Consideration of clinical variables for choosing new anticoagulant alternatives to warfarin for the management of non-valvular atrial fibrillation.

WHAT IS KNOWN AND OBJECTIVE: Patients with non-valvular atrial fibrillation (NVAF) are at risk for stroke and systemic embolism (SSE), and this risk can be decreased with adjusted-dose warfarin. Warfarin, however, is cumbersome to use and requires at least monthly laboratory monitoring. Three new oral anticoagulants (NOACs) that are less cumbersome have been approved as alternatives to warfarin for SSE prevention in NVAF. Selecting a patient-specific alternative to warfarin can be confusing for pharmacists and clinicians. This review details clinical parameters to consider when choosing an alternative to warfarin for a specific patient and summarizes them in a Comparison Table. METHODS: Using available clinical evidence from pivotal trials, US FDA- and Health Canada-approved prescribing information and post-marketing observations, this review provides a summary of important clinical variables for clinicians to consider when choosing patient-centred anticoagulant alternatives to warfarin for prevention of SSE in NVAF. RESULTS AND DISCUSSION: Dabigatran, rivaroxaban and apixaban are approved alternatives to warfarin for primary and secondary prevention of SSE in patients with NVAF. Additionally, apixaban has also been compared to aspirin in patients with NVAF that were considered unsuitable for vitamin K antagonist therapy. Prospective consideration of age, weight, hepatic function, renal function and drug interactions are important clinical parameters to consider when selecting patient-centred alternatives to adjusted-dose warfarin. WHAT IS NEW AND CONCLUSION: Several NOACs are now alternatives to warfarin for SSE prevention in NVAF but require providers to make a shift in strategy from tailoring anticoagulant dose based on anticoagulant effect to selection of the anticoagulant based on clinical variables that affect anticoagulant exposure. These variables and their interactions should be considered in choosing an alternative to warfarin and are summarized in a simple table comparing the new anticoagulants.

Two-dimensional echocardiographic detection of right-sided cardiac intracavitary thromboembolus with pulmonary embolism.

Five patients with pulmonary embolism, in whom right-sided intracardiac thromboembolus was detected by echocardiography and confirmed by either angiography, surgery or postmortem examination, are described. One of these patients died from massive pulmonary embolism after right heart catheterization. In two patients treated medically, either partial or total lysis of the thromboembolus was demonstrated echocardiographically; in another two patients, the right atrial thromboembolus was successfully removed surgically. Typical locations and echocardiographic characteristics of right-sided thromboemboli are described. The potential usefulness of two-dimensional echocardiography in both the diagnosis and the management of patients with right-sided intracardiac thromboembolism is discussed.

Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators.

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.

Two-dimensional echocardiographic identification of complicated aortic root endocarditis: implications for surgery.

Two-dimensional echocardiography successfully displayed the location and extent of aortic root complications, annular abscess or mycotic aneurysm in nine patients with aortic valve endocarditis. Five of the nine patients had prosthetic valve endocarditis and four had native valve endocarditis. The infective process extended into the paravalvular structures, including the interventricular septum (seven patients), right ventricular outflow tract (three patients), interatrial septum (one patient) and anterior mitral valve leaflet (four patients). The amount of aorto-left ventricular discontinuity caused by these complications was quantitated in degrees of annular circumference on the parasternal short axis image and in distance on the parasternal long axis image. The echocardiographic findings were confirmed at surgery and were helpful in the preoperative anticipation of the type of surgical procedure required: aortic valve replacement or composite aortic valve and root replacement. Five patients had prosthetic valve endocarditis with calculated aorto-left ventricular discontinuity of 173 +/- 55 degrees on parasternal short axis images and 1.36 +/- 0.72 cm on parasternal long axis images. Initial surgical repair included three composite aortic root-valve prosthesis implants, one reconstructive procedure with valve replacement and one simple aortic valve replacement. During a follow-up period of 18 months (range 1 to 35), a second reparative procedure was required for only one patient to repair an aortic conduit to coronary artery venous bypass graft. Four patients had native valve endocarditis with calculated aorto-left ventricular discontinuity of 100 +/- 17 degrees on parasternal short axis images and 0.88 +/- 63 cm on parasternal long axis images. Initial surgical repair included two reconstructive procedures with valve replacement and two simple aortic valve replacements. During a follow-up period of 30 months (range 16 to 42), three of these four patients required a second reparative procedure: one each for repair of a paraprosthetic leak, a ventricular septal defect and persistent aorto-left ventricular discontinuity. Two-dimensional echocardiography accurately detected aortic annular abscess and mycotic aneurysm complicating aortic valve endocarditis and the resultant degree of aorto-left ventricular discontinuity. Circumferential aorto-left ventricular discontinuity with these complications is greater for prosthetic than native valve endocarditis and predicts a more extensive surgical repair.(ABSTRACT TRUNCATED AT 400 WORDS)

Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators.

OBJECTIVE: This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND: Although intermittent AF is common, relatively little is known about the attendant risk of stroke. METHODS: A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years. Independent risk factors for ischemic stroke were identified by multivariate analysis. RESULTS: Patients with intermittent AF were, on average, younger (66 vs. 70 years, p < 0.001), were more often women (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001) than those with sustained AF. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). In patients with intermittent AF, independent predictors of ischemic stroke were advancing age (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p = 0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95% confidence interval 4.5 to 14). CONCLUSIONS: In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF.

Propranolol antagonism of phenylpropanolamine-induced hypertension.

Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine.

Efficacy, safety, hemodynamic effects, and pharmacokinetics of high-dose moricizine during short- and long-term therapy.

Moricizine, 15 mg/kg, was given to 10 patients with frequent ventricular ectopic depolarizations, eight of whom had previously been treated unsuccessfully with antiarrhythmic drugs. A single-blind inpatient study was followed by therapy for up to 6 months. Two patients developed aggravation of arrhythmia during inpatient therapy. Of the eight patients who completed the inpatient study, seven achieved greater than or equal to 80% suppression of total ventricular ectopic depolarizations (P less than 0.001). During inpatient therapy the mean of the individual patients' suppression of total ventricular ectopic depolarizations was 87.9%, paired ventricular beats 99.3%, nonsustained ventricular tachycardia 99.6%, and premature atrial contractions 89.0%. Suppression was maintained during long-term therapy. The PR interval increased 27% (P less than 0.001), QRS interval increased 10% (P less than 0.0001), QTc increased 1% (P not significant), and JTc decreased 2% (P not significant). Heart rate, blood pressure, and left ventricular performance at rest and exercise were unchanged by moricizine. Moricizine half-life was 9.2 +/- 3.4 hours. Plasma levels of moricizine decreased after 10 days of therapy, suggesting induction of metabolic enzyme systems.

Indications for echocardiography in patients with ischemic stroke.

The recent availability of two-dimensional echocardiography (2DE) has fostered the expectation that cardiac embolic sources could be identified or excluded with certitude in ischemic stroke patients. As a screening procedure, 2DE has had a low yield. In selected patients, 2DE holds promise as a useful diagnostic test. Stroke patients who may benefit from 2DE include patients under age 45, patients with suspected left atrial myxoma, and patients with known infective endocarditis, prosthetic heart valves, or rheumatic valvular heart disease. In patients with ischemic heart disease, the yield of useful information from 2DE will be low but may, on occasion, influence management.

Two-dimensional echocardiographic detection of left ventricular posterior wall motion abnormalities using an inferior angulation view.

Two-dimensional echocardiography is frequently used to detect left ventricular (LV) wall motion abnormalities. Modification of the apical 4-chamber view by inferior angulation of the transducer provides a superior image for detection of regional wall motion abnormalities of the LV posterior wall. The inferior angulation image was prospectively compared with the standard parasternal short-axis image for detection of posterior LV wall motion abnormalities as defined by contrast left ventriculography in 63 consecutive patients. Posterior wall akinesia was present on the contrast left ventriculogram in 22 of the 63 patients. The parasternal short-axis image was judged technically inadequate for interpretation in 7 patients (11%). The inferior angulation image was technically adequate for interpretation in all patients. The sensitivity, specificity and accuracy of the inferior angulation image for detection of LV posterior wall motion abnormality was 91%, 80% and 84%, respectively, vs 67%, 71% and 70% for the parasternal short-axis image. The differences between the sensitivity, specificity and accuracy for the 2 views were not statistically significant. These observations indicate that the inferior angulation image provides a useful plane for routine echocardiographic analysis of regional LV wall motion either as a primary method to detect posterior wall motion abnormality or as a confirmatory view to document posterior wall motion abnormality.

Observations on detecting left ventricular thrombus with two dimensional echocardiography: emphasis on avoidance of false positive diagnoses.

Observations made in detecting left ventricular thrombus with two dimensional echocardiography in 25 patients are reviewed. In 20 patients thrombus was documented on angiography, surgery postmortem examination or serial two dimensional echocardiographic findings; in the remaining five patients two dimensional echocardiographic findings of thrombus were unequivocal. In all 25 patients wall motion abnormalities ranging from hypokinesia to frank dyskinesia were present at the site of the thrombus. Twenty-three patients had an apical thrombus; two had thrombus adjacent to the inferior wall. Clear delineation of the endocardium and thrombus margin was considered essential to the correct diagnosis of thrombus. Both intracavitary motion of the thrombus margin and a layering effect were noted infrequently although they were of benefit in identifying an intracardiac mass as thrombus. In addition, serial evaluations were helpful in establishing the correct diagnosis. False positive diagnoses can be minimized if one understands certain technical limitations of this method and correctly identifies apical structures that are not thrombi. Axial and lateral resolution problems inherent with this technique can produce intracavitary echoes that may simulate thrombi. In addition, normal or pathologic structures at the apex may also simulate thrombi. These structures include the papillary muscles, muscular trabeculae, chordal structures and tangential information from normal myocardium. Varying the sector orientation or acoustic window, or both, will aid in correctly identifying these structures and distinguishing them from left ventricular thrombi.

Left ventricular diastolic properties and filling characteristics during spontaneous angina pectoris at rest.

Diastolic left ventricular (LV) properties were studied at rest and during spontaneous angina pectoris during cardiac catheterization in 10 patients with severe coronary artery disease. During spontaneous angina there was a significant increase in LV filling pressures through diastole. The right ventricular end-diastolic pressure was measured at rest and during spontaneous angina in 7 of 10 patients and showed an increase from 7 +/- 3 to 10 +/- 4 mm Hg (mean +/- SD) (p less than 0.02). The T index (a measure of LV isovolumic relaxation) at rest was 51 +/- 17 ms and increased during angina to 58 +/- 12 ms (p less than 0.01), indicating an early diastolic relaxation dysfunction. Frame-by-frame LV volumes and corresponding pressures were analyzed from 3 consecutive beats in 5 of 10 patients. In 4 of these 5, the pressure-volume loop shifted upward and slightly to the right during angina. There was a significant increase in the rate of filling during mid-diastole with angina. Left atrial stroke work index increased by 35% during angina, suggesting an increased work load on the left atrium to maintain late diastolic filling.

Frequency of hypokalemia after successfully resuscitated out-of-hospital cardiac arrest compared with that in transmural acute myocardial infarction.

To evaluate the prevalence of hypokalemia in out-of-hospital cardiac arrest, the initial serum potassium and arterial pH values were reviewed from 138 consecutive patients resuscitated from cardiac arrest. For comparison, the same variables were reviewed for 62 consecutive patients who had transmural acute myocardial infarction (AMI) without cardiac arrest. The mean serum potassium level was lower after resuscitation from cardiac arrest (3.6 +/- 0.6 mEq/liter) than during AMI (3.9 +/- 0.5 mEq/liter) (p less than 0.005). The incidence of hypokalemia (potassium less than 3.5 mEq/liter) was greater in patients sustaining cardiac arrest (41%) than in patients who had AMI without cardiac arrest (11%) (p less than 0.001). Hypokalemia was common after cardiac arrest regardless of the occurrence of AMI at the time of arrest. Hypokalemia after cardiac arrest was independent of arterial pH, epinephrine or bicarbonate therapy during resuscitation, or prior therapy with diuretic drugs, digoxin or propranolol. In 10 patients with marked hypokalemia, the serum potassium level returned to normal rapidly (16 hours) during the hospitalization even though only 29% of the predicted potassium requirement was infused before its normalization. Thus, hypokalemia is prevalent immediately after out-of-hospital cardiac arrest, whereas it is uncommon in AMI in the absence of cardiac arrest. The cause and electrophysiologic consequences of this hypokalemia are unknown; in most cases, it is apparently caused by a shift of potassium from the intravascular compartment rather than a total body depletion of potassium.

Dual atrioventricular conduction during an acute inferior myocardial infarction. Electrocardiographic evidence.

A 49-year-old man had electrocardiographic evidence of a dual atrioventricular conduction system which occurred spontaneously during the course of an inferior myocardial infarction. Retrograde concealed conduction involving both conduction systems is proposed as the mechanism to explain the varying patterns of atrioventricular conduction seen.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

We analyzed transesophageal echocardiograms from 772 participants in the Stroke Prevention in Atrial Fibrillation (SPAF-III) study, characterizing spontaneous echocardiographic contrast (SEC) in the left atrium or appendage as faint or dense. The association of dense SEC with stroke risk factors and anatomic, hemodynamic, and hemostatic parameters related to specific thromboembolic mechanisms was evaluated by multivariate analysis. Spontaneous echocardiographic contrast was present in 55% of patients and was dense in 13%. Age (odds ratio [OR] 2.4/decade, P <.001), constant atrial fibrillation (OR 6.9, P <.001), history of hypertension (OR 3. 2, P <.001), and current tobacco smoking (OR 2.6, P =.04) were independent clinical predictors of dense SEC. Multivariate analysis of clinical, echocardiographic, and hemostatic parameters yielded age as the sole independent clinical predictor of dense SEC (OR 2. 4/decade, P <.001). Other independent predictors were measures of left atrial/appendage flow dynamics, left atrial size (OR 2.4/cm diameter, M-mode, P <.001), atherosclerotic aortic plaque (OR 2.8, P =.002), and plasma fibrinogen >350 mg/dL (P <.001). Results were similar when SEC of any density was analyzed. In conclusion, SEC occurred in more than half of these patients with prospectively defined nonvalvular atrial fibrillation but was usually faint. Dense SEC was strongly associated with previously reported clinical predictors of stroke, linking them to thromboembolism through atrial stasis. Diverse pathophysiologic factors including atrial stasis, fibrinogen level, and aortic plaque influence SEC.

Clinical outcomes of PTCA in chronic renal failure: a case-control study for comorbid features and evaluation of dialysis dependence.

We compared clinical outcomes following percutaneous transluminal coronary angioplasty (PTCA) for 77 chronic renal failure (CRF) (dialysis and nondialysis) patients and a control group matched for history of myocardial revascularization, specific revascularization procedure, gender, age, diabetes, number of native vessels diseased, number of vessels dilated, and the specific vessel(s) dilated. CRF patients had a higher incidence of peripheral vascular disease, hypertension, and more complex PTCA target lesion types than controls: 5% vs. 16% Type A, 12% vs. 28% Type B1, 44% vs. 41% Type B2, 39% vs. 15% Type C (p < 0.001). The primary success rate for PTCA in CRF patients and controls was 89% and 97% (p < 0.05). Survival analysis 24 months following PTCA showed a lower composite cardiac event-free survival (angiographic restenosis, myocardial infarction, coronary artery bypass surgery, and cardiac death) for those with CRF than controls, 54% vs. 69% (p = 0.002). Over the study period, 26 CRF patients died (11 from cardiac causes) compared to only 3 control patients (one from a cardiac cause); p < 0.001 for all cause and p < 0.003 for cardiac mortality. We also compared PTCA results between two categories of CRF patients. The first consisted of 49 end-stage renal disease (ESRD) patients on dialysis and the second included 28 patients not on dialysis (13 with creatinine > 2. 0 mg/dL and 15 with ESRD post-renal transplant). Both subgroups had similar coronary anatomy, including PTCA, target lesion type, and acute and long-term outcomes. In conclusion, we observed acceptable primary success and complication rates for PTCA in CRF patients compared with controls matched for comorbid features despite more complex target lesion morphology. Poorer long-term outcomes, however, were apparent for those with CRF regardless of dialysis dependence and likely relate to more extensive atherosclerosis and complex target coronary lesions at index PTCA as well as other features related to CRF.