Marc Sapoval

Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.

BACKGROUND Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. METHODS In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. FINDINGS 106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. INTERPRETATION Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients. FUNDING Ardian.

Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial

BACKGROUND Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension. METHODS The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management. Eligible patients aged 18-75 years received indapamide 1·5 mg, ramipril 10 mg (or irbesartan 300 mg), and amlodipine 10 mg daily for 4 weeks to confirm treatment resistance by ambulatory blood pressure monitoring before randomisation. Patients were then randomly assigned (1:1) to receive either renal denervation plus an SSAHT regimen (renal denervation group) or the same SSAHT alone (control group). The randomisation sequence was generated by computer, and stratified by centres. For SSAHT, after randomisation, spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day were sequentially added from months two to five in both groups if home blood pressure was more than or equal to 135/85 mm Hg. The primary endpoint was the mean change in daytime systolic blood pressure from baseline to 6 months as assessed by ambulatory blood pressure monitoring. The primary endpoint was analysed blindly. The safety outcomes were the incidence of acute adverse events of the renal denervation procedure and the change in estimated glomerular filtration rate from baseline to 6 months. This trial is registered with ClinicalTrials.gov, number NCT01570777. FINDINGS Between May 22, 2012, and Oct 14, 2013, 1416 patients were screened for eligibility, 106 of those were randomly assigned to treatment (53 patients in each group, intention-to-treat population) and 101 analysed because of patients with missing endpoints (48 in the renal denervation group, 53 in the control group, modified intention-to-treat population). The mean change in daytime ambulatory systolic blood pressure at 6 months was -15·8 mm Hg (95% CI -19·7 to -11·9) in the renal denervation group and -9·9 mm Hg (-13·6 to -6·2) in the group receiving SSAHT alone, a baseline-adjusted difference of -5·9 mm Hg (-11·3 to -0·5; p=0·0329). The number of antihypertensive drugs and drug-adherence at 6 months were similar between the two groups. Three minor renal denervation-related adverse events were noted (lumbar pain in two patients and mild groin haematoma in one patient). A mild and similar decrease in estimated glomerular filtration rate from baseline to 6 months was observed in both groups. INTERPRETATION In patients with well defined resistant hypertension, renal denervation plus an SSAHT decreases ambulatory blood pressure more than the same SSAHT alone at 6 months. This additional blood pressure lowering effect may contribute to a reduction in cardiovascular morbidity if maintained in the long term after renal denervation. FUNDING French Ministry of Health.

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P⩽0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P⩾0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of ⩾10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l−1 increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment.

Efficacy of Revascularization For Renal Artery Stenosis Caused by Fibromuscular Dysplasia: A Systematic Review and Meta-Analysis

In patients with fibromuscular dysplasia and renal artery stenosis, renal artery revascularization has been used to cure hypertension or to improve blood pressure control. To provide an up-to-date assessment of the benefits and risks associated with revascularization in this condition, we performed a systematic review of studies in which hypertensive patients with fibromuscular dysplasia renal artery stenosis underwent percutaneous transluminal renal angioplasty or surgical reconstruction. We assessed how often periprocedural complications and hypertension cure and improvement occurred. We selected 47 angioplasty studies (1616 patients) and 23 surgery studies (1014 patients). Combined rates of hypertension cure, defined according to the criteria in each study, after angioplasty or surgery were estimated to be 46% (95% CI: 40% to 52%) and 58% (95% CI: 53% to 62%), respectively, with substantial variations across studies. The probability of being cured was negatively associated with patient age and time of publication. Cure rates using current definitions of hypertension cure (blood pressure <140/90 mm Hg without treatment) were only 36% and 54% after angioplasty and surgery, respectively. The combined risks of periprocedural complications were 12% and 17% after angioplasty and surgery, respectively, with less major complications after angioplasty than surgery (6% versus 15%). In conclusion, angioplasty or surgical revascularization yielded moderate benefits in patients with fibromuscular dysplasia renal artery stenosis, with substantial variation across studies. The blood pressure outcome was strongly influenced by patient age.

Cragg Covered Stents in Hemodialysis Access: Initial and Midterm Results

PURPOSE To report midterm follow-up after implantation of covered stents for hemodialysis access. PATIENTS AND METHODS Over a 2-year period, a Cragg Endopro stent was placed in 14 patients (mean age, 66.6 years +/- 15) to treat angioplasty-induced ruptures (n = 3), pseudoaneurysm (n = 1), postangioplasty residual stenosis (n = 2), and early restenosis (n = 8, four of them in a Wallstent). RESULTS Initial placement was successful in all cases. A clinical inflammatory reaction was observed in all three cases of placement in the forearm. When the covered stent was placed in a stenotic vessel, restenosis always occurred within 6 months. Primary and secondary patencies were 28.5% +/- 13.9 and 67.8% +/- 14.5, respectively, at 6 months. Covered stents were of undoubtable benefit in one case of rupture after Wallstent failure and in one case of restenosis in a Wallstent. CONCLUSION Covered Cragg stents are effective in controlling angioplasty- induced rupture and sometimes for maintaining patency after restenosis in a Wallstent. They do not prevent restenosis and are responsible for an inflammatory reaction of unknown origin and long-term effect.

Sirolimus-eluting versus bare-metal low-profile stent for renal artery treatment (GREAT trial): Angiographic follow-up after 6 months and clinical outcome up to 2 years

PURPOSE To evaluate the patency of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) in the treatment of atherosclerotic renal artery stenosis (RAS). METHODS Between November 2001 to June 2003, 105 consecutive symptomatic patients (53 men; mean age 65.7 years) with RAS were treated with either a bare-metal (n=52) or a drug-eluting (n=53) low-profile Palmaz-Genesis peripheral stent at 11 centers in a prospective nonrandomized trial. The primary endpoint was the angiographic result at 6 months measured with quantitative vessel analysis by an independent core laboratory. Secondary endpoints were technical and procedural success, clinical patency [no target lesion revascularization (TLR)], blood pressure and antihypertensive drug use, worsening of renal function, and no major adverse events at 1, 6, 12, and 24 months. RESULTS At 6 months, the overall in-stent diameter stenosis for BMS was 23.9%+/-22.9% versus 18.7%+/-15.6% for SES (p=0.39). The binary restenosis rate was 6.7% for SES versus 14.6% for the BMS (p=0.30). After 6 months and 1 year, TLR rate was 7.7% and 11.5%, respectively, in the BMS group versus 1.9% at both time points in the SES group (p=0.21). This rate remained stable up to the 2-year follow-up but did not reach significance due to the small sample. Even as early as 6 months, both types of stents significantly improved blood pressure and reduced antihypertensive medication compared to baseline (p<0.01). After 6 months, renal function worsened in 4.6% of the BMS patients and in 6.9% of the SES group. The rate of major adverse events was 23.7% for the BMS group and 26.8% for the SES at 2 years (p=0.80). CONCLUSION The angiographic outcome at 6 months did not show a significant difference between BMS and SES. Renal artery stenting with both stents significantly improved blood pressure. Future studies with a larger patient population and longer angiographic follow-up are warranted to determine if there is a significant benefit of drug-eluting stents in treating ostial renal artery stenosis.

Manual Thromboaspiration and Dilation of Thrombosed Dialysis Access: Mid-term Results of a Simple Concept

PURPOSE To report the feasibility, safety, and effectiveness of manual thromboaspiration as a single means of declotting dialysis access. MATERIALS AND METHODS Between April 1994 and December 1996, 59 consecutive conduits (43 polytetrafluoroethylene [PTFE] grafts, 16 native fistulas) were declotted with 8-F or 7-F angulated catheters. Unmasked stenoses were dilated. Clinical and paraclinical nephrologic surveillance (poor flow, palpation, difficulties with cannulation, increased compression times, increasing venous pressures) led to redilations and stent placements. Rethromboses were treated with further declotting by aspiration. The results are presented according to the life-table method. RESULTS The initial success of 43 of 43 PTFE grafts (mean procedure time, 119 min +/- 29 [standard deviation]) led to a primary patency rate of 85% +/- 5% (SE) at 1 month, 33% +/- 8% at 6 months, and 24% +/- 12% at 1 year. A graft was ligated 6 days after declotting for acute bleeding in one patient given high-dose warfarin. The secondary patency rates were 86% +/- 7% at 6 months and 86% +/- 9% at 1 year, with a mean duration of patency of 5.7 months between two radiologic interventions performed to maintain or to restore patency, and 19 stents were placed at a mean follow-up of 3 months. The success rate was 81% for native fistulas, with primary patency rates of 81% +/- 10% at 1 month, 74% +/- 14% at 6 months, and 60% +/- 27% at 1 year; secondary patency rates of 81% +/- 12% at 6 months and 81% +/- 18% at 1 year. CONCLUSION Thromboaspiration is a safe and effective method for declotting dialysis access, yielding a low rethrombosis rate during the first month. Overall radiologic management with reintervention on average every 6 months results in high secondary patency rates at 1 year (81%-86%).

Eligibility for renal denervation in patients with resistant hypertension: when enthusiasm meets reality in real-life patients.

To the Editor: Percutaneous renal sympathetic denervation (RDN) by radiofrequency ablation is a novel therapeutic intervention that has been shown to decrease blood pressure (BP) significantly ([1][1]) and persistently ([2][2]) in patients with resistant hypertension (RH). However, the evidence

Wallstents and Craggstents in Hemodialysis Grafts and Fistulas: Results for Selective Indications☆

PURPOSE To report the value of selective placement of self-expandable stents (Wallstent and Craggstent) for the treatment of limitations and, occasionally, of complications of dilation in hemodialysis access, and especially for delaying restenosis. MATERIALS AND METHODS This is a retrospective study of a 7-year period, during which 41 Wallstents and 11 Craggstents were placed in 26 polytetrafluoroethylene (PTFE) grafts, 15 native fistulas, and nine central veins of 47 patients. The indications were stenosis recoil (n = 13), recurrent restenosis within 6 months (n = 33), restenosis after 6 months (n = 3), and acute angioplasty-induced rupture (n = 1). Restenosis after stent placement necessitated redilation and percutaneous declotting and 10 additional stent placements. RESULTS Two initial misplacements were corrected immediately. Primary patency rates for PTFE grafts were 58% +/- 10% at 6 months and 23% +/- 10% at 1 year, respectively. Secondary patency rates were 100% at 6 months and 88% +/- 8% at 1 year, respectively. For native fistulas, primary patency rates were 47% +/- 12% at 6 months and 20% +/- 18% at 1 year. Secondary patency rates were 95% +/- 6% at 6 months and 79% +/- 14% at 1 year. It was necessary to reintervene after stent placement to maintain or to restore patency every 9 months for PTFE grafts and every 7.3 months for native fistulas. When stents were placed for treatment of early recurring restenosis, the mean interval between radiologic interventions (redilations or declottings) performed to maintain or to restore patency before stent placement was multiplied by 2.1 after stent placement for both grafts (3.2 months increased to 6.9, P < .01) and native fistulas (2.9 months increased to 6.2, P < .02). CONCLUSIONS Wallstents and Craggstents are valuable for the treatment of failure of regular dilation and they double the intervals between reinterventions for early (< 6 months) recurring stenoses in PTFE grafts and native fistulas.

Reduced Immunoregulatory CD31 + T Cells in Patients With Atherosclerotic Abdominal Aortic Aneurysm

Background—Cell-mediated immunity is considered to contribute to the pathogenesis of abdominal aortic aneurysms (AAA). In particular, infiltrating macrophages and CD8+ T lymphocytes participate in the destruction of the aortic wall extracellular matrix and smooth muscle cells. We surmise that these pathological events are controlled by circulating regulatory lymphocytes. Methods and Results—Circulating CD4+/CD31+ cells were reduced in AAA patients (n=80, 8.9±0.6%) as compared with controls (n=69, 13.7±0.8%; P<0.001) and inversely proportional to AAA size. Exclusion of the aneurysm by an endoprothesis did not affect CD31+ T cell values. Reduction of blood CD4+/CD31+ cells was not attributable to their enrichment in AAA tissue. In contrast, CD8+/CD31+ cells were slightly reduced in the blood while increased in the aneurysmal tissue (29.2±0.5 versus 20.2±4.7% in blood, n=6; P<0.05). Remarkably, high percentages of CD4+/CD31+ cells were able to regulate proliferation and cytokine production of CD8+ lymphocytes, as well as CD8+ cell-mediated cytotoxicity of aortic smooth muscle cells (P<0.01). Finally, CD4+/CD31+ cells reduced the production and activity of metalloproteinase-9 by lipopolysaccharide-stimulated macrophages. Conclusions—Circulating CD4+/CD31+ T cells regulate macrophage and CD8+ T cell activation and effector function in the arterial wall. Their reduction might promote the development of AAA.