Conceptual Considerations for Device-Based Therapy in Acute Decompensated Heart Failure: DRI2P2S.

Acute decompensated heart failure remains the most common cause of hospitalization in older adults, and studies of pharmacological therapies have yielded limited progress in improving outcomes for these patients. This has prompted the development of novel device-based interventions, classified mechanistically based on the way in which they intend to improve central hemodynamics, increase renal perfusion, remove salt and water from the body, and result in clinically meaningful degrees of decongestion. In this review, we provide an overview of the pathophysiology of acute decompensated heart failure, current management strategies, and failed pharmacological therapies. We provide an in depth description of seven investigational device classes designed to target one or more of the pathophysiologic derangements in acute decompensated heart failure, denoted by the acronym DRI2P2S. Dilators decrease central pressures by increasing venous capacitance through splanchnic nerve modulation. Removers remove excess fluid through peritoneal dialysis, aquaphoresis, or hemodialysis. Inotropes directly modulate the cardiac nerve plexus to enhance ventricular contractility. Interstitial devices enhance volume removal through lymphatic duct decompression. Pushers are novel descending aorta rotary pumps that directly increase renal artery pressure. Pullers reduce central venous pressures or renal venous pressures to increase renal perfusion. Selective intrarenal artery catheters facilitate direct delivery of short acting vasodilator therapy. We also discuss challenges posed in clinical trial design for these novel device-based strategies including optimal patient selection and appropriate end points to establish efficacy.

First-in-Man Experience with a Novel Catheter-Based Renal Denervation System of Ultrasonic Ablation in Patients with Resistant Hypertension.

PURPOSE: To report results of renal denervation (RDN) with the first catheter-based, non-balloon occlusion ultrasonic system in patients with resistant hypertension. MATERIALS AND METHODS: In a multicenter, single-arm trial, 39 patients with resistant hypertension (defined as uncontrolled hypertension while taking ≥ 3 antihypertensive medications) were treated. The cohort consisted of 4 groups: severe resistant hypertension (office systolic blood pressure [OSBP] ≥ 160 mm Hg) treated with a unidirectional catheter (group 1; n = 14); severe resistant hypertension treated with a multidirectional catheter (group 2; n = 18); moderate resistant hypertension (OSBP 140-159 mm Hg) treated with a multidirectional catheter (group 3; n = 5); and recurrent severe resistant hypertension, after an initial response to RF RDN (group 4; n = 2). Blood pressure monitoring was performed for 6 months. RESULTS: Severe adverse events were not noted immediately after the procedure or during follow-up. Treatment time was longer with unidirectional than with multidirectional catheters (36.7 min ± 9.6 vs 11.9 min ± 5.8; P < .001). Mean reductions in office blood pressure (systolic/diastolic) at 1, 3, and 6 months were -26.1/-9.6 mm Hg, -28.0/-9.9 mm Hg, and -30.6/-14.1 mm Hg (P < .01 for all). Per-group analysis showed significant OSBP reduction for groups 1 and 2. Patients with isolated systolic hypertension had a significantly smaller reduction in OSBP after 6 months compared with patients with combined systolic/diastolic hypertension (-16.2 mm Hg ± 18.5 vs -9.9 mm Hg ± 33.4; P < .005). CONCLUSIONS: Use of the RDN system was feasible and safe in this phase I study. Significant blood pressure reductions were observed over 6 months, although less in patients with isolated systolic hypertension.

Externally Delivered Focused Ultrasound for Renal Denervation.

OBJECTIVES: The aim of this study was to assess clinical safety and efficacy outcomes of renal denervation executed by an externally delivered, completely noninvasive focused therapeutic ultrasound device. BACKGROUND: Renal denervation has emerged as a potential treatment approach for resistant hypertension. METHODS: Sixty-nine subjects received renal denervation with externally delivered focused ultrasound via the Kona Medical Surround Sound System. This approach was investigated across 3 consecutive studies to optimize targeting, tracking, and dosing. In the third study, treatments were performed in a completely noninvasive way using duplex ultrasound image guidance to target the therapy. Short- and long-term safety and efficacy were evaluated through use of clinical assessments, magnetic resonance imaging scans prior to and 3 and 24 weeks after renal denervation, and, in cases in which a targeting catheter was used to facilitate targeting, fluoroscopic angiography with contrast. RESULTS: All patients tolerated renal denervation using externally delivered focused ultrasound. Office blood pressure (BP) decreased by 24.6 ± 27.6/9.0 ± 15.0 mm Hg (from baseline BP of 180.0 ± 18.5/97.7 ± 13.7 mm Hg) in 69 patients after 6 months and 23.8 ± 24.1/10.3 ± 13.1 mm Hg in 64 patients with complete 1-year follow-up. The response rate (BP decrease >10 mm Hg) was 75% after 6 months and 77% after 1 year. The most common adverse event was post-treatment back pain, which was reported in 32 of 69 patients and resolved within 72 h in most cases. No intervention-related adverse events involving motor or sensory deficits were reported. Renal function was not altered, and vascular safety was established by magnetic resonance imaging (all patients), fluoroscopic angiography (n = 48), and optical coherence tomography (n = 5). CONCLUSIONS: Using externally delivered focused ultrasound and noninvasive duplex ultrasound, image-guided targeting was associated with substantial BP reduction without any major safety signals. Further randomized, sham-controlled trials will be needed to validate this unique approach.

Symplicity multi-electrode radiofrequency renal denervation system feasibility study.

AIMS: The aim of this study was to test the safety and performance of the Symplicity™ multi-electrode radio-frequency renal denervation system which was designed to reduce procedure time during renal denervation. METHODS AND RESULTS: The multi-electrode radiofrequency renal denervation system feasibility study is a prospective, non-randomised, open label, feasibility study that enrolled 50 subjects with hypertension. The study utilises a new renal denervation catheter which contains an array of four electrodes mounted in a helical configuration at 90 degrees from each other to deliver radiofrequency energy simultaneously to all four renal artery quadrants for 60 seconds. The protocol specified one renal denervation treatment towards the distal end of each main renal artery with radiofrequency energy delivered for 60 seconds per treatment. Total treatment time for both renal arteries was two minutes. The 12-month change in office systolic blood pressure (SBP) and 24-hour SBP was -19.2±25.2 mmHg, p<0.001, and -7.6±20.0 mmHg, p=0.020, respectively. There were three patients with access-site complications, none of which was related to energy delivery; all were treated successfully. No new renal artery stenosis or hypertensive emergencies occurred. CONCLUSIONS: The Symplicity multi-electrode radiofrequency renal denervation system was associated with a significant reduction in SBP at 12 months and minimal complications whilst it also reduced procedure time. TRIAL REGISTRATION: NCT01699529.

Central pulse pressure predicts BP reduction after renal denervation in patients with treatment-resistant hypertension.

AIMS: Enhanced vascular ageing is associated with elevated central pulse pressure (cPP), an independent predictor of cardiovascular (CV) events. Although antihypertensive treatment strategies are effective, high residual CV risk remains indicative of advanced and largely irreversible vascular damage. Renal denervation (RDN) has been shown to reduce blood pressure (BP) to various extents in patients with treatment-resistant hypertension (TRH). We hypothesised that cPP predicts BP reduction after RDN. METHODS AND RESULTS: Sixty-three patients with true TRH underwent catheter-based RDN using the Symplicity Flex™ catheter and were followed for six months. At baseline, cPP was assessed by pulse wave analysis (SphygmoCor™). Patients were stratified according to their median cPP (55 mmHg), and called "low cPP" (below the median) or "high cPP" (above the median). Office BP reduction six months after RDN was greater (-22±19/-13±11 vs. -12±20/-5±13 mmHg, p=0.038/0.014) and 24-hr ambulatory blood pressure (ABP) reduction tended to be greater (-11±13/-8±10 vs. -3±18/-4±10 mmHg, p=0.070/0.112) in patients with low cPP compared to those with high cPP. Only cPP (ß=0.687, p=0.001) and baseline systolic BP (ß=-0.564, p<0.001) were independent determinants of office systolic BP reduction after RDN. CONCLUSIONS: Our data suggest that cPP, indicative of the degree of large arterial stiffening, may be helpful to identify responders to RDN.

Interventional management in hypertension: where do we stand?

PURPOSE OF REVIEW: Device-based interventions to lower drug-resistant hypertension have made the management of this disorder more complicated. In this review, we will focus on developments in this approach to blood pressure care which have appeared over the last year in a published or abstract form. RECENT FINDINGS: Much of the recent literature in this area is characterized by very large office systolic blood pressure reductions, on the order of 25 mmHg at 6 months after intervention. However, the largest and the most rigorously conducted trial of renal denervation failed to meet its efficacy endpoint. We will review some speculations on why that may have occurred. SUMMARY: There is little guidance for the management of drug-resistant hypertension in existing guidelines due largely to an absence of clinical trials with hard cardiovascular outcomes; thus, most of the literature relies on short-term (generally less than 1 year) studies that are oriented toward efficacy (i.e., blood pressure reduction per se). With the failure of the Symplicity HTN3 trial to meet its efficacy endpoint, the entire field of renal denervation is under careful scrutiny. From this reviewer's perspective, this finding seems to be more of a speed-bump than a 'road closed' sign for renal denervation, a prompt to reconsider the adequacy of denervation techniques and an encouragement to continue the search for robust predictors of clinical response.

Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial.

AIMS: Renal denervation using the point-by-point application of radiofrequency energy delivered by the first-generation Symplicity system is effective in lowering office blood pressure but may be time-consuming. The OneShot Renal Denervation System with a balloon-mounted spiral electrode potentially shortens and simplifies the procedure. This study is a hypothesis-generating first-in-human study to assess feasibility, and to provide preliminary efficacy and safety data. METHODS AND RESULTS: Eligible patients had a baseline office systolic blood pressure ≥160 mmHg (or ≥150 mmHg for diabetics) and were on two or more antihypertensive medications. Nine patients were enrolled. The primary endpoint, the insertion of the OneShot balloon into each renal artery and the delivery of radiofrequency energy, was achieved in 8/9 (89%) of patients. The one failure (the first patient) was due to generator high-impedance safety shut-off threshold set too low for humans. Adverse events were minor. No patient developed renal artery stenosis. Baseline BP was 185.67 ± 18.7 mmHg and the reductions at 1, 3, 6 and 12 months were 30.1 ± 13.6 (p=0.0004), 34.2 ± 20.2 (p=0.002), 33.6 ± 32.2 (p=0.021) and 30.6 ± 22.0 (p=0.019). CONCLUSIONS: The OneShot renal denervation system successfully delivered radiofrequency energy to the renal arteries in a short and straightforward procedure. Australian New Zealand Clinical Trials Registry - URL: anzctr.org.au. Trial identification: ACTRN12611000987965.

A novel non-vascular system to treat resistant hypertension.

AIMS: To evaluate in a preclinical model the utility of a monopolar electrode catheter delivering radiofrequency (RF) energy placed into the renal pelvis in order to treat resistant hypertension (RH). METHODS AND RESULTS: Sixteen female domestic swine weighing 60-65 kg underwent renal pelvic denervation via ureteral access. Three animals were euthanised immediately after delivery of RF energy; five animals were allowed to survive for seven days, six animals were allowed to survive for 14 days and two animals were allowed to survive for 30 days. Renal cortical norepinephrine levels were measured in all groups of animals. Histopathology of the treated zone was performed to confirm nerve damage. Renal cortical tissue was harvested for determination of tissue norepinephrine by HPLC. The kidneys were then profusion-fixed and harvested for histopathologic analysis. Mean reduction of norepinephrine levels was 60.4% compared to control. Histopathology confirmed nerve ablation in the treated zone. CONCLUSIONS: In this small, preclinical study, we introduce a new non-vascular system to treat resistant hypertension. If the current clinical experience confirms efficacy and safety, this approach may be one way to treat patients who cannot be treated with the standard percutaneous arterial devices.