibility

OBJECTIVES: This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND: Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS: Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS: TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS: TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.     

Hypercoagulability and chronic atrial fibrillation: the role of markers of thrombin generation

BACKGROUND: We have studied 64 patients with congestive heart failure, half of them also with chronic nonvalvular atrial fibrillation (AF). Patients were also stratified according to a history of prior stroke. METHODS: The generation of thrombin was investigated by means of the molecular markers prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT), because AF patients may have a hypercoagulable state. There was only a trend toward higher values of TAT and F1 + 2 for AF patients, while subjects with previous stroke (irrespective of AF) had increased levels of the markers of thrombin generation (TAT stroke+ 18.95 +/- 5.15 vs TAT stroke- 8.34 +/- 2.41; F1 + 2 stroke+ 2.22 +/- 0.29 vs F1 + 2 stroke- 1.32 +/- 0.12). The presence of spontaneous echo contrast (SEC) within left atrium was also investigated in 32 AF patients by transesophageal echocardiography. RESULTS: TAT were significantly higher in subjects (n = 11) with SEC (TAT sec+ 37.5 +/- 13.41 vs TAT sec- 8.7 +/- 2.51, p = 0.008). CONCLUSIONS: Finally, when we grouped into 1) those with both AF and stroke, 2) AF alone, 3) stroke alone and 4) sinus rhythm without stroke, levels of F1 + 2 were higher (and marginally higher TAT) in patients with AF and stroke than in those without stroke, revealing that there is a true clotting activation state in these subjects.     

Impact of atrial fibrillation on the risk of death: the Framingham Heart Study

BACKGROUND: Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. METHODS AND RESULTS: We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes. CONCLUSIONS: In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.     

Contraindications to metformin therapy in patients with NIDDM

OBJECTIVE: Treatment with metformin is occasionally associated with the development of severe lactic acidosis. However, this is usually observed in patients with major contraindications to the drug. In this study, we aimed to determine the prevalence of conditions currently regarded as either contraindications or cautions to the use of metformin in patients with NIDDM. RESEARCH DESIGN AND METHODS: The case notes of metformin-treated NIDDM patients (mean age 62 years) attending a United Kingdom university hospital diabetes clinic over a 3-month period were reviewed according to criteria reflecting a pragmatic view of current prescribing recommendations. RESULTS: Of 89 consecutive patients whose notes could be evaluated in detail, only 41 (46%) had no contraindications or cautions to metformin whatsoever. Concomitant chronic disorders associated with a potentially increased risk of hyperlactatemia were renal impairment (n = 2; plasma creatinine concentrations 1.7 and 2.3 mg/dl, respectively), cardiac failure (n = 2), and chronic liver disease (n = 2). Other potentially relevant disorders included ischemic heart disease (n = 20), clinical proteinuria (n = 14), peripheral vascular disease (n = 22), and pulmonary disease (n = 7). Multiple conditions (i.e., two, three, or four) were present in eight, five, and one patient(s), respectively. CONCLUSIONS: More than half the patients in our series had concomitant conditions or complications conventionally regarded as cautions or contraindications to metformin; approximately 10% had a multiplicity of such conditions. Regular surveillance is necessary to detect the development of complications such as renal impairment. Vigilance is also required in view of the increased risk of major intercurrent illnesses, which may independently disturb lactate metabolism in patients with NIDDM. Metformin should be withdrawn promptly under such circumstances.