Abstract-We aimed to investigate for the first time the blood pressure (BP)-lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10

A pproximately 10% of patients treated for hypertension remain with uncontrolled high blood pressure (BP), despite prescription of antihypertensive drugs.1 Renal sympathetic denervation has been introduced as a new treatment of hypertension apparently resistant to drug treatment.2 However, it has been known for decades that poor drug adherence is a major problem among these patients. 3,4 It is unknown to what degree the decline in BP after renal denervation (RDN) 2 is caused by denervation itself or concomitantly improved drug adherence. We aimed to investigate for the first time the BP lowering effect of RDN in treatment-resistant hypertension after witnessed intake of medication just before qualifying ambulatory BP. Methods Study Design and PatientsPatients referred specifically for RDN from hospitals and specialist practices in the southern part of Norway (n=18) after publication of the Symplicity HTN-2 study 2 were worked up in the nephrology outpatient clinic at Oslo University Hospital, Ullevål in the time period from December 2011 through June 2012. Treatment-resistant hypertension was defined as uncontrolled hypertension (office systolic BP >140 mm Hg), despite regular intake of maximally tolerated doses of ≥3 antihypertensive drugs, including a diuretic. In addition, patients had to qualify by having mean ambulatory daytime systolic BP >135 mm Hg immediately after investigator witnessed intake of their antihypertensive morning drugs. Patients were asked to bring their prescribed medication to the clinical visit with one of the investigators (one of the authors of the article). Medication was documented and administered by the investigator and swallowed by the patient under continuous observation, to secure the intake of prescribed medication in prescribed doses. Patients were then continuously under the observation by the investigator to prohibit throwing up again of the pills until 24-hour ambulatory BP device had been mounted and tested out in a somewhat more lengthy procedure than usually to prolong the period of observation. Patients stayed in the hospital for 2 hours to capture those with potential symptomatic hypotension caused by full intake of medication. Visits with subsequent ambulatory BP measurements were done in the morning, and further observation of patients in the hospital was done during working hours.Plasma and urine metabolites of drugs were not measured because these tests would not have contributed in the present situation. Such tests could have identified the nondrug compliant patients but not secured their intake of medication. See Editorial Commentary, pp 450-452Abstract-It is unknown whether the decline in blood pressure (BP) after renal denervation (RDN) is caused by denervation itself or concomitantly improved drug adherence. We aimed to investigate the BP lowering effect of RDN in true treatmentresistant hypertension by excluding patients with poor drug adherence. Patients with resistant hypertension (n=18) were referred for a thorough clinical and laboratory work-up. Treat...

Nonadherence to drugs is a challenge in hypertension treatment. We aimed to assess the prevalence of nonadherence by serum drug concentrations compared with 2 indirect methods and relate to the prescribed drug regimens in a nationwide multicenter study. Five hundred fifty patients with hypertension using ≥2 antihypertensive agents participated. We measured concentrations of 23 antihypertensive drugs using ultra high performance liquid chromatography tandem mass-spectrometry and compared with patients’ self-reports and investigators’ assessment based on structured interview. We identified 40 nonadherent patients (7.3%) using serum drug concentrations. They had higher office diastolic blood pressure (90 versus 83 mm Hg, P <0.01) and daytime diastolic blood pressure (85 versus 80 mm Hg, P <0.01) though systolic blood pressures did not differ significantly. They had more prescribed daily antihypertensive pills (2.5 versus 2.1 pills, P <0.01) and total daily pills (5.5 versus 4.4 pills, P =0.03). Prescription of fixed-dose combination pills were lower among the nonadherent patients identified by serum concentrations (45.0 versus 67.1%, P <0.01). Fifty-three patients self-reported nonadherence, while the investigators suspected 69 nonadherent patients. These groups showed no or few differences in drug regimens, respectively. In summary, we detected 7.3% prevalence of nonadherence by serum drug measurements in patients using ≥2 antihypertensive agents in a nationwide study; they had higher office and ambulatory diastolic blood pressures, higher number of prescribed daily pills, more daily antihypertensive pills, and less frequent prescriptions of fixed-dose combination pills. Indirect methods showed poor overlap with serum drugs concentrations and no or minimal medication differences. Thus, serum measurements of drugs were useful in detection and characterization of nonadherence to antihypertensive treatment. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03209154.

Purpose:The blood pressure (BP) lowering effect of renal sympathetic denervation (RDN) in treatment-resistant hypertension shows variation amongst the existing randomized studies.The long-term efficacy and safety of RDN requires further investigation. For the first time, we report BP changes and safety up to seven years after RDN, compared to drug adjustment in the randomized Oslo RDN study. Materials and methods:Patients with treatment-resistant hypertension, defined as daytime systolic ambulatory BP ≥135 mmHg after witnessed intake of ≥3 antihypertensive drugs including a diuretic, were randomized to either RDN (n=9) or drug adjustment (n=10). The initial primary endpoint was the change in office BP after six months. The RDN group had their drugs adjusted after one year using the same principles as the Drug Adjustment group.Both groups returned for long-term follow-up after three-and seven years. Results:The decrease in office BP and ambulatory BP (ABPM) after six months did not persist, but gradually increased in both groups. From six months to seven years follow-up, mean daytime systolic ABPM increased from 142±10 to 145±15 mmHg in the RDN group, and from 133±11 to 137±13 mmHg in the Drug Adjustment group, with the difference between them decreasing. In a mixed factor model, a significantly different variance was found between the groups in daytime systolic ABPM (p=0.04) and diastolic ABPM (p=0.01) as well as office diastolic BP (p<0.01), but not in office systolic BP (p=0.18). At long-term followup we unveiled no anatomical-or functional renal impairment in either group. Conclusion:Blood pressure changes up to seven years show a tendency towards a smaller difference in BPs between the RDN and drug adjustment patients. Our data support RDN as a safe procedure, but it remains non-superior to intensive drug adjustment seven years after the intervention.

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