Sebastian Ewen

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 …

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

BACKGROUND Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING Medtronic.

Effect of Renal Denervation on Neurohumoral Activation Triggering Atrial Fibrillation in Obstructive Sleep Apnea

Obstructive sleep apnea is characterized by repetitive collapses of the upper airway, negative thoracic pressure periods, and intermittent hypoxia, stimulating the autonomic nervous system. The increased sympathetic drive during obstructive sleep apnea results in postapneic blood pressure rises and neurohumoral activation potentially involved in the initiation and progression to permanent atrial fibrillation (AF). In a pig model mimicking obstructive sleep apnea, we studied the effects of repetitive obstructive respiratory events for 4 hours on the occurrence of spontaneous AF episodes, postapneic blood pressure rises, and neurohumoral activation. In addition, renal sympathetic denervation was performed to investigate the impact of the sympathetic nervous system. Repetitive obstructive respiratory events caused pronounced postapneic blood pressure rises, prolonged duration of spontaneous AF episodes triggered by spontaneous atrial beats, and increased plasma renin activity and aldosterone concentrations. This was associated with increased nicotinamide adenine dinucleotide phosphate-oxidase activity, reduced antioxidative capacity, and elevated expression of connective tissue growth factor, a redox-sensitive mediator of fibrosis. Renal sympathetic denervation inhibited postapneic blood pressure rises and decreased plasma renin activity and aldosterone concentrations. The occurrence and duration of spontaneous AF were reduced comparable with a combined pharmacological blockade of angiotensin receptor and &bgr;-adrenoceptor. Increased atrial oxidative stress, together with the activation of profibrotic pathways and intermittent hypoxia, was not attenuated after renal sympathetic denervation. Repetitive obstructive respiratory events triggered spontaneous AF, increased atrial oxidative stress, and activated profibrotic pathways in the atrium. Renal sympathetic denervation reduced spontaneous AF and postapneic blood pressure rises by combined reduction of sympathetic drive and components of the circulating renin–angiotensin system. However, the generation of atrial oxidative stress was not modulated.

Reduced Effect of Percutaneous Renal Denervation on Blood Pressure in Patients With Isolated Systolic Hypertension

Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, ≥140/≥90 mm Hg) defined as baseline office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.

Objectives: Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension. Methods: We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) ≥ 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement ≥ 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at www.clinicaltrials.gov (ID: NCT01442883). Results: Mean baseline BP was 156 ± 12/82 ± 13 mmHg, despite treatment with 6.2 ± 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 ± 20 (P < 0.001)/8 ± 14 mmHg (P = 0.005) and average 24-h ambulatory BP by 9 ± 14 (P = 0.009)/4 ± 7 mmHg (P = 0.019). Before RDN, eGFR declined by –4.8 ± 3.8 ml/min per 1.73 m2 per year, and after RDN eGFR improved by +1.5 ± 10 ml/min per 1.73 m2 at 12 months (P = 0.009). Conclusions: Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.

Improvement of albuminuria after renal denervation

OBJECTIVES The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30-300 mg/g, n=37) and macroalbuminuria (≥ 300 mg/g, <2,200 mg/g, n=22). BACKGROUND Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion. METHODS Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex™ catheter (Medtronic Inc., Santa Rosa, CA). RESULTS In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65-496) versus 89 (29-319) mg/g creatinine, p<0.001) and in both subgroups (microalbuminuria: 83 (49-153) versus 58 (17-113) mg/g creatinine, p=0.001; macroalbuminuria: (536 (434-1483) versus 478 (109-1080) mg/g creatinine, p<0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (β=0.340, p=0.039) independent of renal function. Renal function remained unchanged after RDN. CONCLUSIONS In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.

Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry

Aims Catheter-based renal artery denervation (RDN) has been shown to lower blood pressure (BP) in certain patients with uncontrolled hypertension. Isolated systolic hypertension (ISH) (systolic BP [SBP] ≥140 mmHg and diastolic BP <90 mmHg), characterized by increased vascular stiffness, is the predominant hypertensive phenotype in elderly patients. This study compared baseline characteristics and SBP change at 6 months between patients with ISH and combined systolic–diastolic hypertension (CH). Methods and results This study pooled data from 1103 patients from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. A total of 429 patients had ISH, and 674 had CH. Patients with ISH were significantly older than those with CH (66 vs. 55 years), had more type 2 diabetes mellitus (52.9 vs. 34.6%), and a lower estimated glomerular filtration rate (71.8 vs. 78.6 mL/min/1.73 m2); all P < 0.001. At 6 months, the SBP drop for CH patients was −18.7 ± 23.7 mmHg compared with a reduction of −10.9 ± 21.7 mmHg for ISH patients −7.8 mmHg, 95% confidence interval, CI, −10.5, −5.1, P < 0.001). The change in 24-h SBP at 6 months was −8.8 ± 16.2 mmHg in patients with CH vs. −5.8 ± 15.4 mmHg in ISH (−3.0 mmHg, 95% CI −5.4, −0.6, P = 0.015). Presence of ISH at baseline but not age was associated with less pronounced BP changes following the procedure. The strongest predictor of office SBP reduction at 6 months was CH, followed by aldosterone antagonist use and non-use of vasodilators. Conclusion The reduction in BP among patients with ISH following RDN was less pronounced than the reduction in patients with CH. Clinical.Trials.gov identifiers NCT01534299 and NCT01418261.

Drug adherence in patients taking oral anticoagulation therapy

Oral anticoagulation has proven to reduce mortality and morbidity of thromboembolic events. One of the most important determinants of the effectiveness and safety of anticoagulation therapy is the adherence to the prescribed therapy. Vitamin K antagonists are characterized by under-utilization, a narrow therapeutic window and multiple food and drug interactions which contribute to a variable dose–response relationship with the risk of insufficient protection and/or increased bleeding risk. The “new” direct oral anticoagulants have demonstrated equal or superior protection and reduced bleeding risks compared to warfarin and are easier to use because of fixed dosing without monitoring of anticoagulation. Controlling of adherence to the direct oral anticoagulants is difficult. Therefore, continuous and regular medication intake represents a pre-requisite for achieving optimal protection. The present review aims to give an overview about the factors that affect drug adherence in patients taking oral anticoagulation drugs and discusses strategies to improve drug adherence.

Renal denervation and heart failure.

Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve activity. In heart failure sympathetic activation, in particular, renal norepinephrine release is closely associated with morbidity and mortality. Initial studies have shown that renal denervation is able to reduce not only blood pressure but also heart rate, and is associated with a reduction in myocardial hypertrophy, improved glucose tolerance, and ameliorated microalbuminuria. Since some experimental and observational data suggest an antiarrhythmic effect, it is possible that renal denervation might also play a therapeutic role in arrhythmias often occurring in chronic heart failure. The first proof‐of‐concept studies are planned to evaluate the clinical effect of this pathophysiologically plausible method, which might be able to change clinical practice.

Response and non-response to renal denervation: who is the ideal candidate?

Catheter-based renal denervation (RDN) leads to a considerable decrease of blood pressure in the vast majority of patients with resistant hypertension. However, only minor or no blood pressure change is achieved in some patients. This non-reponse is defined as a reduction of office systolic blood pressure of less than 10 mmHg following RDN. The rates of non-response vary between 8-37%. Here several causes are discussed such as inappropriate patient selection, an ineffective procedure, the subordinate contribution of sympathetic activation for the maintenance of hypertension, and patient conditions such as non-adherence to drug therapy. Based on current evidence, an ideal candidate for RDN has high baseline blood pressure, which is known to be the best predictor for blood pressure reduction after RDN. In order to ensure treatment success further criteria have to be fulfilled, such as exclusion of secondary hypertension and optimised medical therapy.