Elisa Grifoni

Bleeding Risk During Oral Anticoagulation in Atrial Fibrillation Patients Older Than 80 Years

OBJECTIVES We sought to evaluate the rate of bleeding in relation to age (<80 and > or =80 years), the quality of anticoagulation (expressed as time spent in international normalized ratio therapeutic range), and factors associated with bleeding events. BACKGROUND Stroke prevention in patients with atrial fibrillation (AF) is an increasingly crucial public health target, particularly in patients ages > or =80 years. METHODS We conducted a prospective observational study on 783 patients with AF on oral anticoagulant treatment (OAT). RESULTS Patients spent a median 14%, 71%, and 15% of time below, within, and above the intended therapeutic range, respectively. No difference in OAT quality was found between patients age <80 and > or =80 years. During follow-up, 94 patients experienced bleeding complications (rate 3.7 x 100 patient/years), 37 major (rate 1.4 x 100 patient/years), and 57 minor (rate 2.2 x 100 patient/years). Different rates of major hemorrhage were observed between patients age <80 and > or =80 years (0.9 vs. 1.9 x 100 patient/years; p = 0.004). Bleeding risk also was greater in patients with a history of previous cerebral ischemic event (odds ratio [OR]: 2.5; 95% confidence interval: 1.3 to 4.8; p = 0.007). A Cox regression analysis confirmed age > or =80 years associated with bleeding risk (OR: 2.0). CONCLUSIONS These results indicate that the rate of major bleeding complications may be kept acceptably low also in very elderly AF patients on OAT, provided a careful management of anticoagulation is obtained.

Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment

The efficacy of adjusted-dose oral anticoagulant treatment (OAT) in the prevention of stroke in atrial fibrillation (AF) is well documented. Available data show that AF patients are widely heterogeneous in terms of ischaemic stroke risk. The role of female gender as a predictor of stroke risk is inconsistent, in particular it is unclear if warfarin treatment is able to prevent stroke equally in both sexes. We performed a prospective study on 780 AF patients on OAT, followed by an Anticoagulation Clinic, to evaluate if female gender is a risk factor for stroke among patients on OAT and if the quality of anticoagulation is different between genders. No difference was found in relation to the quality of anticoagulation between genders (p=0.5). During follow-up 33 patients had major bleedings (rate 1.37 x 100 pt/yrs) but no difference was found between genders in bleeding risk. Forty patients had ischaemic events [rate 1.66 x 100 pt/yrs; males rate 1.2 x 100 pt/yrs; females rate 2.43 x 100 pt/yrs; p=0.042; relative risk (RR) of females vs. males 2.0 (95% confidence interval [CI] 1.3-3.1); p= 0.004]. The higher rate of ischaemic events in females with respect to males was confirmed at Cox regression analysis after correction for age (p=0.009). In addition, strokes occurring in females were more disabling, and RR for severe and fatal stroke, defined according to Modified Rankin scale, of females vs. males was 3.1 (95% CI 1.3-6.5; p=0.001). In conclusion, our data show a higher risk of stroke in anticoagulated AF females with respect to males, despite a similar quality of anticoagulation.

Fibrin Resistance to Lysis in Patients with Pulmonary Hypertension Other Than Thromboembolic

RATIONALE Reportedly, fibrin isolated from patients with chronic thromboembolic pulmonary hypertension (CTEPH) is resistant to lysis. Persistence of regions within the fibrin beta chain, which mediate cell signaling and migration, could trigger the organization of pulmonary thromboemboli into chronic intravascular scars. OBJECTIVES Ascertain whether fibrin resistance to lysis occurs in patients with pulmonary hypertension (PAH) other than CTEPH, and in those with prior pulmonary embolism (PE) and no pulmonary hypertension. METHODS Fibrinogen was purified from 96 subjects (17 with CTEPH, 14 with PAH, 39 with prior PE, and 26 healthy control subjects) and exposed to thrombin to obtain fibrin clots. Plasmin-mediated cleavage of fibrin beta chain was assessed hourly over a 6-hour period by polyacrylamide gel electrophoresis. Fibrin band intensity was measured by densitometry of stained gels. Data were normalized to the band intensity of the undigested protein. MEASUREMENTS AND MAIN RESULTS By 1 hour of digestion, fibrin band intensity had decreased by a median of 25% (interquartile range [IQR], 20 to 27%) in control subjects, and by 15% (IQR, 11 to 18%) in patients with prior PE (P < 0.0001). The 1-hour median reduction in band intensity was 2% (IQR, 1 to 3%) in CTEPH, and 4% (IQR, 2 to 7%) in PAH (P < 0.0001 vs. control subjects and PE). The decline in fibrin band intensity remained significantly different among the four groups up to 6 hours (P < 0.0001). CONCLUSIONS Fibrin resistance to lysis occurs in pulmonary hypertension other than CTEPH and, to a smaller extent, in patients with prior PE and no pulmonary hypertension.

Stroke risk in atrial fibrillation patients on warfarin Predictive ability of risk stratification schemes for primary and secondary prevention

Atrial fibrillation (AF) patients are widely heterogeneous in terms of ischaemic stroke risk, and several risk stratification schemes have been developed. We performed a prospective study on 662 AF patients on long-term oral anticoagulant therapy (OAT), evaluating the agreement among the different schemes and their correlation with adverse events recorded during follow-up. Patients at low risk were similarly distributed among the different models. Instead, patients classed at moderate risk were 49.2% by CHADS(2) score, 27.6% by NICE and 2.3% by ACCP. As a consequence patients classed at high risk were 46.1% by CHADS(2), 69.8% by NICE and 95.3% by ACCP. CHADS(2 )and NICE scores were associated to the best predictive accuracy. A separate analysis was performed for patients on treatment for secondary prevention, and we observed that they were included in high risk groups by all models, except for 14 patients (6.3%) classed at moderate risk by CHADS(2) even though these patients are at very high risk and the use of aspirin could be unsafe for them. During follow-up 32 major bleeding (1.35 per 100 patient/years) and 39 thrombotic events (1.64 per 100 patient/years) were observed. Among patients on OAT for secondary prevention, both bleeding and thrombotic events mostly occurred in high-risk patients. Even if the absolute rate of adverse events is low, this finding seems to confirm the high stroke risk of this group of patients. For patients on secondary prevention there is no need for further stratification and warfarin should be the treatment of choice.

Retinal vein occlusions: a review for the internist

Retinal vein occlusion (RVO) is a disease that is often associated with a variety of systemic disorders including arterial hypertension, diabetes mellitus, dyslipidemia and systemic vasculitis. There are various types of RVO, categorized on the basis of the site of occlusion and on the type of consequent vascular damage. Central retinal vein occlusion (CRVO) is the most clinically relevant type of RVO. In addition to well-known classical risk factors, new thrombophilic factors have been investigated in patients with RVO. Data concerning a number of the parameters remain contradictory; yet, hyperhomocysteinemia and vitamins involved in methionine metabolism appear to play a significant role in the pathogenesis of this disease. Alterations in the fibrinolysis pathway (elevated levels of PAI-1 and Lipoprotein (a)), together with haemorheologic modifications have been recently consistently associated with the disease. Medical treatment includes identification and correction of vascular risk factors. In addition, LMWHs appear to be the best therapeutic approach even if based on a limited number of trials, conducted on a limited number of patients. No data are available on the possible role of antithrombotic strategies in the long-term prevention of recurrent RVO or vascular events.

Impact of glomerular filtration estimate on bleeding risk in very old patients treated with vitamin K antagonists. Results of EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics).

Vitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients ≥80 years naïve to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C-G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding.

The Role of D-dimer Testing in Patients with Suspected Venous Thromboembolism

D-dimer, the final degradation product of cross-linked fibrin, is typically elevated in patients with acute venous thromboembolism. With its high sensitivity and negative predictive value, D-dimer testing may have a role for ruling-out the diagnosis in patients with suspected deep vein thrombosis or pulmonary embolism. For this purpose, D-dimer testing has been integrated in sequential diagnostic strategies including those using pretest clinical probability assessment and imaging techniques. A large variety of assays are now available for D-dimer measurement, with different sensitivities and specificities for the diagnosis of venous thromboembolism. Attempts to standardize the various D-dimer assays have been made but without any definitive answers as yet. The diagnostic yield of D-dimer testing is affected not only by the choice of the appropriate assay but also by patient characteristics. As a consequence, the clinical usefulness of D-dimer testing for the exclusion of suspected venous thromboembolism should be carefully evaluated in special clinical settings.

Lack of activation of renal functional reserve predicts the risk of significant renal involvement in systemic sclerosis

Objective To evaluate if defective activation of renal functional reserve (RFR) in systemic sclerosis (SSc) without clinical signs of renal involvement predicts the risk of developing clinically relevant renal damage. Methods Twenty-eight normotensive SSc patients with normal renal function and no urinary abnormalities were submitted to an intravenous amino acid load to activate RFR. Nineteen patients (six with diffuse cutaneous SSc (dcSSc)) had an RFR activation defect, while nine (two with dcSSc) showed normal RFR. All patients were followed up for 5 years, with periodic evaluation of renal function, urinary protein excretion and systemic blood pressure (BP). Results At admission, patients with normal RFR had lower BP than those with abnormal RFR; no age, disease duration or creatinine clearance (CCr) differences were found. Five years later, patients with abnormal RFR showed, with respect to basal values, a significantly higher CCr reduction than patients with normal RFR (mean percent decrease 15.4±9.5 vs 2.6±3.8, p<0.001). Among patients with abnormal RFR, 13 (68.4%) showed a CCr reduction of ≥2 ml/min/year, with a final CCr of ≤70 ml/min in eight cases; two patients developed microalbuminuria and 10 grade 1 or 2 systemic hypertension. Significant CCr reduction rates were found in eight patients with high BP and in five patients who remained normotensive. No patient with normal RFR had proteinuria or high BP during follow-up. Conclusions Lack of RFR activation is an early sign of renal involvement in SSc, and is a harbinger of an increased risk of developing renal insufficiency and systemic hypertension.

Echocardiographic and biohumoral characteristics in patients with AL and TTR amyloidosis at diagnosis

Few studies have analyzed the clinical and echocardiographic differences between light‐chain (AL) and transthyretin (TTR) amyloidosis.

The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism.

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.