Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections.

OBJECTIVES: The aim of this study was to investigate the diagnostic performance of (99m)Tc-hexamethypropylene amine oxime labeled autologous white blood cell ((99m)Tc-HMPAO-WBC) scintigraphy in patients with suspected infections associated with cardiovascular implantable electronic devices (CIEDs). BACKGROUND: Early, definite recognition of CIED-related infections combined with accurate localization and quantification of disease burden is a prerequisite for optimal treatment strategies. METHODS: All 63 consecutive patients underwent clinical examination, blood chemistry, microbiology, and echography of the cardiac region/venous pathway of the device. Final diagnosis of infection was established in 32 of 63 patients and in 23 of 32 by microbiology. RESULTS: Sensitivity of (99m)Tc-HMPAO-WBC single-photon emission computed tomography/computed tomography (SPECT/CT) was 94% for both detection and localization of CIED-associated infection. SPECT/CT imaging had a definite added diagnostic value over both planar and stand-alone SPECT. Pocket infection was often associated with lead(s) involvement; the intracardiac portion of the lead(s) more frequently exhibited (99m)Tc-HMPAO-WBC accumulation and presented the highest rate of complications, infectious endocarditis, and septic embolism. Two false negative cases and no false positive results were observed. None of the patients with negative (99m)Tc-HMPAO-WBC scintigraphy developed CIED-related infection during follow-up of 12 months. Echography of the cardiac region/venous pathway of the device had 90% specificity, but low sensitivity (81% when intracardiac lead[s] infection only was considered). The Duke criteria had 31% sensitivity for the definite category (100% specificity) and 81% for the definite and possible categories (77% specificity). CONCLUSIONS: (99m)Tc-HMPAO-WBC scintigraphy enabled the confirmation of the presence of CIED-associated infection, definition of the extent of device involvement, and detection of associated complications. Moreover, (99m)Tc-HMPAO-WBC scintigraphy reliably excluded device-associated infection during a febrile episode and sepsis, with 95% negative predictive value.

Ultrasound assessment of the force-frequency relationship from the law of conservation of momentum in patients with left ventricular dysfunction.

Measurement of force-frequency relationship (FFR) is useful in the evaluation of heart rate-dependent contractile dysfunction. The purpose of this study was to evaluate a new Doppler-derived method for assessing FFR. Doppler velocity spectra at the left ventricular (LV) outflow tract was used to estimate mean blood flow velocity (mBFV), ejection time (ET) and velocity-time integral. LV ejection force (LVF) was then calculated according to the law of conservation of momentum: 1060 kg/m³ × (mBFV[m/sec]/ET [s]) × Stroke volume (mL). A symptom-limited, graded, bicycle semi-supine exercise test was performed in 56 patients with LV dysfunction (LV ejection fraction = 27 ± 6%). Measurements were obtained at baseline and serially during the test. The change in FFR was defined as up-sloping when the peak LVF was higher than the baseline value. The change was biphasic when the trend was initially up-sloping, then down-sloping; it was flat or negative when peak LVF was less than the baseline value. LVF was 30 ± 12 mN in patients with up-sloping FFR (n = 39) and 15 ± 6 mN in those with biphasic or flat FFR (n = 17; p < 0.0001). The ultrasound assessment of the FFR was highly concordant with a previously validated method based on pressure-end-systolic volume index ratio (κ = 0.75; 95% confidence interval, 0.55-94.0). The evaluation of the LVF using Doppler is an alternative method for the assessment of FFR during stress echocardiography in patients with LV dysfunction.

Prevalence and clinical characteristics of adult patients with congenital heart disease in Tuscany.

AIMS: The clinical features of the adult population with congenital heart disease (CHD) are still not well characterized, particularly in the subset with more severe lesions. We report the data collected in the National Association of Hospital Cardiologists Toscana grown-up CHD (GUCH) registry over its first 8-month enrolment period. METHODS: The Registry included consecutive patients aged more than 16 years with a documented diagnosis of CHD, enrolled in seven different Tuscan hospitals using a web-based electronic form. Severe CHD was defined as cyanotic CHD, or acyanotic lesion with significant haemodynamic impact requiring surgical and/or percutaneous correction. RESULTS: Between November 2009 and June 2010 a total of 1641 patients (mean age 41.8 ±â€Š19.3 years, 52.2% women) were enrolled. Atrial septal defect was the most common lesion, accounting for more than one-third of cases. Atrial and ventricular septal defects together accounted for about half of all CHDs. Nearly one-third of patients had New York Heart Association (NYHA) class 2 or more. A history of recurrent arrhythmias was reported in 15% of cases, and 12% of patients were on oral anticoagulants at the time of enrolment. The prevalence of pulmonary hypertension was 6%, and the prevalence of Eisenmenger syndrome was 1.2%. Severe CHD was present in 42% of patients. Younger age, higher NYHA class, male sex, and the need for oral anticoagulants were the only independent predictors of severe CHD. CONCLUSION: Information about the clinical characteristics and the CHD type distribution of a sample of Tuscan GUCH population was provided. Severe CHD accounts for about 40% of all CHDs in this population. CHD severity is associated with younger age, male gender, worse NYHA class, and need for oral anticoagulation.

Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis.

UNLABELLED: The clinical performance of the Duke Endocarditis Service criteria to establish the diagnosis of infectious endocarditis (IE) can be improved through functional imaging procedures such as radiolabeled leukocytes ((99m)Tc-hexamethylpropyleneamine oxime [HMPAO]-labeled white blood cells [WBC]). METHODS: We assessed the value of (99m)Tc-HMPAO-WBC scintigraphy including SPECT/CT acquisitions in a series of 131 consecutive patients with suspected IE. Patients with permanent cardiac devices were excluded. (99m)Tc-HMPAO-WBC scintigraphy results were correlated with transthoracic or transesophageal echocardiography, blood cultures, and the Duke criteria. RESULTS: Scintigraphy was true-positive in 46 of 51 and false-negative in 5 of 51 cases (90% sensitivity, 94% negative predictive value, and 100% specificity and positive predictive value). No false-positive results were found, even in patients with early IE evaluated within the first 2 mo from the surgical procedure. In 24 of 51 patients with IE, we also found extracardiac uptake, indicating septic embolism in 21 of 24. Despite the fact that septic embolism was found in 11 of 18 cases of Duke-definite IE, most of the added value from the (99m)Tc-HMPAO-WBC scan for decision making was seen in patients in whom the Duke criteria yielded possible IE. The scan was particularly valuable in patients with negative or difficult-to-interpret echocardiographic findings because it correctly classified 11 of 88 of these patients as having IE. Furthermore, 3 patients were falsely positive at echocardiography but correctly negative at (99m)Tc-HMPAO-WBC scintigraphy: these patients had marantic vegetations. CONCLUSION: Our results demonstrate the ability of (99m)Tc-HMPAO-WBC scintigraphy to reduce the rate of misdiagnosed cases of IE when combined with standard diagnostic tests in several situations: when clinical suspicion is high but echocardiographic findings are inconclusive; when there is a need for differential diagnosis between septic and sterile vegetations detected at echocardiography; when echocardiographic, laboratory, and clinical data are contradictory; and when valve involvement (especially of a prosthetic valve) needs to be excluded during febrile episodes, sepsis, or postsurgical infections.

Peak power output to left ventricular mass: an index to predict ventricular pumping performance and morbidity in advanced heart failure.

BACKGROUND: Similar to power-to-weight ratio and weight-to-power ratio, which are measurements of the actual performance of any engine, the ratios of peak power output to left ventricular (LV) mass (peak power/mass) and of peak LV mass to power output (peak mass/power) are indices of LV performance potentially useful in heart failure (HF). This Doppler echocardiographic study was designed to evaluate peak power/mass and peak mass/power in patients with advanced HF compared with healthy subjects and to assess their prognostic value. METHODS: Power output was measured at rest and at peak exercise in 75 subjects, 60 patients with advanced HF (LV ejection fraction ≤ 35%) and 15 controls. Peak LV power output (W) was calculated as the maximal product of (133 × 10⁻6) × stroke volume (mL) × mean arterial pressure (mm Hg) × heart rate (beats/min). LV mass was assessed using a standard M-mode echocardiographic method. RESULTS: Peak power/mass was 1.84 ± 0.46 W/100 g and 0.76 ± 0.31 W/100 g, and peak mass/power was 32 ± 10 g/m²/W and 84 ± 38 g/m²/W in controls and in patients with HF, respectively (both P values < .0001). Peak power/mass was a powerful predictor of outcome on multivariate logistic regression analysis (hazard ratio, 0.907; P = .009). On receiver operating characteristic curve analysis, the areas under the curve for HF-related events were greater for peak power/mass (P = .002) and peak mass/power (P = .011) with respect to resting ejection fraction. Comparisons of Cox models showed that peak power/mass added prognostic value to a model that included age, New York Heart Association class, etiology, ejection fraction, and diastolic dysfunction (P < .0001). CONCLUSION: Peak power/mass is useful to discriminate and risk stratify patients with advanced HF with additional power with respect to ejection fraction.

Validation of an echo-Doppler decision model to predict left ventricular filling pressure in patients with heart failure independently of ejection fraction.

AIMS: To test a decision model for non-invasive estimation of left ventricular filling pressure (LVFP) in patients with left ventricular (LV) dysfunction and a wide range of ejection fractions (EF). METHODS AND RESULTS: In patients with LV dysfunction (n = 270; EF = 42 +/- 16%), classification and regression tree (CART) analysis was used to generate a model for the prediction of elevated LVFP, defined as pulmonary capillary wedge pressure (PCWP) >15 mmHg, in a derivation cohort (n = 178). At each step of the decision tree, nodes including single or multiple criteria connected by Boolean operators were tested to achieve the best information entropy gain. Averaged mitral-to-myocardial early velocities ratio (E/e') > or =13 OR E-wave deceleration time <150 ms was closely associated with elevated LVFP. Alternatively, prediction of PCWP >15 mmHg needed the following criteria to be satisfied: (i) intermediate E/e' (13 > E/e' > 8); (ii) left atrial volume index >40 mL/m(2) OR ratio of mitral E-wave and colour M-mode propagation velocity >2 OR difference in duration of pulmonary vein and mitral flow at atrial contraction >30 ms; (iii) estimated pulmonary artery systolic pressure >35 mmHg. Patients were correctly allocated according to PCWP with an 87% sensitivity and a 90% specificity. Compared with the best single parameter estimating LVFP, a 17% relative increase in accuracy was achieved in patients with EF >50%. The model was prospectively validated in a testing group (n = 92): 80% sensitivity, 78% specificity. CONCLUSION: This sequential testing is useful to non-invasively predict LVFP in patients with LV dysfunction, especially in those with preserved EF.

Circulating matrix metalloproteinase-3 and metalloproteinase-9 and tissue Doppler measures of diastolic dysfunction to risk stratify patients with systolic heart failure.

Abnormal matrix metalloproteinase (MMP) activity and diastolic dysfunction may affect left ventricular (LV) remodeling and prognosis, but it is not known whether the combined evaluation of MMP-3 and MMP-9 and variables of diastolic dysfunction are useful for the risk stratification of patients with systolic heart failure (HF). Therefore, this study was designed to assess the value of combining circulating levels of MMPs and tissue Doppler measures of LV diastolic dysfunction to risk-stratify patients with systolic HF. Consecutive patients with systolic HF due to either ischemic or nonischemic cardiomyopathy (n = 134) and LV ejection fractions <45% were submitted to complete echocardiographic and Doppler examinations. The ratio of mitral E peak velocity and averaged e' velocity (E/e') was calculated. Plasma levels of MMP-3 and MMP-9 were measured at the time of index echocardiography. All-cause mortality was defined as the end point. The mean LV ejection fraction was 28 +/- 9%. There was a total of 32 deaths during follow-up (24 +/- 14 months). Several clinical, biochemical, Doppler, and echocardiographic parameters were associated with the outcome on univariate Cox regression analysis. After statistical adjustment for the potentially confounding factors by multivariate analysis, E/e' (hazard ratio 1.11, p = 0.0028), ejection fraction (hazard ratio 0.92, p = 0.017), and MMP-9 (hazard ratio 1.01, p = 0.027) remained significant independent predictors of the end point. Kaplan-Meier curves showed that survival was worse in patients with E/e' ratios >/=13 and MMP-9 levels >89.9 ng/mL (p <0.0001). In conclusion, the assessment of circulating MMP levels and tissue Doppler measures of LV diastolic dysfunction may improve the prognostic stratification of patients with systolic HF.

Effects of GIK (glucose-insulin-potassium) on stress-induced myocardial ischaemia.

Despite the evidence in experimental animal models that insulin, or GIK (glucose-insulin-potassium), improves left ventricular function and perfusion during both acute and chronic ischaemia, clinical studies have generated conflicting results. We tested the hypothesis that pretreatment with GIK attenuates the vascular and functional effects of stress-induced myocardial ischaemia in humans. Twenty-two patients with evidence of inducible myocardial ischaemia were enrolled; 11 patients with normal ventricular function underwent two dipyridamole echocardiography tests, and 11 with regional contractility defects from previous myocardial infarction were submitted to two ECG exercise tests combined with 201Tl myocardial perfusion scintigraphy; the tests were preceded by 60 min of either normal saline or an isoglycaemic GIK infusion. On a stress echocardiogram, a 30% reduction in the severity of ischaemia was observed. On ECG ergometry, GIK infusion slightly increased the time to ischaemia (+0.6 min, P=0.07); however, the higher workload (+8%, P=0.07) was achieved at a similar rate-pressure plateau. On scintigraphy, an increase in ischaemic segments (+48%, P<0.001) was imaged mainly at the expense of viable (but non-ischaemic) and non-viable segments, which were reduced by 60%. GIK affected stress-induced left ventricular underperfusion only marginally (GIK: 39.7+/-2.5 compared with saline: 35.4+/-2.2 units, P<0.05), but significantly improved its acute reversibility (-42+/-4 compared with -25+/-4%, P<0.001). We conclude that GIK pretreatment attenuates the effect of ischaemia on myocardial contractility, slightly improves exercise tolerance and causes a more rapid and diffuse recovery of post-ischaemic reperfusion.

Coronary flow reserve in idiopathic dilated cardiomyopathy: relation with left ventricular wall stress, natriuretic peptides, and endothelial dysfunction.

Studies have demonstrated impaired coronary blood flow reserve (CBFR) in idiopathic dilated cardiomyopathy (IDCM). It was the aim of this study to examine the potential underlying mechanisms for CBFR reduction in patients with IDCM by Doppler ultrasound techniques. Forty-eight clinically stable patients with heart failure caused by IDCM (New York Heart Association classes 1-3) were evaluated by echocardiographic and Doppler techniques with the assessments of CBFR and brachial artery flow-mediated dilation (FMD). CBFR was estimated as the hyperemic (dipyridamole: 0.84 mg/kg in 10 minutes, intravenously) to resting coronary diastolic peak velocities ratio. N-terminal pro-brain natriuretic peptide (Nt-pro-BNP) plasma levels were measured at the time of the index echocardiogram. Left ventricular (LV) ejection fraction was 30% +/- 8%, and wall motion score index was 2.0 +/- 0.25. The best correlation with CBFR was found with LV wall thickness-to-cavity radius (r = 0.77, P < .0001). A strong correlation of log-transformed Nt-pro-BNP levels was observed with CBFR (r = -0.64; P < .0001). No significant correlation was documented between CBFR and FMD. The stepwise regression model showed that LV wall thickness-to-cavity radius was the strongest independent predictor of CBFR followed by New York Heart Association class and log-transformed Nt-pro-BNP leading to a cumulative R value of 0.82 (P < .0001). The results of the study indicate that by measuring variables related to LV end-diastolic wall stress, such as LV wall thickness-to-cavity radius and plasma Nt-proBNP, it is possible to have information about CBFR in patients with heart failure secondary to IDCM.

N-terminal protype-B natriuretic peptide and Doppler diastolic variables are incremental for risk stratification of patients with NYHA class I-II systolic heart failure.

BACKGROUND: In systolic heart failure (HF), preventing the development of severe symptoms, before patients are in advanced NYHA functional classes, is a worthwhile target of therapy. Early recognition of left ventricular (LV) diastolic dysfunction and neuroendocrine activation may have an important impact on patient's outcome. AIM: To investigate whether N-terminal proBNP (NT-proBNP) and mitral flow and tissue Doppler (TD) diastolic parameters are incremental for risk stratification of systolic HF patients in NYHA class I and II. METHODS: The study consisted of 232 consecutive outpatients with systolic HF (ejection fraction [EF] 544 pg/ml (hazards ratio [HR]: 2.66; p=0.012), EF <37% (HR: 2.45; p=0.006), E

Prognostic value of N-terminal pro-type-B natriuretic peptide and Doppler left ventricular diastolic variables in patients with chronic systolic heart failure stabilized by therapy.

Prognostication of patients with chronic heart failure (HF) stabilized by therapy may be difficult. Therefore, the aim was to evaluate whether combined assessment of plasma N-terminal pro-B natriuretic peptide (NT-pro-BNP) and Doppler left ventricular (LV) diastolic variables was relevant to the prognosis of patients with stable HF. Outpatients with LV systolic HF (ejection fraction < or =45%), classified using clinical criteria as decompensated (n = 94) and stable HF (n = 219), underwent a complete Doppler echocardiographic study. NT-pro-BNP was measured together with mitral wave velocities, E wave deceleration time, and tissue Doppler early septal annular velocity. Median follow-up was 22 months. Freedom from all-cause mortality or HF hospitalization at 24 months was worst (44%) in patients with decompensated HF, intermediate (58%) in patients with stable HF with NT-pro-BNP higher than the median (>1,129 pg/ml), and best (92%) in patients with lower NT-pro-BNP (log-rank p <0.0001). In patients with stable HF, NT-pro-BNP >1,129 pg/ml (hazard ratio [HR] 2.84, p = 0.003), E wave deceleration time <150 ms (HR 2.31, p = 0.004), and tissue Doppler early septal annular velocity <8 cm/s (HR 2.18, p = 0.01) were predictors of the end point at multivariate analysis. The addition of Doppler LV diastolic variables and NT-pro-BNP significantly improved the chi-square test for outcome prediction (from 14.4 to 46.4). In conclusion, NT-pro-BNP and spectral and tissue Doppler variables of LV diastolic dysfunction added independent and incremental contributions to prognostic stratification of patients with stable HF.

Plasma N-terminal protype-B natriuretic peptide levels in risk assessment of patients with mitral regurgitation secondary to ischemic and nonischemic dilated cardiomyopathy.

BACKGROUND: Functional mitral regurgitation (MR) is a factor affecting prognosis of patients with chronic left ventricular (LV) dysfunction. The aim of the study was to investigate whether the evaluation of plasma N-terminal protype-B natriuretic peptide (NT-proBNP) concentrations is useful for prognostic assessment of patients with functional MR due to either ischemic or nonischemic chronic LV dysfunction. METHODS: Echocardiograms were obtained in 207 patients with chronic LV dysfunction (ejection fraction or=0.7 cm raised MR grade to severe. Median follow-up duration was 29 months. RESULTS: The NT-proBNP levels increased significantly with MR severity. At multivariate analysis, NT-proBNP was an independent predictor of cardiac death (hazard ratio 2.17, CI 1.10-4.30, P = .026) and the most powerful predictor of cardiac death or heart failure-related hospitalization (hazard ratio 3.19, CI 1.89-5.37, P < .0001). A progressively worse outcome was apparent when patients were stratified by a graded increase in MR severity and by quartiles of NT-proBNP levels. Increased NT-proBNP concentrations and more-than-mild MR identified patients with the highest risk of cardiac mortality. CONCLUSION: Assessment of plasma NT-proBNP allows for stratifying patients with functional MR regardless of their degree of valvular incompetence. Even in case of only mild or moderate MR, but increased NT-proBNP, patients have to face poor outcome.

Post-cardioversion transesophageal echocardiography (POSTEC) strategy with the use of enoxaparin for brief anticoagulation in atrial fibrillation patients: the multicenter POSTEC trial (a pilot study).

OBJECTIVES: In patients with atrial fibrillation (AF), we sought to evaluate the feasibility and safety of a new transesophageal echocardiography (TEE)-guided strategy, aimed at selecting, 7 days post-cardioversion, those patients who are at low risk (i.e. who can terminate anticoagulation after a second TEE) and those at high risk (i.e. who have to continue it). METHODS: We enrolled 206 patients with non-valvular AF into a randomized, multicenter clinical trial. Group A patients underwent a TEE-guided cardioversion with heparin and at least 4 weeks of oral anticoagulation therapy (OAT) after cardioversion. Group B patients received enoxaparin and underwent a TEE-guided cardioversion. After 7 days, a second TEE was carried out. In the absence of TEE thromboembolic risk factors and left atrial appendage (LAA) dysfunction anticoagulation was discontinued. RESULTS: In group A, 88 out of 102 patients underwent TEE and cardioversion was efficacious in 77 of 78. In group B, 100 out of 104 patients underwent TEE and cardioversion was efficacious in 80 of 87 patients; 55 patients underwent the second TEE and enoxaparin was stopped in 50 without LAA dysfunction. In group A, one transient ischemic attack and one sudden cardiac death occurred. In group B, one patient with complex aortic plaques suffered a stroke during enoxaparin. There was a minor hemorrhage in groups A and B, and a severe hemorrhage in a patient during OAT because of persistent atrial stunning. Hospitalization length and duration of anticoagulation were significantly shorter in group B. CONCLUSIONS: The pre/post-cardioversion TEE strategy with enoxaparin in AF may constitute a feasible and safe approach in selecting patients at low thromboembolic risk who can benefit from precocious termination of anticoagulation (7 days after cardioversion). It may be also useful to identify those patients in whom a life-lasting anticoagulation could be beneficial. A larger trial to confirm these findings is under way.

Right ventricular dysfunction is a major predictor of outcome in patients with moderate to severe mitral regurgitation and left ventricular dysfunction.

BACKGROUND: This study aimed to assess the prognostic value of right ventricular (RV) dysfunction in patients with secondary mitral regurgitation (MR) by simple methods of echocardiographic measurement. Although both RV dysfunction and functional MR may affect prognosis of patients with heart failure (HF) due to left ventricular (LV) dysfunction, information is lacking regarding the impact of RV dysfunction in patients with functional MR. METHODS: Among 356 consecutive patients with chronic HF due to LV dysfunction (ejection fraction < or = 45%), 107 met the entry criteria of moderate to severe MR as assessed by a vena contracta width > or = 0.5 cm. Tricuspid annular plane systolic excursion (TAPSE) was acquired to evaluate RV function. Median follow-up duration was 21 months. RESULTS: Among patients with a vena contracta width > or = 0.5 cm, 30 (28%) died and 28 (26%) were hospitalized for worsening HF. By multivariate analysis, TAPSE < or = 14 mm (hazard ratio [HR] 2.83, P = .027) and LV ejection fraction (HR 2.17, P = .099) were predictive of death from all causes. Independent predictors of freedom from all-cause mortality or hospitalization for worsening HF were New York Heart Association class (HR 2.15, P = .027), age (HR 1.98, P = .021) and TAPSE < or = 14 mm (HR 1.96, P = .031). At 24 months, survival was 45% in those with the worse TAPSE, whereas it was 82% in those with TAPSE > 14 mm (log-rank statistic = 0.0002). Aminoterminal pro-type B natriuretic peptide plasma levels were higher in patients with vena contracta width of > or = 0.5 cm and TAPSE < or = 14 mm. CONCLUSIONS: This study shows that RV function, assessed by TAPSE, plays a major role in the outcome of patients with functional moderate to severe MR.

Non-obstructive prosthetic aortic valve thrombosis presenting with acute myocardial infarction and stroke in a patient with inadequate low-molecular-weight heparin treatment. The unlucky patient and the (pseudo)prudent physician.

Non-obstructive prosthetic valve thrombosis is a rare and underestimated complication in patients with left-sided mechanical heart valves. Systemic embolisation, mainly involving the cerebral circulation, often represents the first clinical manifestation. We report a case of multiple, successive embolizations in the coronary and cerebral circulation, presenting with an acute myocardial infarction and stroke in a patient with latent, non-obstructive thrombosis of a mechanical bileaflet aortic valve. Because of scheduled urological surgery, chronic vitamin K antagonist treatment had previously been discontinued and replaced with low-molecular-weight heparin, at inadequate dosage. Following coronary arteriography, brain computed tomography scan and transoesophageal echocardiography, thrombolysis was performed successfully. This case emphasises the utility of performing transoesophageal echocardiography routinely in the presence of ischaemic signs in patients with mechanical heart valves. In patients requiring discontinuation of oral anticoagulant therapy, accurate management and continuous monitoring of alternative medications are needed in order to avoid severe thromboembolic complications.