Subclinical atherosclerosis evolution during 5 years of anti-TNF-alpha treatment in psoriatic arthritis patients.

OBJECTIVES: Our aim was to evaluate subclinical atherosclerosis progression during 5 years of anti-tumour necrosis factor (TNF)-α treatment in psoriatic arthritis (PsA) patients. METHODS: Thirty-two consecutive PsA patients starting TNF-α inhibitors were enrolled and evaluated at baseline (T0), 2 years (FU1) and 5 years (FU2) of treatment. Arterial structural properties were evaluated by B-mode ultrasound of mean carotid intima-media thickness (mean-IMT) and maximum IMT (M-MAX) in each segment (common, bulb, internal), bilaterally. Endothelial function was assessed by post-occlusion flow-mediated dilation (FMD) of the brachial artery using high-sensitivity ultrasonography. Treatment response was studied through DAS28 (disease activity score) and inflammatory biomarkers (C-reactive protein, TNF-α, osteoprotegerin). Metrologic and metabolic data were collected. RESULTS: At T1, a significant decrease of DAS28 (4.2±0.7 vs. 2.3±0.8, p<0.001) and CRP (11.25±9.16 vs. 2.91±1.72, p<0.01) was observed. Efficacy was preserved at FU2 (DAS28 2.4±0.9, CRP 2.73±2.51; p=ns vs. FU1). Systolic blood pressure and BMI remained stable throughout the follow-up, while diastolic blood pressure decreased significantly from FU1 to FU2 (80±10 vs. 74±7 mmHg, p=0.001). From T0 to FU1 there was an increase of IMT-mean and M-MAX (0.7±0.1 vs. 0.9±0.4 and 0.9±0.2 vs. 1.1±0.4, p<0.01). At FU2, IMT-mean and M-max did not change significantly (0.9±0.3 and 1.1±0.3, p=ns vs. FU1). No significant variation in FMD values was observed during the study period. CONCLUSIONS: A slight progression of subclinical atherosclerosis in PsA was observed in the first 2 years of anti-TNF-α treatment. This process seemed to decelerate in follow-up extension to 5 years.

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation.

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Intima-media thickness remodelling in hypertensive subjects with long-term well-controlled blood pressure levels.

Aim of this study was to evaluate in a long follow-up the carotid artery remodelling in a cohort of young hypertensive subjects having good blood pressure (BP) control. We studied 20 grade I hypertensives (HT) by assessing the B-mode ultrasound of mean carotid intima-media thickness (mean-IMT) and maximum IMT (M-MAX) in each carotid artery segment (common, bulb, internal), bilaterally. We compared their ultrasound measurements with those recorded 5 and 10 years earlier. While the first 5-year follow-up was observational, in the second 5-year follow-up, lifestyle modifications and/or pharmacological therapy were started to obtain well-controlled BP levels. Office BP was measured at the time of the ultrasound studies and every 6 months during the follow-up. BP levels were: 10 years 144/91 mmHg, 5 years 143/90 mmHg and 129 ± 79 mmHg at the time of the study. In the first 5-year observational follow-up, both mean-IMT and M-MAX increased (Δ 0.116 and Δ 0.165 mm, respectively, p < 0.0005). In the 5-year intervention follow-up, characterized by well-controlled BP, mean-IMT slightly but significantly increased (Δ 0.084 mm, p = 0.004), whereas M-MAX remained stable (Δ 0.026 mm). In our HT, well-controlled BP levels were able to prevent pro-atherogenic remodelling (expressed by M-MAX). Conversely, good BP control slightly decreased but did not stop the progression in mean-IMT, which is likely to reflect some hypertrophy of the arterial media layer.

ANMCO Position Paper: long-term follow-up of patients with pulmonary thromboembolism.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, is the third most common cause of cardiovascular death. The management of the acute phase of VTE has already been described in several guidelines. However, the management of the follow-up (FU) of these patients has been poorly defined. This consensus document, created by the Italian cardiologists, wants to clarify this issue using the currently available evidence in VTE. Clinical and instrumental data acquired during the acute phase of the disease are the cornerstone for planning the FU. Acquired or congenital thrombophilic disorders could be identified in apparently unprovoked VTE during the FU. In other cases, an occult cancer could be discovered after a VTE. The main targets of the post-acute management are to prevent recurrence of VTE and to identify the patients who can develop a chronic thromboembolic pulmonary hypertension. Knowledge of pathophysiology and therapeutic approaches is fundamental to decide the most appropriate long-term treatment. Moreover, prognostic stratification during the FU should be constantly updated on the basis of the new evidence acquired. Currently, the cornerstone of VTE treatment is represented by both the oral and the parenteral anticoagulation. Novel oral anticoagulants should be an interesting alternative in the long-term treatment.

The optimal duration of anticoagulant therapy after unprovoked venous thromboembolism - still a challenging issue.

As about 50 % of patients with unprovoked venous thromboembolism (VTE) will develop new episodes after discontinuing therapy, indefinite treatment is suggested in patients with low or moderate bleeding risk. Baseline and post-baseline factors can help clinicians to identify patients at high risk of recurrence, who require extended treatment. Residual vein obstruction and D-dimer assay have been shown to be suitable methods for assessing the risk of VTE recurrences after a first unprovoked VTE. In treatment for VTE the use of direct oral anticoagulants (DOAC) is growing instead of the standard adjusted dose of vitamin K antagonists. The DOAC safety profile has recently been strengthened with systematic reviews and meta-analyses. Idarucizumab is only approved for the reversal of dabigatran etexilate; intravenous antidotes for factor Xa inhibitors are under development. Their advent is of great interest. In the extended treatment of VTE sulodexide has been demonstrated to significantly decrease the risk of recurrences with an excellent safety profile. Aspirin is substantially less effective than oral anticoagulants in preventing recurrences but could play a role among patients who decided to stop anticoagulants. In conclusion, for the secondary prevention of VTE several options are available, without a recognised best choice regarding the treatment duration and the choice of drugs. An individual strategy taking into account risk of recurrence, bleeding risk, therapeutic options, and patient preferences is appropriate.

Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism.

The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.

The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation.

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding.

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, "sticky" red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial-mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data.

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

Heart disease may be a risk factor for pulmonary embolism without peripheral deep venous thrombosis.

BACKGROUND: Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain. METHODS AND RESULTS: We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45,282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59,790 had deep venous thrombosis alone; 541,561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6-47.8] and 32.4 [95% CI, 29.8-35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0-24.2] and 22.1 [95% CI, 18.7-26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6-10.7] and 12.7 [95% CI, 11.6-13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3-16.1), whereas the odds ratio was 74.6 (95% CI, 28.4-195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern. CONCLUSION: Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.

Venous thromboembolism and arterial complications.

An increasing body of evidence suggests the likelihood of a link between venous and arterial thrombosis. The two vascular complications share several risk factors, such as age, obesity, smoking, diabetes mellitus, blood hypertension, hypertriglyceridemia, and metabolic syndrome. Moreover, there are many examples of conditions accounting for both venous and arterial thrombosis, such as the antiphospholipid antibody syndrome, hyperhomocysteinemia, malignancies, infections, and the use of hormonal treatment. Finally, several recent studies have consistently shown that patients with venous thromboembolism are at a higher risk of arterial thrombotic complications than matched control individuals. We, therefore, speculate the two vascular complications are simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Future studies are needed to clarify the nature of this association, to assess its extent, and to evaluate its implications for clinical practice.

Thromboembolic Complications in COVID-19 Patients Hospitalized in Italian Ordinary Wards: Data from the Multicenter Observational START-COVID Register.

Background Coronavirus disease 2019 (COVID-19) infection causes acute respiratory insufficiency with severe interstitial pneumonia and extrapulmonary complications; in particular, it may predispose to thromboembolic disease. The reported incidence of thromboembolic complications varies from 5 to 30% of cases. Aim We conducted a multicenter, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe the clinical characteristics of patients at admission and bleeding and thrombotic events occurring during the hospital stay. Results The number of hospitalized patients included in the START-COVID-19 Register was 1,135, and the number of hospitalized patients in ordinary wards included in the study was 1,091, with 653 (59.9%) being males and 71 years (interquartile range 59-82 years) being the median age. During the observation, two (0.2%) patients had acute coronary syndrome episodes and one patient (0.1%) had an ischemic stroke; no other arterial thrombotic events were recorded. Fifty-nine patients had symptomatic venous thromboembolism (VTE) (5.4%) events, 18 (30.5%) deep vein thrombosis (DVT), 39 (66.1%) pulmonary embolism (PE), and 2 (3.4%) DVT+PE. Among patients with DVT, eight (44.4%) were isolated distal DVT and two cases were jugular thrombosis. Among patients with PE, seven (17.9%) events were limited to subsegmental arteries. No fatal PE was recorded. Major bleeding events occurred in nine (1.2%) patients and clinically relevant nonmajor bleeding events in nine (1.2%) patients. All bleeding events occurred among patients receiving thromboprophylaxis, more frequently when treated with subtherapeutic or therapeutic dosages. Conclusion Our findings confirm that patients admitted to ordinary wards for COVID-19 infection are at high risk for thromboembolic events. VTE recorded among these patients is mainly isolated PE, suggesting a peculiar characteristic of VTE in these patients.

Optimal duration of anticoagulation in patients with venous thromboembolism.

The risk of recurrent venous thromboembolism (VTE) approaches 40 per cent of all patients after 10 yr of follow up. This risk is higher in patients with permanent risk factors of thrombosis such as active cancer, prolonged immobilization from medical diseases, and antiphospholipid syndrome; in carriers of several thrombophilic abnormalities, including deficiencies of natural anticoagulants; and in patients with unprovoked presentation. Patients with permanent risk factors of thrombosis should receive indefinite anticoagulation, consisting of subtherapeutic doses of low molecular weight heparin in cancer patients, and oral anticoagulants in all other conditions. Patients whose VTE is triggered by major surgery or trauma should be offered three months of anticoagulation. Patients with unprovoked VTE, including carriers of thrombophilia, and those whose thrombotic event is associated with minor risk factors (such as hormonal treatment, minor injuries, long travel) should receive at least three months of anticoagulation. The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk. Post-baseline variables, such as the D-dimer determination and the ultrasound assessment of residual thrombosis can help identify those patients in whom anticoagulation can be safely discontinued. As a few emerging anti-Xa and anti-IIa compounds seem to induce fewer haemorrhagic complications than conventional anticoagulation, while preserving at least the same effectiveness, these have the potential to open new scenarios for decisions regarding the duration of anticoagulation in patients with VTE.

Weight-adjusted versus fixed dose heparin thromboprophylaxis in hospitalized obese patients: A systematic review and meta-analysis.

BACKGROUND: Fixed dose unfractionated or low molecular weight heparin is the recommended treatment for venous thromboembolism (VTE) prevention in hospitalized patients. However, its efficacy has been questioned in obese population. Results of previous studies on weight-adjusted doses of heparin for VTE prevention are contradictory. Different anticoagulant regimens are used in clinical practice, but their role remains to be elucidated. AIMS: To clarify the efficacy and safety of weight-adjusted dose heparin for VTE prevention in obese subjects hospitalized for medical and surgical conditions. METHODS: Twelve studies were identified as reporting VTE occurrence, major or minor bleeding and anti-Xa levels. A random-effect meta-analysis was conducted to derive odds ratios (OR) comparing fixed vs weight adjusted-doses heparins on VTE occurrence, bleeding, anti-Xa levels. Medical and surgical patients, prospective vs retrospective and quality of studies were extracted for moderators and meta-regression analysis. RESULTS: Weight-adjusted dose heparin administration was not associated with reduced VTE occurrence (6320/13317 patients, OR 1.03, 95% C.I. 0.79 to 1.35), nor increased bleeding (5840/10906 patients, OR 0.84, 95% C.I. 0.65 to 1.08), but it was associated with higher anti-Xa levels (284/294 patients, ES 2.04, 95% C.I. 1.16 to 2.92, p<0.0001). A significant heterogeneity was present for comparison of anti-Xa levels (I2=94%, p=0.0001) but not for VTE occurrence or bleeding (I2=7.6% and 12.8% respectivel). None of the moderators explained the heterogeneity of the results among primary studies. CONCLUSION: Weight-adjusted dose as compared to fixed-dose of heparins in the prevention of VTE in obese patients was not associated with a lower risk of VTE nor a higher risk of bleeding.