Antithrombotic therapy in peripheral arterial disease.

Background: Patients with peripheral arterial disease (PAD) are at increased risk for major adverse cardiovascular events (MACE) such as cardiovascular death, myocardial infarction, and stroke as well as major adverse limb events (MALE) such as amputation and acute limb ischemia. Therefore, prevention of thrombotic events is crucial to improve the prognosis of PAD patients. This review article concludes current evidence and guideline recommendations about antithrombotic therapy in PAD patients.Antithrombotic therapy is highly effective to reduce MACE and MALE events in PAD patients. Recently, the concept of dual pathway inhibition (low-dose rivaroxaban plus acetylic salicylic acid (ASA) has been tested in the COMPASS and VOYAGER-PAD trial. Compared to ASA alone dual pathway inhibition was superior to prevent MACE and MALE. After peripheral revascularization, in particular the risk for acute limb ischemia was reduced. In contrast, the risk for major bleeding is increased. Therefore, current guidelines recommend the combination of low-dose rivaroxaban and ASA in PAD patients with low bleeding risk. In patients with high bleeding risk, a single antiplatelet drug (preferable clopidogrel) is indicated. In patients with atherosclerotic vascular disease and indication for oral anticoagulation, no additional antiplatelet drug is necessary, as this would increase the risk of bleeding without improving the prognosis. Conclusion: Antithrombotic treatment reduces MACE and MALE and is recommended in all patients with PAD. Individual bleeding risk should always be considered based on the current data situation and an individual benefit-risk assessment must be carried out.

Differential Inhibition of Platelet Reactivity by Dual Therapy With Aspirin and Low-Dose Rivaroxaban in Peripheral Arterial Disease: A Pilot Study.

Patients with peripheral arterial disease (PAD) benefit from combination therapy with acetylsalicylic acid (ASA, 100 mg, one time per day) plus low-dose rivaroxaban (2.5 mg, two times per day) compared to ASA monotherapy. In particular, major adverse cardiac and limb events were significantly reduced after peripheral endovascular revascularization (EVR). In this pilot study, the platelet activation status in vivo and platelet reactivity in vitro were longitudinally analyzed by flow cytometric assays and calibrated automated thrombography in platelet-rich plasma (PRP) from 10 patients with PAD receiving ASA (100 mg, one time per day) before EVR, ASA plus clopidogrel (75 mg, one time per day) after EVR, and ASA plus rivaroxaban (2.5 mg, two times per day) during a long-term follow-up. Platelet responsiveness to clopidogrel was compared to additional 10 patients with stable PAD and clopidogrel (75 mg, one time per day) monotherapy. ASA plus rivaroxaban treatment resulted in a significantly decreased thrombin peak in PRP for two triggers, namely, low concentration of tissue factor (TF) and thrombin, compared to ASA monotherapy. TF-controlled thrombin generation was additionally characterized by a significantly prolonged lag time in PRP and platelet-free plasma during ASA plus rivaroxaban combination therapy. In comparison, ASA plus clopidogrel treatment presented a significant reduction of the thrombin peak in PRP, which was less pronounced than during subsequent ASA plus rivaroxaban therapy. Platelet responsiveness to clopidogrel was observed for 60% of patients receiving ASA plus clopidogrel and clopidogrel monotherapy, respectively. Blocking of CD36 on the platelet surface further reduced the thrombin peak in PRP induced by TF for all three therapy regimes. Platelet activation in vivo and in response to the GPVI-agonist convulxin or thrombin in vitro was similar, whereas integrin αIIbß3 activation and α-granule release induced by the PAR-1 activating peptide TRAP-6 were significantly diminished during ASA plus rivaroxaban treatment compared to ASA monotherapy. In conclusion, the data of this pilot study indicate an inhibitory effect of rivaroxaban on the thrombin propagation phase of CD36-sensitive platelet thrombin formation in patients with PAD treated with ASA plus rivaroxaban combination therapy, which is associated with decreased PAR-1 but not thrombin-mediated platelet activation.

[Conservative treatment of peripheral arterial disease]. / Konservative Therapie der peripheren arteriellen Verschlusskrankheit.

Patients with peripheral arterial disease (PAD) often have polyvascular atherosclerosis and are at increased risk of major adverse cardiovascular events (MACE), such as cardiovascular death, myocardial infarction or stroke, and major adverse limb events (MALE), such as amputation and acute limb ischemia. Therefore, the aim of conservative treatment is the reduction of MACE and MALE. In patients with intermittent claudication, the aim is also to extend walking distance. Management of risk factors includes smoking cessation, statin therapy, reduction of low-density lipoprotein cholesterol (target < 55 mg/dL and reduction to at least 50% of baseline value), normalization of blood glucose and treatment of arterial hypertension (target < 140/90 mm Hg). Moreover, antithrombotic treatment should include antiplatelet therapy (acety salicylic acid 100 mg or clopidogrel 75 mg). In patients at high thrombotic risk and low bleeding risk combination of acetlylic acid 100 mg and rivaroxaban 2 × 2.5 mg is indicated. In patients with intermittent claudication exercise therapy is highly recommended. Despite the high risk, in particular patients with PAD are often undertreated in clinical practice.

Tissue optical perfusion pressure: a simplified, more reliable, and faster assessment of pedal microcirculation in peripheral artery disease.

Oscillometry is an alternative to continuous-wave Doppler (cw-Doppler) to determine peripheral artery disease (PAD) severity using the ankle-brachial index (ABI). cw-Doppler ABI differentiates systolic pressure of ATP and ADP where either one of both values in most patients is higher (high) and the other value is lower (low). In contrast, oscillometric ABI measures the strongest signal and hence misses the lower value. Both do not take pedal perfusion into consideration. Simultaneous determination of tissue microperfusion cares for pedal PAD. ABI was determined by cw-Doppler and oscillometry. Tissue optical perfusion pressure (TOPP) was taken from the first toe using photoplethysmography. 323 patients were evaluated retrospectively in 3 independent groups. group 1 (99 patients) compared TOPP and oscillometric ABI with systolic cw-Doppler-pressure and cw-Doppler ABI. In group 2 (103 patients) TOPP was compared with toe pressure (TP). In group3 (121 symptomatic patients) TOPP and ABI at rest and after stress were compared (ultrasound examination and magnetic resonance angiography (MRA) or computer tomography angiography (CTA) as control). Bland-Altman-plot analysis presented no significant difference between oscillometric ABI and the high cw-Doppler ABI (group 1). TOPP showed a difference of 26mmHg to the low cw-Doppler-pressure and none to the high cw-Doppler-pressure. In group 2 TOPP correlates to TP but presented a difference of 37 mmHg. group 3 showed weak or no correlation between ABI and walking distance. Oscillometric ABI correlates significantly to TOPP. To conclude, data after stress present a better correlation than at rest. We conclude that TOPP provides absolute values of pedal macro-/microcirculation at rest and after stress tests.NEW & NOTEWORTHY This new application of photoplethysmography investigated the microcirculation in peripheral artery disease at the level of the toe pad and determined the tissue optical perfusion pressure as the first pulsatile signal during automatic cuff deflation at the ankle. It is the first time that this method has been integrated for simultaneous routine examination in an automatic oscillometric ankle-brachial index (ABI) system. This quick and simple measurement technique provides clinical information on the microcirculation downstream the routine ABI measurement at rest and in particular after stress test.

Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants.

As a result of the successful completion of their respective phase III studies compared with vitamin K antagonists (VKAs), four direct oral anticoagulants (DOACs) have been approved for the treatment and secondary prevention of venous thromboembolism (VTE). These DOACs-apixaban, dabigatran, edoxaban, and rivaroxaban-have subsequently seen a steady uptake among clinicians since their approval. Despite the suitability of DOACs for a broad range of patients, they are not appropriate in certain situations, whereas in others they require additional considerations such as dose reductions. Subanalyses of phase III trials and studies on specific VTE patient populations have been conducted to evaluate the safety and efficacy of the DOACs in a broad range of settings, such as patients with renal impairment, patients with cancer, patients of childbearing potential, patients with multiple comorbidities and pediatric patients. Furthermore, many recent guidance documents from important hematological societies and other specialists have incorporated several of these developments. These documents also identify the patients for whom DOACs are not suitable and where traditional anticoagulation options such as heparins or VKAs should be considered instead. This review provides an overview of key VTE patient subgroups, the clinical evidence supporting the use of anticoagulation in these patients, and a discussion of the most appropriate approaches to their management, including considerations such as dosing, acute and extended treatment durations, and DOAC selection.

Contemporary results with the biosynthetic glutaraldehyde denatured ovine collagen graft (Omniflow II) in femoropopliteal position.

OBJECTIVE: The objective of this study was to analyze the outcome of a contemporary series of femoropopliteal bypass operations with the glutaraldehyde denatured polyester mesh-reinforced ovine collagen prosthesis (OCP; Omniflow II [LeMaitre Vascular, Inc, Burlington, Mass]). The experience of two tertiary centers regarding long-term graft function, secondary reinterventions, and biodegeneration of the OCP prosthesis is presented. METHODS: Between January 2006 and January 2014, a series of 205 consecutive operations with the OCP in the femoropopliteal position (54 above knee and 151 below knee) were performed in 194 patients in 202 limbs for disabling claudication (72), chronic critical ischemia (105), acute ischemia (18), popliteal artery aneurysm (4), degeneration of a venous or prosthetic graft (5), and infection of a synthetic bypass graft (1). Grafts were observed with duplex ultrasound scan supplemented by additional angiography in case of recurrent ischemia with prospective documentation of follow-up data in a computerized vascular database. Retrospective analysis of graft patency, limb salvage, and diagnosis of aneurysmal graft degeneration was performed. RESULTS: The 30-day mortality was 3.9%. Early thrombotic bypass occlusion occurred in 8.2% of cases. Four early graft infections could be successfully managed by local treatment with graft preservation. After a mean (median) follow-up of 56 (55) months (range, 1-135 months), primary patency, primary assisted patency, secondary patency, and limb salvage were 71%, 78%, 78%, and 91% for above-knee bypass and 40%, 50%, 63%, and 87% for below-knee bypass at 5 years. Biodegeneration in the form of graft aneurysm or graft stenosis was detected in 26 grafts (12.6%), resulting in secondary open or endovascular procedures in 16 cases. CONCLUSIONS: The OCP provides satisfactory medium- and long-term patency and limb salvage in the femoropopliteal position. Aneurysmal degeneration or graft stenosis may develop over time, demanding lifelong duplex ultrasound surveillance and secondary intervention if needed. Its possible infection-resistant behavior in a contaminated field combined with an acceptable graft patency and limb salvage justifies the use of this graft in the absence of autologous vein.

Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis.

Previous reports have investigated the impact of age on D-Dimer testing in elderly individuals with suspected deep vein thrombosis (DVT), but data on the age-related diagnostic value of D-dimer in a sample covering a broad age range are limited. The present study determined age-specifically the diagnostic accuracy of D-dimer and compared it to C-reactive protein (CRP), a marker of inflammation, in 500 patients with suspected DVT from the VTEval project (NCT02156401). Sensitivity of D-dimer was lower in patients < 60 years in comparison to patients ≥ 60 years (∆-16.8%), whereas specificity was 27.9% higher. Lowest levels of sensitivity were detected for female sex, unprovoked DVT, low thrombotic burden, and distal DVT. A fixed D-dimer threshold of 0.25 mg/L FEU resulted in elevated sensitivity for patients < 60 with a reduction of false negatives by 40.0% for proximal DVT and by 50.0% for distal DVT. In patients < 60 years, D-dimer and CRP demonstrated comparable diagnostic performance for both proximal and distal DVT (p > 0.05). In conclusion, these data outline a clinically-relevant limitation of D-dimer testing among younger patients with suspected DVT indicating a necessity for age-adapted cut-off values. Further research is required to decrypt the role of inflammation in the pathophysiology and diagnosis of venous thrombosis.

Crural Bypass for Critical Lower Limb Ischemia with Omniflow II Prosthesis.

Background Reports about the use of the Omniflow II prosthesis (Bio Nova International, Victoria, Australia) in a crural position in patients with critical lower limb ischemia are rare. Methods All crural bypass operations were registered in a database. Primary end points of the study were amputation-free survival, limb salvage, and long-term patency. Results From January 2007 to December 2012, we implanted 27 Omniflow II prostheses in the crural position for critical lower limb ischemia. Of these, 12 crural bypasses were conducted with adjuvant distal arteriovenous fistula as a means to increase bypass flow in the presence of severely impaired intraoperative runoff or revision for early failure. Fifteen Omniflow II prosthesis bypasses were performed in the crural position without fistula. Overall, two patients died postoperatively. The limb salvage rate was 92% in the fistula group compared with 60% in the nonfistula group after a median observation time of 19 months in patients getting Omniflow prosthesis bypasses. Conclusion Omniflow II prosthesis in patients with critical lower limb ischemia and absence of sufficient autologous vein is durable. Moreover, the use of adjuvant distal arteriovenous fistula may increase the chance of limb salvage in this group of patients.

Rationale and design of three observational, prospective cohort studies including biobanking to evaluate and improve diagnostics, management strategies and risk stratification in venous thromboembolism: the VTEval Project.

INTRODUCTION: Venous thromboembolism (VTE) with its two manifestations deep vein thrombosis (DVT) and pulmonary embolism (PE) is a major public health problem. The VTEval Project aims to investigate numerous research questions on diagnosis, clinical management, treatment and prognosis of VTE, which have remained uncertain to date. METHODS AND ANALYSIS: The VTEval Project consists of three observational, prospective cohort studies on VTE comprising cohorts of individuals with a clinical suspicion of acute PE (with or without DVT), with a clinical suspicion of acute DVT (without symptomatic PE) and with an incidental diagnosis of VTE (PE or DVT). The VTEval Project expects to enrol a total of approximately 2000 individuals with subsequent active and passive follow-up investigations over a time period of 5 years per participant. Time points for active follow-up investigations are at months 3, 6, 12, 24 and 36 after diagnosis (depending on the disease cohort); passive follow-up investigations via registry offices and the cancer registry are performed 48 and 60 months after diagnosis for all participants. Primary short-term outcome is defined by overall mortality (PE-related death and all other causes of death), primary long-term outcome by symptomatic VTE (PE-related death, recurrence of non-fatal PE or DVT). The VTEval Project includes three 'all-comer' studies and involves the standardised acquisition of high-quality data, covering the systematic assessment of VTE including symptoms, risk profile, psychosocial, environmental and lifestyle factors as well as clinical and subclinical disease, and it builds up a large state-of-the-art biorepository containing various materials from serial blood samplings. ETHICS AND DISSEMINATION: The VTEval Project has been approved by the local data safety commissioner and the responsible ethics committee (reference no. 837.320.12 (8421-F)). Trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT02156401.

ß-Blockers in patients with intermittent claudication and arterial hypertension: results from the nebivolol or metoprolol in arterial occlusive disease trial.

The use of ß-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone. The ß-blocker nebivolol possesses vasodilating, endothelium-dependent, NO-releasing properties that might be beneficial in peripheral arterial disease. The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients. A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind randomized to receive 5 mg of nebivolol (N=65) or 95 mg of metoprolol (N=63) once daily. End points were changes in ankle-brachial index, initial and absolute claudication distance, endothelial function assessed by flow-mediated dilatation of the brachial artery, blood pressure, and quality of life using the claudication scale questionnaire. End point analysis was possible in 109 patients (85.2%). After the 48-week treatment period, ankle-brachial index and absolute claudication distance improved significantly in both patient groups (P<0.05 for both), with no difference across treatments. A significant increase of initial claudication distance was found in the nebivolol group. Adjusted mean change of initial claudication distance was 33.9% after nebivolol (P=0.003) and 16.6% after metoprolol (P=0.12) treatment. Quality of life was not influenced by either treatment, and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol (P=0.16). Both drugs were equally effective in lowering blood pressure. In conclusion, ß-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year. In the direct comparison, there was no significant difference between nebivolol and metoprolol.