Guillaume Bobrie

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.

Detection of masked hypertension by home blood pressure measurement: is the number of measurements an important issue?

BackgroundOffice blood pressure (OBP) and home blood pressure (HBP) enable the identification of patients with masked hypertension. Masked hypertension is defined by normal OBP and high HBP and is known as a pejorative cardiovascular risk factor. ObjectiveThe objective was to evaluate in the SHEAF study the influence of the number of office or home blood pressure measurements on the classification of patients as masked hypertensives. MethodsPatients with OBP <140/90 mmHg (mean of six values: three measurements at two separate visits, V1 and V2) and HBP >135/85 mmHg (mean of all valid measurements performed over a 4-day period) were the masked hypertensive reference group. The consistency of the classification was evaluated by using five definitions of HBP values (mean of the 3, 6, 9, 12 and 15 first measurements) and two definitions of OBP values (mean of three measurements at V1 and mean of three measurements at V2). ResultsAmong the 4939 treated hypertensives included in the SHEAF study, 463 (9.4%) were classified as masked hypertensives (reference group). By decreasing the number of office or home measurements, the prevalence of masked hypertension ranged from 8.9–12.1%. The sensitivity of the classification ranged from 94–69% therefore 6–31% of the masked hypertensives were not detected. The specificity ranged from 98–94% therefore 1–6% of patients were wrongly classified as masked hypertensives. ConclusionA limited number of home and office BP measurements allowed the detection of masked hypertension with a high specificity and a low sensitivity. A sufficient number of measurements (three measurements at two visits for OBP and three measurements in the morning and in the evening over 2 days for HBP) are required to diagnose masked hypertension.

True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence.

Objectives: We assessed the influence of medication adherence on blood pressure (BP) control and target organ damage in a pre-specified analysis of a published trial comparing sequential nephron blockade (SNB) or sequential renin–angiotensin system blockade (SRASB) in patients with resistant hypertension. Methods: Patients were randomized to SNB (n = 82) or SRASB (n = 82) and studied at baseline and after 12 weeks. BP was measured by ambulatory blood pressure monitoring. Carotid–femoral pulse wave velocity (PWV) was measured by applanation tonometry and left ventricular mass (LVM) by echocardiography. Low medication adherence was assessed through plasma irbesartan concentration below 20 ng/ml; urinary N-acetyl-seryl-aspartyl-lysyl-proline/creatinine ratio below 4 nmol/mmol; last medication intake before visit greater than 24 h and pill counting below 80% of theoretical intake. Medication adherence score (sum of items, max = 4) is defined as low (medication adherence score <2) or acceptable (medication adherence score ≥2). Results: Among 164 patients, 134 (81.7%) had acceptable medication adherence and 30 (18.3%) low medication adherence, with similar proportions in the SNB and SRASB arms. After 12 weeks, in patients with acceptable medication adherence, BP was more frequently controlled in those treated with SNB (64%), than SRASB (18%; P < 0.001). The difference in daytime SBP was −11.5 mmHg [95% confidence interval (CI) −15.4 to −7.5, P < 0.0001] in patients with acceptable medication adherence. In contrast, in patients with low medication adherence, the difference between groups was smaller and not significant (−9.4 mmHg, 95% CI −20.4 to 1.7, P = 0.09). Independently of BP changes, PWV and LVM decreased more in the SNB than in the SRASB arm when medication adherence was acceptable (−0.52 m/s, 95% CI −1.3 to −0.007, P = 0.047; and −24 g/m2, 95% CI −36 to −12, P = 0.0003), whereas no significant changes were observed in low medication adherence patients. Conclusion: Medication adherence contributes to BP-lowering and regression of target organ damage. The differential effects of SNB and SRASB is observed in patients with acceptable medication adherence, and not in patients with low medication adherence.

New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension

There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.

Greater efficacy of aldosterone blockade and diuretic reinforcement vs. dual renin-angiotensin blockade for left ventricular mass regression in patients with resistant hypertension.

Objectives: We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies – mineralocorticoid receptor blockade (MRB) and dual renin–angiotensin system blockade (RASB) – in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension. Methods: After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20–40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5–10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12. Results: Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m2 in the MRB group, whereas it increased by 1.8 ± 19.1 g/m2 in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e′ ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP. Conclusion: In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

Twenty-Four-Hour Blood Pressure Monitoring to Predict and Assess Impact of Renal Denervation: The DENERHTN Study (Renal Denervation for Hypertension).

The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure (BP) lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report here the effect of denervation on 24-hour BP and its variability and look for parameters that predicted the BP response. Patients with resistant hypertension were randomly assigned to denervation plus stepped-care treatment or treatment alone (control). Average and standard deviation of 24-hour, daytime, and nighttime BP and the smoothness index were calculated on recordings performed at randomization and 6 months. Responders were defined as a 6-month 24-hour systolic BP reduction ≥20 mm Hg. Analyses were performed on the per-protocol population. The significantly greater BP reduction in the denervation group was associated with a higher smoothness index (P=0.02). Variability of 24-hour, daytime, and nighttime BP did not change significantly from baseline to 6 months in both groups. The number of responders was greater in the denervation (20/44, 44.5%) than in the control group (11/53, 20.8%; P=0.01). In the discriminant analysis, baseline average nighttime systolic BP and standard deviation were significant predictors of the systolic BP response in the denervation group only, allowing adequate responder classification of 70% of the patients. Our results show that denervation lowers ambulatory BP homogeneously over 24 hours in patients with resistant hypertension and suggest that nighttime systolic BP and variability are predictors of the BP response to denervation. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01570777.

Deciphering the Role of Vasopressin in Primary Aldosteronism

CONTEXT The role of vasopressin (AVP) in the pathophysiology of primary aldosteronism (PA) remains unclear. OBJECTIVES The primary aim of this study was to investigate AVP secretion in PA by measuring the plasma concentration of copeptin (PCop), the C-terminal portion of provasopressin. The secondary aim was to assess renal sensitivity to AVP. DESIGN AND SETTING This was a cross-sectional study in a tertiary-care hospital. PROTOCOL We recruited 115 patients with PA, 48 patients with essential hypertension (EH), and 108 normotensive healthy subjects (HS). Blood was sampled for biochemical and hormonal evaluations in fasting condition after 1-h rest in supine position. Osmolality was determined in 24-h urine. PCop was determined by immunoassay. MAIN OUTCOME MEASURE The main outcome measure was adjusted difference in PCop between groups. RESULTS After adjustment for sex, body mass index, systolic blood pressure, natremia, and kalemia, PCop was significantly higher in patients with PA than in HS (geometric mean ratio, 1.61; 95% confidence interval [CI], 1.26-2.06; P < .0001) and patients with EH (1.40; 95% CI, 1.08-1.82; P = .0070) PCop was positively correlated with natremia (P = .0094). Urine osmolality was significantly lower in patients with PA than in HS (0.82; 95% CI, 0.74-0.92; P = .0002) and 24-h urinary output was significantly higher in patients with PA than in HS (1.32; 95% CI, 1.11-1.56; P = .0005). The relationship between urine osmolality and PCop was shifted downward in patients with PA but was similar in patients with EH and HS, indicating peripheral resistance to AVP. CONCLUSION PCop increases in patients with PA in response to an increase in natremia and a renal resistance phenomenon, indicating that AVP release is chronically stimulated in PA.

Abdominal Aortic Calcifications Influences the Systemic and Renal Hemodynamic Response to Renal Denervation in the DENERHTN (Renal Denervation for Hypertension) Trial

Background The DENERHTN (Renal Denervation for Hypertension) trial confirmed the efficacy of renal denervation (RDN) in lowering daytime ambulatory systolic blood pressure when added to standardized stepped‐care antihypertensive treatment (SSAHT) for resistant hypertension at 6 months. Methods and Results This post hoc exploratory analysis assessed the impact of abdominal aortic calcifications (AAC) on the hemodynamic and renal response to RDN at 6 months. In total, 106 patients with resistant hypertension were randomly assigned to RDN plus SSAHT or to the same SSAHT alone (control group). Total AAC volume was measured, with semiautomatic software and blind to randomization, from the aortic hiatus to the iliac bifurcation using the prerandomization noncontrast abdominal computed tomography scans of 90 patients. Measurements were expressed as tertiles. The baseline‐adjusted difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the RDN and control groups was −10.1 mm Hg (P=0.0462) in the lowest tertile and −2.5 mm Hg (P=0.4987) in the 2 highest tertiles of AAC volume. Estimated glomerular filtration rate remained stable at 6 months for the patients in the lowest tertile of AAC volume who underwent RDN (+2.5 mL/min per 1.73 m2) but decreased in the control group (−8.0 mL/min per 1.73 m2, P=0.0148). In the 2 highest tertiles of AAC volume, estimated glomerular filtration rate decreased similarly in the RDN and control groups (P=0.2640). Conclusions RDN plus SSAHT resulted in a larger decrease in daytime ambulatory systolic blood pressure than SSAHT alone in patients with a lower AAC burden than in those with a higher AAC burden. This larger decrease in daytime ambulatory systolic blood pressure was not associated with a decrease in estimated glomerular filtration rate. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01570777.

Automated interpretation of home blood pressure assessment (Hy-Result software) versus physician's assessment: a validation study.

ObjectiveHy-Result is the first software for self-interpretation of home blood pressure measurement results, taking into account both the recommended thresholds for normal values and patient characteristics. We compare the software-generated classification with the physician’s evaluation. Design methodThe primary assessment criterion was whether algorithm classification of the blood pressure (BP) status concurred with the physician’s advice (blinded to the software’s results) following a consultation (n=195 patients). Secondary assessment was the reliability of text messages. ResultsIn the 58 untreated patients, the agreement between classification of the BP status generated by the software and the physician’s classification was 87.9%. In the 137 treated patients, the agreement was 91.9%. The &kgr;-test applied for all the patients was 0.81 (95% confidence interval: 0.73–0.89). After correction of errors identified in the algorithm during the study, agreement increased to 95.4% [&kgr;=0.9 (95% confidence interval: 0.84–0.97)]. For 100% of the patients with comorbidities (n=46), specific text messages were generated, indicating that a physician might recommend a target BP lower than 135/85 mmHg. Specific text messages were also generated for 100% of the patients for whom global cardiovascular risks markedly exceeded norms. ConclusionClassification by Hy-Result is at least as accurate as that of a specialist in current practice (http://www.hy-result.com).

HY-Quest, standardized patient questionnaire to be completed at home before a first visit for hypertension: a validation study in specialized centres in France.

Objective: To evaluate a patient questionnaire (HY-QUEST) to be completed at home before consulting in a hypertension clinic for the first time. Methods: HY-QUEST is a questionnaire translated into patient language of the items from a standardized computerized medical record used since 1975 and regularly updated. This questionnaire contains 97 closed and seven free-text questions designed to evaluate cardiovascular risk and possible secondary hypertension, and to guide therapeutic strategy. One hundred and thirty-three new patients were asked to complete it at home and to bring it with them to their first visit in the hypertension clinic. The primary end-point was completeness of the answers. Other end-points were legibility and correctness of the answers. Results: Questionnaires were available for 128 out of 133 patients (96%). More than 80% of the 97 closed questions were answered in 121 out of 128 questionnaires [94.6%; 95% confidence interval (CI) 90.7–98.5] and no question had a response rate less than 85%. The answers were legible in 85% of the closed questions and the concordance rate with the physicians assessment was 94%. Among the 101 treated patients, 72 (71.3%; 95% CI 62.5–80.1) were able to provide the correct names, doses and schedule of their antihypertensive treatments. Conclusion: The HY-QUEST questionnaire can be completed by most patients with few missing or incorrect answers. It is well accepted by patients and provides useful information to orient the first consultation in a hypertension clinic. Whether the same approach is feasible and useful in primary care remains to be investigated.