Melvin D. Lobo

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design

Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25 Whatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial

BACKGROUND Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension. METHODS We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498. FINDINGS 83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting. INTERPRETATION Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. FUNDING ROX Medical.

Joint UK societies' 2014 consensus statement on renal denervation for resistant hypertension.

Resistant hypertension continues to pose a major challenge to clinicians worldwide and has serious implications for patients who are at increased risk of cardiovascular morbidity and mortality with this diagnosis. Pharmacological therapy for resistant hypertension follows guidelines-based regimens although there is surprisingly scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressure. Recently there has been considerable interest in the use of endoluminal renal denervation as an interventional technique to achieve renal nerve ablation and lower blood pressure. Although initial clinical trials of renal denervation in patients with resistant hypertension demonstrated encouraging office blood pressure reduction, a large randomised control trial (Symplicity HTN-3) with a sham-control limb, failed to meet its primary efficacy end point. The trial however was subject to a number of flaws which must be taken into consideration in interpreting the final results. Moreover a substantial body of evidence from non-randomised smaller trials does suggest that renal denervation may have an important role in the management of hypertension and other disease states characterised by overactivation of the sympathetic nervous system. The Joint UK Societies does not recommend the use of renal denervation for treatment of resistant hypertension in routine clinical practice but remains committed to supporting research activity in this field. A number of research strategies are identified and much that can be improved upon to ensure better design and conduct of future randomised studies.

Unilateral Carotid Body Resection in Resistant Hypertension A Safety and Feasibility Trial

Summary Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future

Abstract

Device-based Therapy for Hypertension.

Hypertension continues to be a major contributor to global morbidity and mortality, fuelled by an abundance of patients with uncontrolled blood pressure despite the multitude of pharmacological options available. This may occur as a consequence of true resistant hypertension, through an inability to tolerate current pharmacological therapies, or non-adherence to antihypertensive medication. In recent years, there has been a rapid expansion of device-based therapies proposed as novel non-pharmacological approaches to treating resistant hypertension. In this review, we discuss seven novel devices—renal nerve denervation, baroreflex activation therapy, carotid body ablation, central iliac arteriovenous anastomosis, deep brain stimulation, median nerve stimulation, and vagal nerve stimulation. We highlight how the devices differ, the varying degrees of evidence available to date and upcoming trials. This review also considers the possible factors that may enable appropriate device selection for different hypertension phenotypes.

Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension.

Background Options for interventional therapy to lower blood pressure (BP) in patients with treatment‐resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH. Methods and Results The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment‐resistant hypertension (office systolic BP ≥140 mm Hg, average daytime ambulatory BP ≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24‐hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: −29±21 mm Hg versus ISH: −22±31 mm Hg, P=0.445) and 24‐hour ambulatory systolic BP (CH: −14±20 mm Hg versus ISH: −13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction ≥10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932). Conclusions Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24‐hour ambulatory systolic BP in patients with combined and isolated systolic hypertension. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.

Management of Hypertensive Patients With Multiple Drug Intolerances: A Single-Center Experience of a Novel Treatment Algorithm

Multiple drug intolerance to antihypertensive medications (MDI‐HTN) is an overlooked cause of nonadherence. In this study, 55 patients with MDI‐HTN were managed with a novel treatment algorithm utilizing sequentially initiated monotherapies or combinations of maximally tolerated doses of fractional tablet doses, liquid formulations, transdermal preparations, and off‐label tablet medications. A total of 10% of referred patients had MDI‐HTN, resulting in insufficient pharmacotherapy and baseline office blood pressure (OBP) of 178±24/94±15 mm Hg. At baseline, patients were intolerant to 7.6±3.6 antihypertensives; they were receiving 1.4±1.1 medications. After 6 months on the novel MDI‐HTN treatment algorithm, both OBP and home blood pressure (HBP) were significantly reduced, with patients receiving 2.0±1.2 medications. At 12 months, OBP was reduced from baseline by 17±5/9±3 mm Hg (P<.01, P<.05) and HBP was reduced by 11±5/12±3 mm Hg (P<.01 for both) while patients were receiving 1.9±1.1 medications. Application of a stratified medicine approach allowed patients to tolerate increased numbers of medications and achieved significant long‐term lowering of blood pressure.

Interventional procedures and future drug therapy for hypertension

Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.

Central Iliac Arteriovenous Anastomosis for Hypertension: Targeting Mechanical Aspects of the Circulation

Raised blood pressure is the leading attributable risk factor for global morbidity and mortality. Real world data demonstrates that half of treated patients are at elevated cardiovascular risk because of inadequately controlled BP. In addition to pharmacotherapy, certain interventional strategies to reduce blood pressure and cardiovascular risk in hypertension can be considered according to international guidelines. One of the newer technologies entering this field is a proprietary arteriovenous coupler device that forms a fixed flow arteriovenous conduit in the central vasculature. In this review, we examine the development of and rationale for the creation of a central arteriovenous anastomosis in patients with hypertension and review the proposed mechanisms by which it may ameliorate hypertension. We critically review the clinical trial evidence base to date and postulate on future therapeutic directions.