Adherence to antihypertensive drug treatment in patients with apparently treatment-resistant hypertension in the INSPiRED pilot study.

PURPOSE: Drug adherence may be a major problem in the therapy of hypertension and in the diagnosis of therapy resistance. Adherence can be assessed by indirect methods or by direct methods like drug detection in urine with liquid chromatography-mass spectrometric methods. MATERIALS AND METHODS: The current analysis included patients with apparently treatment- resistant hypertension (TRH) referred for renal denervation (RDN) and included in the the INSPiRED pilot trial (NCT01505010). Adherence was repeatedly assessed by toxicological urine analysis over a time range of up to 17 months in a total of 18 patients. RESULTS: In the first urine samples of 18 patients the adherence rate (percentage of number of detected vs. prescribed medical drugs) ranged from 0 to 100% with a median of 73.2%. In further urine samples collected during the following up to 17 months every individual patient exhibited considerable changes in the adherence rate, neither a constancy nor a tendency could be deduced. CONCLUSIONS: Urine analysis results exhibit variation over time and an assessment at a certain time point cannot be regarded as representative or predictor for future behavior. Therefore, it appears necessary to perform drug adherence testing repeatedly over time.

Predictors of blood pressure control in patients with resistant hypertension after intensive management in two expert centres: the Brussels-Torino experience.

Background: Management of resistant hypertension (RHTN) is challenging and often implies the use of complex polypharmacy and interventional therapies. The main objectives of this study were (i) to describe the characteristics of patients with RHTN referred to two expert centres; (ii) to identify predictors of blood pressure (BP) control after intensive management. Methods: We reviewed electronic medical files of all patients referred for RHTN to the Brussels and Torino centres, and extracted detailed clinical data, informations on drug adherence and psychological profile. All patients with confirmed diagnosis of RHTN, according to office and ambulatory BP monitoring (ABPM) measurements, were considered eligible. Results: 313 patients (51% men; age: 56 ± 12 years; office BP 177/98 mmHg; 24-hour ABPM 153/90 mmHg) were included. At the end of follow-up (median: 2 years [1-4]), only 26% of patients (n = 81) reached BP control. When compared to patients remaining resistant, patients eventually controlled had lower pulse pressure (71 vs. 82 mmHg, p < 0.001), less often myocardial infarction (6% vs. 20%, p < 0.005) and showed a higher recourse to cognitive reappraisal as far as emotion regulation is concerned (4.8 ± 1.1 vs. 3.9 ± 1.2, p = 0.009; ERQ Questionnaire). In a multivariate analysis looking for predictors of controlled BP, only the psychological characteristic of cognitive reappraisal (i.e., changing one's thoughts about a potentially emotion-eliciting event) remained significant (OR 2.06 [1.10; 3.84], p = 0.02). Conclusions: Even in expert centres, only a minority of patients with RHTN reached BP control, irrespective of the centre involved or the interventions applied. Patients who eventually responded to therapy had lower arterial stiffness and less cardiac organ damage. Furthermore, besides vascular damage, the single predictor of BP control was the ability to modify the emotional impact of stressful situations.

Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography.

OBJECTIVES: Relatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated. METHODS: This study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma. RESULTS: MRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366 days post RDN, MRA showed a new stenosis (25-49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable. CONCLUSIONS: We observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12 months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients. KEY POINTS: • The incidence of vascular changes 12 months post RDN was 3.1%. • No renal vascular or parenchymal changes other than stenoses were observed. • Ablations were applied near the stenosis in only one of three patients.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension.

OBJECTIVE: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. METHODS: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age <70 years; systolic/diastolic office blood pressure (BP) ≥ 140/90 mm Hg; 24-h BP ≥130/80 mm Hg; glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m2; body mass index <40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (n = 9) or combined with RDN by the EnligHTN™ multi-electrode system (n = 6). RESULTS: The baseline-adjusted between-group differences amounted to 19.5/10.4 mm Hg (change in control vs. intervention group, +7.6/+2.2 vs. -11.9/-8.2 mm Hg; P = .088) for office BP, 22.4/13.1 mm Hg (+0.7/+0.3 vs. -21.7/-12.8; mm Hg; P ≤ .049) for 24-h BP, the primary efficacy endpoint, and 2.5 mL/min/1.73 m2 (+1.5 vs. -1.1 mL/min/1.73 m2; P = .86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (P ≤ .036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. CONCLUSIONS: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension.

OBJECTIVE: The blood pressure (BP)-lowering effect of renal sympathetic nervous denervation (RDN) in resistant hypertension (rHT) shows large variation among studies. METHODS: We meta-analyzed summary statistics of randomized clinical trials on RDN in rHT. For continuous outcomes, we assessed heterogeneity by Cochran's Q test and used random-effect models weighted for the inverse of the variance. We assessed safety by assessing the risk of major adverse events from stratified contingency tables. RESULTS: Of 5652 patients screened in seven trials, 985 (17.4%) qualified and were randomized to control (n = 397) or RDN with SYMPLICITY(™) catheters (n = 588). Follow-up was 6 months. In both control and RDN patients, antihypertensive treatment was continued or optimized. At enrolment, age averaged 58.1 years, systolic/diastolic office and 24 h BP 168.5/93.3 mmHg and 151.8/86.1 mmHg, respectively, and estimated glomerular filtration rate (eGFR) 79.3 ml/min/1.73 m². For BP outcomes, there was heterogeneity among trials. Pooled effects (control minus RDN) were -4.9/-3.5 mmHg (95% confidence interval, -20.9 to 11.1/-8.9 to 1.9) for office BP, -2.8/-1.5 mmHg (-6.5 to 0.8/-3.3 to 0.4) for 24 h BP and 0.81 ml/min/1.73 m² (-1.69 to 3.30) for eGFR. Removing one trial at a time produced confirmatory results. Adverse events occurred in 7.4% and 9.9% of control and RDN patients, respectively (p = 0.24). CONCLUSION: In selected rHT patients maintained on antihypertensive drugs, RDN with the SYMPLICITY systems does not significantly decrease BP but is safe. Future trials with next-generation catheters should aim at identifying responders in patients with evidence of sympathetic nervous overactivity.

Renal denervation after Symplicity HTN-3: an update.

After three years of excessive confidence, overoptimistic expectations and performance of 15 to 20,000 renal denervation procedures in Europe, the failure of a single well-designed US trial--Symplicity HTN-3--to meet its primary efficacy endpoint has cast doubt on renal denervation as a whole. The use of a sound methodology, including randomisation and blinded endpoint assessment was enough to see the typical 25-30 mmHg systolic blood pressure decrease observed after renal denervation melt down to less than 3 mmHg, the rest being likely explained by Hawthorne and placebo effects, attenuation of white coat effect, regression to the mean and other physician and patient-related biases. The modest blood pressure benefit directly assignable to renal denervation should be balanced with unresolved safety issues, such as potentially increased risk of renal artery stenosis after the procedure (more than ten cases reported up to now, most of them in 2014), unclear long-term impact on renal function and lack of morbidity-mortality data. Accordingly, there is no doubt that renal denervation is not ready for clinical use. Still, renal denervation is supported by a strong rationale and is occasionally followed by major blood pressure responses in at-risk patients who may otherwise have remained uncontrolled. Upcoming research programmes should focus on identification of those few patients with truly resistant hypertension who may derive a substantial benefit from the technique, within the context of well-designed randomised trials and independent registries. While electrical stimulation of baroreceptors and other interventional treatments of hypertension are already "knocking at the door", the premature and uncontrolled dissemination of renal denervation should remain an example of what should not be done, and trigger radical changes in evaluation processes of new devices by national and European health authorities.

Rationale and design of the Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial.

UNLABELLED: The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term efficacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering efficacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20-69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTN(TM), SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular filtration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT 01505010.

Impact of frailty scores on outcome of octogenarian patients undergoing transcatheter aortic valve implantation.

BACKGROUND: For selected patients with symptomatic aortic stenosis, transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement (AVR). In addition to co-morbidities, frailty has to be taken into account in the decision-making process. Criteria for patient selection, according to current guidelines, include EuroSCORE and STS score but frailty is not easy to quantify. ISAR (Identification of Seniors At Risk) detects seniors at risk for adverse health outcome after an emergency visit and SHERPA (Score Hospitalier d'Evaluation du Risque de Perte d'Autonomie) assesses the risk of functional decline after hospitalization. OBJECTIVES: The aim of the present study was to evaluate the impact of ISAR and SHERPA scores in the prediction of patient outcome afterTAVI. METHODS AND RESULTS: A prospective cohort of 30 consecutive octogenarian patients (16 males, 86 +/- 3 y, EuroSCORE 34 +/- 12%) underwent a transfemoral TAVI and a complete geriatric assessment in our institution. Survival at one year was 73%. The ISAR score was similar between both groups (3.1 +/- 1 vs. 3.6 +/- 1; P = 0.10) but the SHERPA score was significantly higher in non-survivors (7.8 +/- 1.6) than among survivors (4.9 +/- 2.4; P = 0.001). With multivariate analysis, SHERPA score and BMI were independent predictors of 1-year mortality. Kaplan-Meier analysis showed that 1-year survival was significantly lower in patients with than in those without a SHERPA score > 7 (40 vs. 89%; P = 0.004). CONCLUSIONS: The result of this study showed that SHERPA score predicts 1-year survival after transfemoral TAVI and could be considered as a useful frailty score in patient selection.

Resheathing of self-expanding bioprosthesis: Impact on procedural results, clinical outcome and prosthetic valve durability after transcatheter aortic valve implantation.

BACKGROUND: New transcatheter aortic valves were recently developed, enabling to resheath and reposition the prosthesis. The aim of the present study was to investigate whether the resheath manoeuvre did not impair the outcome of patients and the bioprosthesis durability after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: On the 346 consecutive patients (84 ±â€¯7 yrs-old, mean STS 6.7 ±â€¯5%) undergoing a transfemoral TAVI in our institution since January 2008, 170 patients were implanted using a self-expanding valve (SEV). Among those, 39 (Group 1) required resheathing to achieve a successful implantation, while 131 did not require it (Group 2, N = 131). A balloon-expanding valve (BEV) was used in 176 patients (Group 3). Baseline characteristics were similar between groups. Device success was 98%, the rate of in-hospital death was 2%, and the number of procedural complications was similarly low, with no significant difference between groups. The follow-up was complete in 337 of 338 patients undergoing a successful TAVI (781 patients-year). Kaplan-Meier analysis showed that overall survival was 80 ±â€¯2% and 42 ±â€¯3% at 1 and 5 years respectively, with no difference between groups. On multivariate analysis, acute kidney injury, post-dilatation, pulmonary hypertension, porcelain aorta and STS score, but not resheath, were independant predictors of death after TAVI. The annual event rate of structural valve deterioration was 0.6% patients-year, and similar between groups. CONCLUSIONS: Our study shows that SEV resheath did not impair the procedural results, the outcome of patients nor the valve durability at short term after TAVI.

Alcohol-Mediated Renal Denervation Using the Peregrine System Infusion Catheter for Treatment of Hypertension.

OBJECTIVES: The aim of this multicenter, open-label trial was to evaluate the safety and efficacy of alcohol-mediated renal denervation using a novel catheter system (the Peregrine System Infusion Catheter) for the infusion of dehydrated alcohol as a neurolytic agent into the renal periarterial space. BACKGROUND: The number of hypertensive patients with uncontrolled blood pressure (BP) remains unacceptably low. The renal sympathetic nervous system has been identified as an attractive therapeutic target. METHODS: Forty-five patients with uncontrolled hypertension on ≥3 antihypertensive medications underwent bilateral renal denervation using the Peregrine Catheter with 0.6 ml alcohol infused per renal artery. RESULTS: All patients were treated as intended. Mean 24-h ambulatory BP reduction at 6 months versus baseline was -11 mm Hg (95% confidence interval [CI]: -15 to -7 mm Hg) for systolic BP and -7 mm Hg (95% CI: -9 to -4 mm Hg) for diastolic BP (p < 0.001 for both). Office systolic BP was reduced by -18/-10 mm Hg (95% CI: -25 to -12/-13 to -6 mm Hg) at 6 months. Antihypertensive medications were reduced in 23% and increased in 5% of patients at 6 months. Adherence to the antihypertensive regimen remained stable over time. The primary safety endpoint, defined as the absence of periprocedural major vascular complications, major bleeding, acute kidney injury, or death within 1 month, was met in 96% of patients (95% CI: 85% to 99%). Two patients had major adverse events of periprocedural access-site pseudoaneurysms, with major bleeding in one. There were no deaths or instances of myocardial infarction, stroke, transient ischemic attack, or renal artery stenosis. Transient microleaks were noted in 42% and 49% of the left and right main renal arteries, respectively. There were 2 cases of minor vessel dissection that resolved without treatment. CONCLUSIONS: Primary results from this trial suggest that alcohol-mediated renal denervation using the Peregrine Catheter safely reduces blood pressure and as such may represent a novel approach for the treatment of hypertension.