Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Risk Factors For Stroke, Myocardial Infarction, or Death Following Carotid Endarterectomy: Results From the International Carotid Stenting Study.

OBJECTIVES: Carotid endarterectomy (CEA) is standard treatment for symptomatic carotid artery stenosis but carries a risk of stroke, myocardial infarction (MI), or death. This study investigated risk factors for these procedural complications occurring within 30 days of endarterectomy in the International Carotid Stenting Study (ICSS). METHODS: Patients with recently symptomatic carotid stenosis >50% were randomly allocated to endarterectomy or stenting. Analysis is reported of patients in ICSS assigned to endarterectomy and limited to those in whom CEA was initiated. The occurrence of stroke, MI, or death within 30 days of the procedure was reported by investigators and adjudicated. Demographic and technical risk factors for these complications were analysed sequentially in a binomial regression analysis and subsequently in a multivariable model. RESULTS: Eight-hundred and twenty-one patients were included in the analysis. The risk of stroke, MI, or death within 30 days of CEA was 4.0%. The risk was higher in female patients (risk ratio [RR] 1.98, 95% CI 1.02-3.87, p = .05) and with increasing baseline diastolic blood pressure (dBP) (RR 1.30 per +10 mmHg, 95% CI 1.02-1.66, p = .04). Mean baseline dBP, obtained at the time of randomization in the trial, was 78 mmHg (SD 13 mmHg). In a multivariable model, only dBP remained a significant predictor. The risk was not related to the type of surgical reconstruction, anaesthetic technique, or perioperative medication regimen. Patients undergoing CEA stayed a median of 4 days before discharge, and 21.2% of events occurred on or after the day of discharge. CONCLUSIONS: Increasing diastolic blood pressure was the only independent risk factor for stroke, MI, or death following CEA. Cautious attention to blood pressure control following symptoms attributable to carotid stenosis could reduce the risks associated with subsequent CEA.

Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication.

BACKGROUND: A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). METHODS: MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). RESULTS: The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0·947 and 0·987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (-1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. CONCLUSION: Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events.

The management of venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE Guideline CG144.

Venous thromboembolic disease (VTE) is a common presentation in acute medicine and ensuring fast, accurate diagnosis and appropriate management is important. Getting it right not only reduces mortality but can also reduce the long-term complications associated with the disease such as post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension.

Combined (mechanical and pharmacological) modalities for the prevention of venous thromboembolism in joint replacement surgery.

We performed a systematic review and meta-analysis to compare the efficacy of intermittent mechanical compression combined with pharmacological thromboprophylaxis, against either mechanical compression or pharmacological prophylaxis in preventing deep-vein thrombosis (DVT) and pulmonary embolism in patients undergoing hip or knee replacement. A total of six randomised controlled trials, evaluating a total of 1399 patients, were identified. In knee arthroplasty, the rate of DVT was reduced from 18.7% with anticoagulation alone to 3.7% with combined modalities (risk ratio (RR) 0.27, p = 0.03; number needed to treat: seven). There was moderate, albeit non-significant, heterogeneity (I(2) = 42%). In hip replacement, there was a non-significant reduction in DVT from 8.7% with mechanical compression alone to 7.2% with additional pharmacological prophylaxis (RR 0.84) and a significant reduction in DVT from 9.7% with anticoagulation alone to 0.9% with additional mechanical compression (RR 0.17, p < 0.001; number needed to treat: 12), with no heterogeneity (I(2) = 0%). The included studies had insufficient power to demonstrate an effect on pulmonary embolism. We conclude that the addition of intermittent mechanical leg compression augments the efficacy of anticoagulation in preventing DVT in patients undergoing both knee and hip replacement. Further research on the role of combined modalities in thromboprophylaxis in joint replacement and in other high-risk situations, such as fracture of the hip, is warranted.

Primary prevention of venous thromboembolism.

Venous thromboembolism (VTE) is the most common cause of preventable in-hospital mortality and all hospitalized patients should be VTE risk assessed. The VTE risk should be weighed up against risk of bleeding on an individualized basis to guide choice of prophylaxis. The most common method of mechanical thromboprophylaxis is graduated compression stockings, although others, such as intermittent pneumatic devices, are available. Stockings have the greatest benefit when used in combination with pharmacological prophylaxis. However, stockings are contraindicated in some patients, including those with stroke or peripheral arterial disease. Various options for pharmacological thromboprophylaxis are available. The most commonly used agents are the low-molecular-weight heparins, but newer orally active agents may play an increasing role in the future.

Diagnostic tests and strategies in venous thromboembolism.

Venous thromboembolism (VTE) is a term including deep vein thrombosis (DVT) and pulmonary embolism (PE). Timely and accurate diagnosis of both is essential as delayed or missed diagnoses can result in death or longer term complications. Patients with suspected DVT should initially undergo a pretest probability Wells score. Depending on pretest probability Wells score they should then either proceed to two-point ultrasound scanning or D-dimer testing. Likewise, patients suspected of PE should undergo a two-level PE Wells score, and, if scored likely, a computed tomography pulmonary angiogram (CTPA), or, if there is a low pretest probability score, D-dimer testing. If positive, patients should undergo CTPA. Ventilation perfusion scanning (V/Q scan) or V/Q SPECT should be considered in place of CTPA if there is allergy to contrast media or renal impairment.

Interpretation of patient-reported outcome measures for varicose vein surgery.

OBJECTIVES: Since 2009 the National Health Service (NHS) has been collecting patient-reported outcome measures (PROMs) following varicose vein interventions. The objective of this manuscript was to interrogate the one-year PROMs data with respect to varicose vein intervention and to discuss its potential impact on the provision of service. METHODS: We interrogated the one-year PROMs data with respect to potential impact on the provision of service. RESULTS: In total, 37,521 varicose vein operations were performed during the study period (1 April 2009-30 April 2010). A total of 15,808 preoperative questionnaires were completed and returned and 12,509 were linked to Hospital Episode Statistics episodes. A total of 8127 postoperative questionnaires were completed and linked to the preoperative questionnaires. For the EuroQuol (EQ) 5D questionnaire average preoperative score across the completed data-set was 0.773. The postoperative health gain was 0.094. Fifty-three percent of patients had improved postoperative scores, 33% reported no change, while 14% reported a reduction in their postoperative EQ-5D score. Pain/discomfort was the only domain where patients reported any negative symptoms; 72% (5390) reported pain/discomfort preoperatively and 37% (2804) postoperatively. In total, 62.6% (4685) reported no pain/discomfort following surgery A total of 7167 complete, linked and eligible data-sets were observed for the Aberdeen Varicose Vein Questionnaire (AVVQ). The average preoperative score was 18.75. The average postoperative score was 10.76. This represented a reduction in symptom scores of one-half following intervention. The lowest improvements were witnessed in patients with the lowest preoperative scores (least severe symptoms). Additional postoperative questions highlighted the improvements conferred from varicose vein surgery with 90.3% of patients reporting an improvement in their problems from varicose veins following surgery and 85% describing their operative results as excellent, very good or good. CONCLUSION: These data have shown variable improvements following venous interventions. PROMs are likely to have significant implications for health care in the NHS on a number of levels including provision of funding and future planning of services.

A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

Prevalence and predictors of persistent health status impairment in patients referred to a vascular clinic with intermittent claudication.

BACKGROUND: The goal of treatment for lower extremity peripheral artery disease is often to improve health status. Factors associated with failure to improve are unknown. METHODS: Health status was assessed with the Peripheral Artery Questionnaire (PAQ) at baseline and 2 years in 344 patients referred to vascular clinics. Improvement was defined as an increase of ≥5 points on the PAQ Summary Score. Multivariable logistic regression identified patient and treatment characteristics associated with impaired baseline health status, and predictors of no improvement (<5 points). RESULTS: Older age, bilateral symptoms, female sex and prior revascularization were associated with impaired baseline health status. At 2 years 36% reported unimproved health status. Factors associated with no improvement were older age (Odds Ratio 1.67/decade, CI 1.28, 2.19), better baseline health status (OR 1.40/10-points, CI 1.24, 1.59), beta blocker use (OR 2.53, CI 1.37, 4.68), prior stroke (OR 4.12, CI 1.33, 12.77) and bilateral claudication (OR 1.79, CI 1.07, 2.99). SUMMARY: Older patients, women, and those with bilateral symptoms or prior revascularization have worse health status at vascular referral. Over 1/3 of patients' health status did not improve over 2 years; older patients and those with bilateral or milder symptoms, prior stroke or using beta blockers were less likely to improve.

Can combined (mechanical and pharmacological) modalities prevent fatal VTE?

AIM: The aim of this paper was to perform a systemic review and meta-analysis of the efficacy of combined modalities (intermittent pneumatic leg compression and pharmacological prophylaxis, treatment group) against single modalities alone (control group) in preventing pulmonary embolism (PE), including fatal PE and deep-vein thrombosis (DVT) in high-risk patients. METHODS: Databases searched included the Cochrane Central Register of Controlled Trials, the Specialized Register of the Peripheral Vascular Diseases Group, MEDLINE and EMBASE. RESULTS: Seventeen studies, six of them randomized controlled trials (RCTs), which enrolled a total of 9998 patients in a variety of specialties were identified. Sixteen of the included studies evaluated the role of combined modalities on the incidence of symptomatic PE. These showed a reduction in symptomatic PE from 2.83% (122/4313) in the control group to 0.86% (33/3838) in the treatment group. Odds ratio was 0.34, 95% Confidence interval (CI) 0.23 to 0.50. Fatal PE was reduced from 0.56% (11/1972) in the control group to 0.07% (1/1377) in the treatment group (results were available in 10 studies). Odds ratio was 0.37 (95% CI; 0.09 to 1.48). Fourteen studies investigated the role of combined modalities on the incidence of DVT. These showed a reduction in DVT from 6.18% (200/3238) in the control group to 2.05% (63/3074) in the treatment group. Odds ratio was 0.31, 95% CI 0.23 to 0.43. CONCLUSION: Combined prophylactic modalities decrease significantly the incidence of PE and DVT, compared to single modalities, but the reduction seen in fatal PE did not reach statistical significance. Further research on the role of combined modalities in reducing DVT and PE is necessary.

Clinical experience of a new NPWT system in diabetic foot ulcers and post-amputation wounds.

OBJECTIVE: The primary aim of this pilot observational study was to assess the reduction in wound depth and area achieved with a new negative pressure wound therapy (NPWT) system in diabetic patients with foot ulcers and post-amputation wounds. Secondary aims were to assess pain levels, extent of exudate removal, and ease of use of the system for both the patient and care giver. METHOD: Patients in both acute and home care settings were enrolled into this 4-week study. Dressings were changed three times per week. Wound area and depth, exudate removal and pain severity were evaluated at each dressing change. At the final visit, the investigators and patients were surveyed with respect to equipment and dressings used in the study. RESULTS: Sixteen patients were enrolled into the study. Data relating to 14 patients with a variety of post-amputation wounds were included in the intention-to-treat (ITT) analysis. The post-amputation wounds showed a general trend for a reduction in the median wound surface area between baseline (22.9cm2; range 0.5-55) and the final visit (15.3cm2; range 2.4-63.5). This equates to a median change (calculated from the percentage change in wound area for each patient individually) of -41% (range -82% to +15%). There was also a general trend in reduction in the median depth between baseline (17mm; range 0-35) to final visit (5mm; range 0-35). One patient presented with a foot ulcer that demonstrated a 50% reduction in depth from baseline to the final assessment. The device effectively managed wound exudate and most patients reported low pain levels during therapy. Ease of use of the system was rated very highly by investigators and patients. CONCLUSION: This pilot study indicates that the use of the new NPWT system can be expected to have a positive effect on the healing of post-amputation wounds and foot ulcers in patients with diabetes. The findings demonstrate that the system is easy to use, effectively controls exudate and minimises pain and inconvenience for patients being treated with NPWT. DECLARATION OF INTEREST: This study was sponsored by Mölnlycke Heath Care (Gothenburg, Sweden) and Medela AG (Baar, Switzerland). The authors have no other conflicts of interest that are directly relevant to the content of this manuscript.

Post-thrombotic syndrome: prevention is better than cure.

Post-thrombotic syndrome (PTS) can be debilitating to patients and have a major economic impact on health-care services. It arises after deep venous thrombosis (DVT) due to residual venous obstruction or valvular reflux, leading to increased venous pressure in the microcirculation. While the inflammatory process at the time of DVT may aid thrombus resolution, it may also promote destruction of venous valves. The diagnosis of PTS is principally clinical and patients typically complain of leg heaviness, swelling, pain, itching, cramps, ulcer and signs of lipodermatosclerosis. Several clinical scales or classifications have been used but it is recommended that Villalta scale is the most suitable. Risk factors for PTS include a proximal DVT and recurrent thrombosis as well as obesity and prior varicose veins. Poor quality of anticoagulation control may also be a factor. Established PTS is usually managed along the same lines as chronic venous hypertension with compression therapy and leg elevation. Surgery has only a limited role but may benefit some patients. Further trials are desperately needed to define the role of acute thrombolysis and mechanical thrombectomy, which seem to be promising treatments in the studies to date. For patients who have had a DVT more attention should be given to prescribing and using compression hosiery.