Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb.

BACKGROUND: Standard treatment for deep vein thrombosis (DVT) aims to reduce immediate complications. Use of thrombolytic clot removal strategies (i.e. thrombolysis (clot dissolving drugs), with or without additional endovascular techniques), could reduce the long-term complications of post-thrombotic syndrome (PTS) including pain, swelling, skin discolouration, or venous ulceration in the affected leg. This is the fourth update of a Cochrane Review first published in 2004. OBJECTIVES: To assess the effects of thrombolytic clot removal strategies and anticoagulation compared to anticoagulation alone for the management of people with acute deep vein thrombosis (DVT) of the lower limb. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries to 21 April 2020. We also checked the references of relevant articles to identify additional studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) examining thrombolysis (with or without adjunctive clot removal strategies) and anticoagulation versus anticoagulation alone for acute DVT. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. We assessed the risk of bias in included trials with the Cochrane 'Risk of bias' tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we calculated the risk ratio (RR) with the corresponding 95% confidence interval (CI). We pooled data using a fixed-effect model, unless we identified heterogeneity, in which case we used a random-effects model. The primary outcomes of interest were clot lysis, bleeding and post thrombotic syndrome. MAIN RESULTS: Two new studies were added for this update. Therefore, the review now includes a total of 19 RCTs, with 1943 participants. These studies differed with respect to the thrombolytic agent, the doses of the agent and the techniques used to deliver the agent. Systemic, loco-regional and catheter-directed thrombolysis (CDT) strategies were all included. For this update, CDT interventions also included those involving pharmacomechanical thrombolysis. Three of the 19 included studies reported one or more domain at high risk of bias. We combined the results as any (all) thrombolysis interventions compared to standard anticoagulation. Complete clot lysis occurred more frequently in the thrombolysis group at early follow-up (RR 4.75; 95% CI 1.83 to 12.33; 592 participants; eight studies) and at intermediate follow-up (RR 2.42; 95% CI 1.42 to 4.12; 654 participants; seven studies; moderate-certainty evidence). Two studies reported on clot lysis at late follow-up with no clear benefit from thrombolysis seen at this time point (RR 3.25, 95% CI 0.17 to 62.63; two studies). No differences between strategies (e.g. systemic, loco-regional and CDT) were detected by subgroup analysis at any of these time points (tests for subgroup differences: P = 0.41, P = 0.37 and P = 0.06 respectively). Those receiving thrombolysis had increased bleeding complications (6.7% versus 2.2%) (RR 2.45, 95% CI 1.58 to 3.78; 1943 participants, 19 studies; moderate-certainty evidence). No differences between strategies were detected by subgroup analysis (P = 0.25). Up to five years after treatment, slightly fewer cases of PTS occurred in those receiving thrombolysis; 50% compared with 53% in the standard anticoagulation (RR 0.78, 95% CI 0.66 to 0.93; 1393 participants, six studies; moderate-certainty evidence). This was still observed at late follow-up (beyond five years) in two studies (RR 0.56, 95% CI 0.43 to 0.73; 211 participants; moderate-certainty evidence). We used subgroup analysis to investigate if the level of DVT (iliofemoral, femoropopliteal or non-specified) had an effect on the incidence of PTS. No benefit of thrombolysis was seen for either iliofemoral or femoropopliteal DVT (six studies; test for subgroup differences: P = 0.29). Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included four trials in femoral and iliofemoral DVT, and results from these are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion. AUTHORS' CONCLUSIONS: Complete clot lysis occurred more frequently after thrombolysis (with or without additional clot removal strategies) and PTS incidence was slightly reduced. Bleeding complications also increased with thrombolysis, but this risk has decreased over time with the use of stricter exclusion criteria of studies. Evidence suggests that systemic administration of thrombolytics and CDT have similar effectiveness. Using GRADE, we judged the evidence to be of moderate-certainty, due to many trials having small numbers of participants or events, or both. Future studies are needed to investigate treatment regimes in terms of agent, dose and adjunctive clot removal methods; prioritising patient-important outcomes, including PTS and quality of life, to aid clinical decision making.

Thrombolysis for acute deep vein thrombosis.

BACKGROUND: Standard treatment for deep vein thrombosis aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome (PTS) including pain, swelling, skin discolouration, or venous ulceration in the affected leg. This is the third update of a review first published in 2004. OBJECTIVES: To assess the effects of thrombolytic therapy and anticoagulation compared to anticoagulation alone for the management of people with acute deep vein thrombosis (DVT) of the lower limb as determined by the effects on pulmonary embolism, recurrent venous thromboembolism, major bleeding, post-thrombotic complications, venous patency and venous function. SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2016). In addition the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 1)). Trial registries were searched for details of ongoing or unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT were considered. DATA COLLECTION AND ANALYSIS: For this update (2016), LW and CB selected trials, extracted data independently, and sought advice from MPA where necessary. We assessed study quality with the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). Data were pooled using a fixed-effect model unless significant heterogeneity was identified in which case a random-effects model was used. GRADE was used to assess the overall quality of the evidence supporting the outcomes assessed in this review. MAIN RESULTS: Seventeen RCTs with 1103 participants were included. These studies differed in the both thrombolytic agent used and in the technique used to deliver it. Systemic, loco-regional and catheter-directed thrombolysis (CDT) were all included. Fourteen studies were rated as low risk of bias and three studies were rated as high risk of bias. We combined the results as any (all) thrombolysis compared to standard anticoagulation. Complete clot lysis occurred significantly more often in the treatment group at early follow-up (RR 4.91; 95% CI 1.66 to 14.53, P = 0.004) and at intermediate follow-up (RR 2.44; 95% CI 1.40 to 4.27, P = 0.002; moderate quality evidence). A similar effect was seen for any degree of improvement in venous patency. Up to five years after treatment significantly less PTS occurred in those receiving thrombolysis (RR 0.66, 95% CI 0.53 to 0.81; P < 0.0001; moderate quality evidence). This reduction in PTS was still observed at late follow-up (beyond five years), in two studies (RR 0.58, 95% CI 0.45 to 0.77; P < 0.0001; moderate quality evidence). Leg ulceration was reduced although the data were limited by small numbers (RR 0.87; 95% CI 0.16 to 4.73, P = 0.87). Those receiving thrombolysis had increased bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006; moderate quality evidence). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow-up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included two trials in femoral and iliofemoral DVT, and results from these are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion. AUTHORS' CONCLUSIONS: Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Evidence suggests that systemic administration and CDT have similar effectiveness. Strict eligibility criteria appears to improve safety in recent studies and may be necessary to reduce the risk of bleeding complications. This may limit the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. Using GRADE assessment, the evidence was judged to be of moderate quality due to many trials having low numbers of participants. However, the results across studies were consistent and we have reasonable confidence in these results.

Thrombolysis for acute deep vein thrombosis.

BACKGROUND: Standard treatment for deep vein thrombosis aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome (PTS) (pain, swelling, skin discolouration, or venous ulceration) in the affected leg. This is the second update of a review first published in 2004. OBJECTIVES: To assess the effects of thrombolytic therapy and anticoagulation versus anticoagulation in the management of people with acute deep vein thrombosis (DVT) of the lower limb as determined by the effects on pulmonary embolism, recurrent venous thromboembolism, major bleeding, post-thrombotic complications, venous patency and venous function. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and CENTRAL (2013, Issue 4). SELECTION CRITERIA: Randomised controlled trials (RCTs) examining thrombolysis and anticoagulation versus anticoagulation for acute DVT were considered. DATA COLLECTION AND ANALYSIS: In the previous review of 2010, one review author (LW) selected trials, extracted data and assessed study quality, with checking at all stages by the other review author (MPA). If necessary, we sought additional information from trialists. For this update (2013), LW and CB selected trials, extracted data independently, and sought advice from MPA where necessary. All studies, existing and new, required full risk of bias assessment in line with current Cochrane procedures. Two of LW, CB and MA independently assessed risk of bias with discussion with the third author where necessary. MAIN RESULTS: Seventeen studies with 1103 participants were included. Complete clot lysis occurred significantly more often in the treatment group in early follow up (risk ratio (RR) 4.91; 95% confidence interval (CI) 1.66 to 14.53, P = 0.004) and at intermediate follow up (RR 2.37; 95% CI 1.48 to 3.80, P = 0.0004). A similar effect was seen for any degree of improvement in venous patency. Significantly less PTS occurred in those receiving thrombolysis, (RR 0.64; 95% CI 0.52 to 0.79, P < 0.0001). Leg ulceration was reduced although the data were limited by small numbers (RR 0.48; 95% CI 0.12 to 1.88, P = 0.29). Those receiving thrombolysis had significantly more bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis is now not commonly used and catheter-directed thrombolysis (CDT) is the more favoured means of administration. This has been studied in iliofemoral DVT, and results from two trials are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion. AUTHORS' CONCLUSIONS: Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Strict eligibility criteria are necessary to reduce the risk of bleeding complications and this limits the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. In recent years CDT is the most studied route of administration, and results appear to be similar to systemic administration.

Do novel risk biomarkers reflect the severity of peripheral arterial disease?

The association between novel atherosclerotic risk biomarkers and severity of peripheral arterial disease (PAD) was assessed. Patients (n = 133) with PAD were recruited. Established risk biomarkers including low- and high-density cholesterol, triglycerides, and blood pressure were measured. Novel risk biomarkers including plasma C-reactive protein, von Willebrand factor (vWF), interleukin 6, red cell folate (RCF), vitamin B12, total homocysteine (tHcy), and Hcy genotypes were also determined. The severity of PAD was evaluated, using ankle-brachial pressure index (ABPI), brachial-knee, and brachial-ankle pulse wave velocity (bk- and ba-PWV). Plasma tHcy and systolic blood pressure had a positive independent correlation with bk-PWV (ß = +0.56, P = .02 and ß = +0.38, P < .001, respectively). Red cell folate had an independent inverse correlation with bk-PWV (ß = -0.01, P = .01). Systolic blood pressure showed an independent positive correlation with ba-PWV only after adjustment for other risk biomarkers (ß = +0.1, P = .04). Novel markers, plasma tHcy, and RCF levels correlated with the severity of PAD.

Are femorodistal bypass grafts for acute limb ischemia worthwhile / Vantagem associada ao uso de enxertos femorodistais para isquemia aguda de membros

Background: It has been shown that autogenous veins are associated with the best limb salvage rates for femorodistal bypass surgery. However, in emergency settings, when an autogenous vein is unavailable, use of synthetic graft material or amputation is a critical decision to make. Objective: To assess the appropriateness of femorodistal bypass grafts for acute limb ischemia in emergency settings. Methods: Patients who underwent emergent bypass and elective femorodistal bypass surgery between 1996 and 2006 were reviewed retrospectively in a single center. Results: There were 147 patients of which 84 had elective and 63 had emergent bypass. The graft patency rates for elective admissions were 44 and 25 percent vs. 25 and 23 percent for admissions for acute femorodistal graft surgery at 2 and 4 years, respectively (p < 0.004). Admissions for acute ischemia who were treated with prosthetic grafts had a primary patency of 24 vs. 27 percent for vein grafts at 2 years and 24 vs. 23 percent at 4 years (p = 0.33). In the acute femorodistal grafts group, primary patency at 2 years for vein and prosthetic grafts was 27 and 24 percent as compared to 42 and 32 percent for electives. These values for cumulative limb salvage rates for elective bypasses were 73 and 63 percent as compared to 52 percent at both time points in the acute femorodistal graft group (p < 0.004). In emergency settings, the limb salvage rate for acute femorodistal bypass with prosthetic grafts was 38 percent, and for vein grafts it was 62 percent at both time points (p = 0.08). Conclusion: The long term limb salvage rate of 38 percent suggests that emergent femorodistal revascularization is worthwhile.

Contexto: Já foi mostrado que veias autógenas estão associadas às melhores taxas de salvamento de membros para a cirurgia de bypass femorodistal. No entanto, em cenários de emergência, quando não há uma veia autógena disponível, é crítica a decisão entre o uso de material de enxerto sintético ou a amputação. Objetivo: Avaliar a adequação de enxertos femorodistais para isquemia aguda de membros em cenários de emergência. Métodos: Pacientes submetidos a cirurgia de bypass de urgência e cirurgia de bypass femorodistal eletiva entre 1996 e 2006 foram retrospectivamente revisados em um único centro. Resultados: Havia 147 pacientes, dentre os quais 84 haviam sido submetidos à cirurgia de bypass eletiva e 63 à cirurgia de bypass de urgência. As taxas de patência dos enxertos para internações eletivas foram 44 e 25 por cento versus 25 e 23 por cento para internações para cirurgia aguda de enxerto femorodistal a dois e quatro anos, respectivamente (p < 0,004). Internações por isquemia aguda que foram tratadas com enxertos prostéticos tiveram patência primária de 24 versus 27 por cento para enxertos venosos a 2 anos e 24 versus 23 por cento a 4 anos (p = 0,33). No grupo de enxertos femorodistais agudos, patência primária a 2 anos para enxertos venosos e prostéticos foi de 27 e 24 por cento, comparado a 42 e 32 por cento para eletivas. Esses valores para taxas de salvamento de membros em bypasses eletivos foram 73 e 63 por cento, comparadas a 52 por cento em ambos pontos no tempo para o grupo de enxerto femorodistal agudo (p < 0,004). Em cenários de emergência, a taxa de salvamento de membros para bypass femorodistal com enxertos prostéticos foi de 38 por cento e para enxertos venosos a taxa foi de 62 por cento em ambos pontos no tempo (p = 0,08). Conclusão: A taxa de 38 por cento para salvamento de membros a longo prazo indica que a revascularização femorodistal de urgência é vantajosa.

Photoplethysmography, an easy and accurate method for measuring ankle brachial pressure index: can photoplethysmography replace Doppler?

OBJECTIVE: To assess the accuracy of ankle brachial pressure index (ABPI) assessed by photoplethysmography (PPG) compared with continuous wave Doppler (CW-Doppler). METHODS: Ankle brachial pressure index was measured in a standard manner using both PPG and Doppler probes. For PPG-ABPI, a PPG probe was placed on the index finger and great toe, and a microcomputer determined the ABPI. These values were compared with the ABPI measured manually using an 8-MHz Doppler probe. Correlation and agreement between PPG and Doppler ABPI were assessed by Lin's correlation coefficient and Bland-Altman plots. RESULTS: In all, 133 claudicants were assessed. There was a strong correlation between the 2 ABPI methods (beta = .79 and 95% limits of agreement of -0.23 to 0.24). CONCLUSION: Measuring ABPI automatically using the PPG technique is an effective alternative for Doppler ABPI. PPG-ABPI is completely objective, fast, and accurate.

Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: A case-control study and meta-analysis.

OBJECTIVE: Hyperhomocysteinaemia is associated with peripheral arterial disease (PAD). There are inter-individual variations in the metabolism of homocysteine because of genetic polymorphisms. This study analyzed the role of one polymorphism that is associated with raised homocysteine, as a risk factor for PAD. METHODS: This study considered the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with the incidence of PAD by performing a case-control study and a cross sectional study of homocysteine levels. We recruited 133 patients with PAD in Norfolk and compared the MTHFR allele distribution with 457 healthy individuals. We also carried out a meta-analysis to place our data within the context of other published studies. We searched Medline, Embase, and Cochrane databases up to March 2008 for any studies on the association between MTHFR C677T polymorphism and PAD. RESULTS: The MTHFR C677T allele frequencies in the cases and controls were 0.37 and 0.33, and the odds ratios for the association of the 677 T allele or TT genotype with PAD were 1.18 (95% Confidence Interval [CI] 0.89, 1.58) and 1.99 (95% CI 1.09, 3.63). Homozygotes for the MTHFR C677T mutation had higher concentrations of plasma total homocysteine, odds ratio 2.82 (95% CI 1.03, 7.77) compared to homozygotes for the MTHFR 677 CC genotype. Twelve of 72 articles retrieved from the database search reported the prevalence of mutations in PAD patients. A meta-analysis of 9 appropriate studies, including our own, showed that being homozygous for the C677T allele was associated with an increased risk of PAD, pooled odds ratio 1.36 (95% CI 1.09, 1.68). CONCLUSION: We have found a strong association between raised homocysteine, the TT genotype, and PAD.

The association between ankle brachial pressure index and pulse wave velocity: clinical implication of pulse wave velocity.

OBJECTIVE: The aim of this study was to assess the relationship between ankle brachial pressure index and pulse wave velocity in patients with peripheral arterial disease. METHODS: Brachial-knee and brachial-ankle pulse wave velocity were measured by pneumoplethysmography using cuffs in a standard technique. Correlation between pulse wave velocity and Doppler-ankle brachial pressure index was assessed by Spearman correlation and receiver operating curves. RESULTS: A total of 133 claudicants were assessed. Analysis by developing receiver operating curves for ankle brachial pressure index and pulse wave velocity showed that patients with ankle brachial pressure index over 0.6 were more likely to have a bk-pulse wave velocity over 9.2 m/s and ba-pulse wave velocity over 9.5 m/s. CONCLUSION: These results show for the first time that nondiabetic vascular patients may have measurable significant arterial stiffness independent of an impaired ankle brachial pressure index. These data suggest that pulse wave velocity may be valuable in screening and evaluating the severity of peripheral arterial disease.

The effects of increasing obesity on outcomes of vascular surgery.

The aim of this study was to determine whether vascular patients are becoming progressively more obese and whether morbid obesity affects outcomes from vascular surgery. Data for the index vascular procedures of infrainguinal bypass, carotid endarterectomy, and abdominal aortic aneurysm (AAA) repair were collected in a computer database for 1996-2006. Body mass index (BMI) was stratified into <18.5 kg/m2 as underweight, >35 kg/m2 as morbidly obese, and other as control (18.5 < BMI < 35). The data were analyzed with respect to operation duration, length of stay, complication rates, and mortality rates. Results were adjusted for potential confounding variables, including mode of admission, diabetes, cardiac history, renal function, and smoking. A total of 1,317 patients were reviewed, and 1,105 cases were deemed suitable for analysis. The incidence of morbid obesity increased in a linear manner from 1.3% to 9% over the 10-year period. The operation duration was longer for morbidly obese subjects compared with normals. This was only statistically significant for AAA repair category, with a mean operating time of 158.4 +/- 65.5 min for patients with BMI <35 kg/m2 vs. 189.8 +/- 92.2 min for morbidly obese patients (p < 0.014). Infection rates were consistently higher in the morbidly obese group; however, this reached a statistically significant rate among AAA repair cases (43.5% [n = 16] vs. 34.8% [n = 159], p < 0.004). There were no significant differences in other complications, graft failure, length of stay, or mortality. Vascular patients are becoming progressively more obese. Procedures performed on morbidly obese subjects take longer, and these patients have higher rates of infectious complications. This is mainly attributable to AAA. This did not translate into poorer final outcomes in this study, although significant differences might emerge from a larger sample.

Colonic infarction following endovascular AAA repair: a multifactorial complication.

PURPOSE: To report a case of colonic infarction following endovascular abdominal aortic aneurysm (AAA) repair in a patient with both internal iliac arteries (IIA) unobstructed by the endograft. CASE REPORT: A 73-year-old man presented with blue toes as a result of emboli from a 6.4-cm AAA. As he was medically at high risk for open repair and his aneurysm morphology was suitable for a modular bifurcated endovascular graft, a Zenith endograft was used to exclude the aneurysm. Twenty hours after the successful procedure, in which both IIAs were preserved, the patient regurgitated coffee-ground vomit; an upper gastrointestinal endoscopy found a small Mallory-Weiss tear and antral gastritis. A proton-pump inhibitor was begun, but his symptoms progressed. Laparotomy revealed transmural ischemia and infarction of the upper rectum, sigmoid, descending colon, and the splenic flexure; a colonic resection with formation of Hartmann's pouch and colostomy was performed. He made a slow but uncomplicated recovery. CONCLUSIONS: Colonic necrosis can complicate endovascular AAA repair even when both IIAs are preserved. Advantageously, the clinical signs of severe colonic ischemia in endograft patients are not obscured by aftereffects of a laparotomy.