Editor's Choice - Randomised Clinical Trial of Supervised Exercise Therapy vs. Endovascular Revascularisation for Intermittent Claudication Caused by Iliac Artery Obstruction: The SUPER study.

OBJECTIVE: International guidelines recommend supervised exercise therapy (SET) as primary treatment for all patients with intermittent claudication (IC), yet primary endovascular revascularisation (ER) might be more effective in patients with iliac artery obstruction. METHODS: This was a multicentre RCT including patients with IC caused by iliac artery stenosis or occlusion (NCT01385774). Patients were allocated randomly to SET or ER stratified for maximum walking distance (MWD) and concomitant SFA disease. Primary endpoints were MWD on a treadmill (3.2 km/h, 10% incline) and disease specific quality of life (VascuQol) after one year. Additional interventions during a mean follow up of 5.5 years were recorded. RESULTS: Between November 2010 and May 2015, 114 patients were allocated to SET, and 126 to ER. The trial was terminated prematurely after 240 patients were included. Compliance with SET was 57/114 (50%) after six months. Ten patients allocated to ER (8%) did not receive this intervention. One year follow up was complete for 90/114 (79%) SET patients and for 104/126 (83%) ER patients. The mean MWD improved from 187 to 561 m in SET patients and from 196 to 574 m in ER patients (p = .69). VascuQol sumscore improved from 4.24 to 5.58 in SET patients, and from 4.28 to 5.88 in ER patients (p = .048). Some 33/114 (29%) SET patients had an ER within one year, and 2/114 (2%) surgical revascularisation (SR). Some 10/126 (8%) ER patients had additional ER within one year and 10/126 (8%) SR. After a mean of 5.5 years, 49% of SET patients and 27% of ER patients underwent an additional intervention for IC. CONCLUSION: Taking into account the many limitations of the SUPER study, both a strategy of primary SET and primary ER improve MWD on a treadmill and disease specific Qol of patients with IC caused by an iliac artery obstruction. It seems reasonable to start with SET in these patients and accept a 30% failure rate, which, of course, must be discussed with the patient. Patients continue to have interventions beyond one year.

Cost Effectiveness of Endovascular Revascularisation vs. Exercise Therapy for Intermittent Claudication Due to Iliac Artery Obstruction.

OBJECTIVE: To compare cost effectiveness of endovascular revascularisation (ER) and supervised exercise therapy (SET) as primary treatment for patients with intermittent claudication (IC) due to iliac artery obstruction. METHODS: Cost utility analysis from a restricted societal perspective and time horizon of 12 months. Patients were included in a multicentre randomised controlled trial (SUPER study, NCT01385774, NTR2648) which compared effectiveness of ER and SET. Health status and health related quality of life (HRQOL) were measured using the Euroqol 5 dimensions 3 levels (EQ5D-3L) and VascuQol-25-NL. Incremental costs were determined per allocated treatment and use of healthcare during follow up. Effectiveness of treatment was determined in quality adjusted life years (QALYs). The difference between treatment groups was calculated by an incremental cost utility ratio (ICER). RESULTS: Some 240 patients were included, and complete follow up was available for 206 patients (ER 111 , SET 95). The mean costs for patients allocated to ER were €4 031 and €2 179 for SET, a mean difference of €1 852 (95% bias corrected and accelerated [bca] bootstrap confidence interval 1 185 - 2 646). The difference in QALYs during follow up was 0.09 (95% bcaCI 0.04 - 0.13) in favour of ER. The ICER per QALY was €20 805 (95% bcaCI 11 053 - 45 561). The difference in VascuQol sumscore was 0.64 (95% bcaCI 0.39 - 0.91), again in favour of ER. CONCLUSION: ER as a primary treatment, results in slightly better health outcome and higher QALYs and HRQOL during 12 months of follow up. Although these differences are statistically significant, clinical relevance must be discussed due to the small differences and relatively high cost of ER as primary treatment.

Estimation of Intraglomerular Pressure Using Invasive Renal Arterial Pressure and Flow Velocity Measurements in Humans.

BACKGROUND: Glomerular hyperfiltration resulting from an elevated intraglomerular pressure (Pglom) is an important cause of CKD, but there is no feasible method to directly assess Pglom in humans. We developed a model to estimate Pglom in patients from combined renal arterial pressure and flow measurements. METHODS: We performed hemodynamic measurements in 34 patients undergoing renal or cardiac angiography under baseline conditions and during hyperemia induced by intrarenal dopamine infusion (30 µg/kg). For each participant during baseline and hyperemia, we fitted an adapted three-element Windkessel model that consisted of characteristic impedance, compliance, afferent resistance, and Pglom. RESULTS: We successfully analyzed data from 28 (82%) patients. Median age was 58 years (IQR, 52-65), median eGFR was 95 ml/min per 1.73 m2 (IQR, 74-100) using the CKD-EPI formula, 30% had microalbuminuria, and 32% had diabetes. The model showed a mean Pglom of 48.0 mm Hg (SD=10.1) at baseline. Under hyperemia, flow increased by 88% (95% CI, 68% to 111%). This resulted in a 165% (95% CI, 79% to 294%) increase in afferent compliance and a 13.1-mm Hg (95% CI, 10.0 to 16.3) decrease in Pglom. In multiple linear regression analysis, diabetes (coefficient, 10.1; 95% CI, 5.1 to 15.1), BMI (0.99 per kg/m2; 95% CI, 0.38 to 1.59), and renal perfusion pressure (0.42 per mm Hg; 95% CI, 0.25 to 0.59) were significantly positively associated with baseline Pglom. CONCLUSIONS: We constructed a model on the basis of proximal renal arterial pressure and flow velocity measurements that provides an overall estimate of glomerular pressure and afferent and efferent resistance in humans. The model provides a novel research technique to evaluate the hemodynamics of CKD on the basis of direct pressure and flow measurements. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Functional HEmodynamics in patients with and without Renal Artery stenosis (HERA), NL40795.018.12 at the Dutch national trial registry (toetsingonline.nl).

Effect of Endovascular Treatment With Medical Management vs Standard Care on Severe Cerebral Venous Thrombosis: The TO-ACT Randomized Clinical Trial.

Importance: To date, only uncontrolled studies have evaluated the efficacy and safety of endovascular treatment (EVT) in patients with cerebral venous thrombosis (CVT), leading to the lack of recommendations on EVT for CVT. Objective: To evaluate the efficacy and safety of EVT in patients with a severe form of CVT. Design, Setting, and Participants: TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) was a multicenter, open-label, blinded end point, randomized clinical trial conducted in 8 hospitals in 3 countries (the Netherlands, China, and Portugal). Patients were recruited from September 2011 to October 2016, and follow-up began in March 2012 and was completed in December 2017. Adult patients with radiologically confirmed CVT who had at least 1 risk factor for a poor outcome (mental status disorder, coma state, intracerebral hemorrhage, or thrombosis of the deep venous system) were included. Data were analyzed according to the intention-to-treat principle from March 2018 to February 2019. The trial was halted after the first interim analysis for reasons of futility. Interventions: Patients were randomized to receive either EVT with standard medical care (intervention group) or guideline-based standard medical care only (control group). The EVT consisted of mechanical thrombectomy, local intrasinus application of alteplase or urokinase, or a combination of both strategies. Patients in the intervention group underwent EVT as soon as possible but no later than 24 hours after randomization. Main Outcomes and Measures: Primary end point was the proportion of patients with a good outcome at 12 months (recovered without a disability; modified Rankin Scale [mRS] score of 0-1). Secondary end points were the proportion of patients with an mRS score of 0 to 1 at 6 months and an mRS score of 0 to 2 at 6 and 12 months, outcome on the mRS across the ordinal continuum at 12 months, recanalization rate, and surgical interventions in relation to CVT. Safety end points included symptomatic intracranial hemorrhage. Results: Of the 67 patients enrolled and randomized, 33 (49%) were randomized to the intervention group and 34 (51%) were randomized to the control group. Patients in the intervention group vs those in the control group were slightly older (median [interquartile range (IQR)] age, 43 [33-50] years vs 38 [23-48] years) and comprised fewer women (23 women [70%] vs 27 women [79%]). The median (IQR) baseline National Institutes of Health Stroke Scale score was 12 (7-20) in the EVT group and 12 (5-20) in the standard care group. At the 12-month follow-up, 22 intervention patients (67%) had an mRS score of 0 to 1 compared with 23 control patients (68%) (relative risk ratio, 0.99; 95% CI, 0.71-1.38). Mortality was not statistically significantly higher in the EVT group (12% [n = 4] vs 3% [n = 1]; P = .20). The frequency of symptomatic intracerebral hemorrhage was not statistically significantly lower in the intervention group (3% [n = 1] vs 9% [n = 3]; P = .61). Conclusions and Relevance: The TO-ACT trial showed that EVT with standard medical care did not appear to improve functional outcome of patients with CVT. Given the small sample size, the possibility exists that future studies will demonstrate better recovery rates after EVT for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT01204333.

Implementation of uterine artery embolization for symptomatic fibroids in the Netherlands: an inventory and preference study.

BACKGROUND AND PURPOSE: The Dutch national guideline on heavy menstrual bleeding was updated and published in 2013. It recommended (for the first time) that uterine artery embolization (UAE) should be part of counseling of women with symptomatic fibroids. We aimed to evaluate the implementation of UAE for symptomatic uterine fibroids in the Netherlands and to investigate gynecologists preference and other influential factors. METHODS: The primary outcome was to examine the UAE/hysterectomy ratio before and after introduction of the 2013 guideline by the use of annual hospital reports. The secondary outcome assessed factors that could influence implementation by means of a questionnaire to gynecologists. RESULTS: A total of 29/30 (97%) UAE+ hospitals and 36/52 (69%) UAE- hospitals sent their annual reports. The UAE/hysterectomy percentages in 2012, 2013 and 2014 were 7,0%, 7.0% and 6.9%, respectively. Regarding the questionnaire, the response rates were 88% and 91%, respectively. In both groups we observed a high self-perceived tendency for UAE counseling (90% versus 70%, p = .001). Approximately 50% of gynecologists from UAE- hospitals indicate they have insufficient information about UAE for appropriate counseling and 40% doubts the effectiveness of UAE. Furthermore, in the majority of gynecologists some 'urban myths' about the effectiveness and side-effects of UAE seem to persevere. CONCLUSION: Adding UAE as a treatment option to the national guideline did not change the number of performed UAEs for symptomatic fibroids. It might be useful to develop an option grid in order to offer appropriate, independent counseling and encourage shared decision making.

Testing the sympathetic nervous system of the foot has a high predictive value for early amputation in patients with diabetes with a neuroischemic ulcer.

OBJECTIVE: There is evidence from the literature that dysfunctionality of the sympathetic nervous system of the foot with subsequent loss of local autoregulation could be a predictor of early amputation in patients with diabetes with a neuroischemic ulcer. To confirm this we tested the functionality of the sympathetic nervous system in the foot in a consecutive group of 31 patients with diabetes with critical limb ischemia and non-healing neuroischemic ulcer. RESEARCH DESIGN AND METHODS: Prospective cohort with retrospective analysis after 12 months of routinely acquired clinical data. All patients in the study group underwent angiography of the foot as part of a routine angioplasty procedure. Primary study endpoint was lower extremity amputation-free survival at 12 months. Because of the study design no other endpoints could be analyzed. The functionality of the sympathetic nervous system was tested with perfusion angiography. RESULTS: Thirty-one patients were followed for 12 months. The Capillary Resistance Index (CRI) was used to measure the response of the sympathetic nervous system. CRI≥0.9 is the cut-off point for a non-responsive sympathetic nervous system. All patients (n=11) with a CRI≥0.9 underwent a major amputation before 12 months. Of all patients with a CRI only 15% underwent major amputation. The positive predictive value for major amputation before 12 months for patients with a CRI ≥ 0.9 was 100%. CONCLUSIONS: A non-responsive sympathetic nervous system of the foot is a strong predictor of early major amputation (log rank p<0.001; HR 14.22; 95% CI 3.64 to 55.51).

Incidence, Predictors, and Impact of Vascular Complications After Transfemoral Transcatheter Aortic Valve Implantation With the SAPIEN 3 Prosthesis.

Vascular complications (VCs) after transfemoral transcatheter aortic valve implantation (TAVI) have always been reported to occur frequently. Studies addressing VCs have been conducted with older-generation prostheses. We aimed to evaluate the incidence, predictors, and impact of VCs after transfemoral TAVI with the balloon-expandable SAPIEN 3. We report a single-center retrospective analysis of 400 consecutive patients of a prospectively acquired cohort. All patients underwent transfemoral TAVI with SAPIEN 3 between January 2014 and December 2016. VC was defined according to the Valve Academic Research Consortium. In this cohort 83 patients had VCs (20.8%), 5.8% major and 15.0% minor. Sheath-to-iliofemoral artery ratio was the only predictor of major VCs (odds ratio 7.51, 95% confidence interval 1.61 to 34.95, p = 0.010). The area under the receiver-operator characteristic curve for sheath-to-iliofemoral artery ratio was 0.63 (poor accuracy). Thirty-day mortality rates were 17.4%, 1.7%, and 0.6% for major, minor, and no VCs, respectively (log-rank p ≤0.001). After adjustment, only major VCs were associated with 30-day mortality (adjusted hazard ratio 48.31, 95% confidence interval 7.80 to 299.24). Mortality from 30 days until 1 year did not differ between patients with and without VCs (log-rank p = 0.61). In conclusion we report that VCs remain an issue of transfemoral TAVI with the SAPIEN 3, and their prediction continues to be difficult, albeit the low-incidence, major VCs were associated with higher 30-day mortality. However, after these first 30 days, they were not of influence on survival anymore.

Renal sympathetic nerve activity after catheter-based renal denervation.

BACKGROUND: Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy. METHODS: In 21 RHT patients (median age 60 years), we performed 123I-mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after 123I-mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented 123I-mIBG uptake. Renal 123I-mIBG washout was calculated between 15 min and 4 h. RESULTS: After RDN office-based systolic BP decreased from 172 to 153 mmHg (p = 0.036), while diastolic office BP (p = 0.531), mean 24 h systolic and diastolic BP (p = 0.602, p = 0.369, respectively), PRA (p = 0.409) and plasma catecholamines (p = 0.324) did not significantly change post-RDN. Following RDN, 123I-mIBG renal uptake at 15 min was 3.47 (IQR 2.26-5.53) compared to 3.08 (IQR 2.79-4.95) before RDN (p = 0.289). Renal 123I-mIBG washout did not change post-RDN (p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal 123I-mIBG parameters. CONCLUSIONS: No changes were observed in renal 123I-mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy.

Predictive Parameters for Clinical Outcome in Patients with Critical Limb Ischemia Who Underwent Percutaneous Transluminal Angioplasty (PTA): A Systematic Review.

PURPOSE: To identify possible risk factors in predicting clinical outcome in critical limb ischemia (CLI) patients undergoing percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: PubMed and EMBASE were searched for studies analyzing CLI and clinical outcome after PTA from January 2006 to April 2017. Outcome measures were ulcer healing, amputation free survival (AFS)/limb salvage and overall survival. Data on predictive factors for ulcer healing, AFS/limb salvage and survival were extracted. RESULTS: Ten articles with a total of 2448 patients were included, all cohorts and based on prospective-designed databases. For ulcers, it seems that complete healing can be achieved in most of the patients within 1 year. No significant predictive factors were found. AFS/limb salvage: AFS rates for 1, 2 and 3 years ranged from 49.5 to 75.2%, 37 to 58% and 22 to 59%, respectively. Limb salvage rates for 1, 2 and 3 years ranged from 71 to 95%, 54 to 93.3% and 32 to 92.7%, respectively. All studies had different univariate and multivariate outcomes for predictive factors; however, age and diabetes were significant predictors in at least three studies. Survival: Survival rates for 1, 2 and 3 years ranged from 65.4 to 91.5%, 45.7 to 76% and 37.3 to 83.1%, respectively. Different predictive factors were found; however, age was found in 2 out of 5 studies reporting on predictive factors. CONCLUSIONS: In several studies two factors, age and diabetes, were found as predictive factors for AFS/limb salvage and survival in patients with CLI undergoing PTA. Therefore, we believe that these factors should be taken into account in future research. LEVEL OF EVIDENCE: Level 2a.

Hyperbaric Oxygen Therapy in the Treatment of Ischemic Lower- Extremity Ulcers in Patients With Diabetes: Results of the DAMO2CLES Multicenter Randomized Clinical Trial.

OBJECTIVE: Conflicting evidence exists on the effects of hyperbaric oxygen therapy (HBOT) in the treatment of chronic ischemic leg ulcers. The aim of this trial was to investigate whether additional HBOT would benefit patients with diabetes and ischemic leg ulcers. RESEARCH DESIGN AND METHODS: Patients with diabetes with an ischemic wound (n = 120) were randomized to standard care (SC) without or with HBOT (SC+HBOT). Primary outcomes were limb salvage and wound healing after 12 months, as well as time to wound healing. Other end points were amputation-free survival (AFS) and mortality. RESULTS: Both groups contained 60 patients. Limb salvage was achieved in 47 patients in the SC group vs. 53 patients in the SC+HBOT group (risk difference [RD] 10% [95% CI -4 to 23]). After 12 months, 28 index wounds were healed in the SC group vs. 30 in the SC+HBOT group (RD 3% [95% CI -14 to 21]). AFS was achieved in 41 patients in the SC group and 49 patients in the SC+HBOT group (RD 13% [95% CI -2 to 28]). In the SC+HBOT group, 21 patients (35%) were unable to complete the HBOT protocol as planned. Those who did had significantly fewer major amputations and higher AFS (RD for AFS 26% [95% CI 10-38]). CONCLUSIONS: Additional HBOT did not significantly improve complete wound healing or limb salvage in patients with diabetes and lower-limb ischemia.