We reviewed medical records of consecutive patients who received catheter-based radiofrequency RDN (Symplicity Flex™ or Spyral™, Medtronic, Minneapolis, MN, USA) for uncontrolled hypertension in three medical centers between September 2013 and August 2019 under approval of Institutional Review Boards, MacKay Memorial Hospital (IRB No. 20MMHIS087e), which waived the requirement for informed consent in this retrospective study. As of August 2019, patients meeting inclusion criteria were consecutively identified by the same inclusion and exclusion criteria from three hospitals, including the first 18 patients in the prior single-center pilot study [11]. Patient records were de-identified to preserve patient privacy and the study was performed in accordance with the guidelines of ICH-GCP (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use–Good clinical practice). Patients had no previous diagnosis of secondary hypertension, such as primary aldosteronism, although some had a reported history of obstructive sleep apnea and chronic kidney disease (CKD, defined as eGFR [estimated glomerular filtration rate] 60 mL/min/1.73 m${}^2$). Diabetes was usually diagnosed as HbA1c (Glycated Hemoglobin) $>$6.5%, fasting sugar $>$126 mg/dL on at least 2 separate measurements, or taking anti-diabetic agents. The stroke diagnosis was according to brain imaging studies and the neurologists’ documentation. All classifications were determined by an independent review of the patients’ medical record. Patients with primary aldosteronism identified by confirmatory tests, imaging studies, and/or NP-59 scintigraphy consistent with recommendations of the Taiwan Society of Aldosteronism [12] were excluded, as were patients with treatable proclaimed secondary causes, stage 5 CKD and patients on hemodialysis. We reviewed the patients’ baseline characteristics, prescribed antihypertensive medications, and pre-/post-procedural changes in BP via the electronic medical records of three hospitals around Taipei.

Patients were divided into two groups, including control patients (group A) and those meeting at least one criteria in the predictive triad (group B). This preprocedural triad consisted of the following characteristics prior to RDN: (1) more than 10 mmHg of BP reduction after at least 14-day use of aldosterone antagonist, (2) ratio of serum aldosterone concentration to plasma renin activity (ARR) $>$30, or (3) the presence of slow flow on the renal angiogram. Slow flow refers to TIMI-2 flow, which is defined as delayed or sluggish antegrade flow with complete filling of the distal territory [13]. The ARR was calculated at the time of baseline 24-hour ambulatory BP measurement (ABPM) on contemporary antihypertensive medications.

Most patients had office BP measurement at 0, 1, 3, 6 and 12 months and 24-hour ABPM at 0, 1, 3–6 and 12 months after RDN. The medication was adjusted by the physicians’ decision for clinical needs. The number of medications prescribed was recorded at 0, 1, 3, 6, and 12 months by reviewing the electronic medical records.

Consistent with previous studies, RDN responders were defined by any of the following criteria: (1) 24-hour systolic BP reduction $\ge$6 mmHg without increasing antihypertensive medication, or (2) withdrawal of $\ge$1 class of antihypertensive medication [1, 2, 14]. Otherwise, the patient was labeled a non-responder.

All data were analyzed using SPSS version 24.0 for Windows (IBM Corp., Chicago, IL, USA). Comparison of the baseline characteristics and blood pressure during times of follow-up between group A and B were examined using the Mann-Whitney U test for continuous variables, the Fisher’s exact test for categorical variables and analysis of covariance (ANCOVA) for baseline difference adjustment.

After excluding 3 cases with stage 5 CKD, 46 consecutive patients were enrolled in the study, of which 27 (59%) were in group A and 19 (41%) in group B. Five of 46 patients (11%) had two features of the triad and none had all three. The regimen of aldosterone antagonist was spironolactone 25 mg once daily. No significant differences between the groups in baseline patient demographics, BP, comorbidities, or neurohormones were observed. However, group A patients had a numerically higher mean 24-hour heart rate (70.7 bpm vs. 65.3 bpm, p = 0.071) and comparable 24-hour systolic (140.0 mmHg vs. 144.0 mmHg, p = 0.577) and diastolic BP (77.5 bpm vs. 76.6 bpm, p = 0.928). Group A subjects were prescribed fewer antihypertensive agents (4.0 vs. 4.9, p = 0.014) and fewer aldosterone antagonist (3.7% vs. 47.4%, p = 0.001). The proportion of CKD (55.6% vs. 80%, p = 0.350) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (66.7% vs. 89.5%, p = 0.092) was lower in group A, but without statistical significance (Table 1). The baseline ARR was 8.5 and 93.5 in group A and B (p = 0.012), respectively. Aldosterone antagonist was associated with a systolic BP reduction of 11 mmHg in those prescribed the drug. There were no procedure-related complications.

On average, office systolic BP was 154.4 $\pm$ 22.8 mmHg in group A and 164.3 $\pm$ 27.7 mmHg in group B (p = 0.310) at baseline. At 3- and 6-months post RDN, mean office systolic BP was 137.9 mmHg vs. 133.2 mmHg, respectively. Among the groups, the average reduction in office systolic BP was similar (–18.5 $\pm$ 22.8 mmHg vs. –19.3 $\pm$ 27.6 mmHg, p = 0.916) at 1 month. However, the difference between group A and B became greater at 3 months (–14.3 $\pm$ 23.2 mmHg vs. –30.7 $\pm$ 29.8 mmHg, p = 0.057) and 12 months (–12.4 $\pm$ 23.5 mmHg vs. –29.9 $\pm$ 25.5 mmHg, p = 0.046) (Table 2). The difference at 12 months remained significant after adjusting the baseline BP (p for model 1 = 0.048) and other confounding factors (p for model 2 = 0.025) (Table 2). Observed differences at 6- and 12-months post RDN might have been attenuated due to drug withdraw, especially in the group B. Mean 24-hour systolic BP at baseline was 140.0 $\pm$ 12.8 mmHg vs. 144.0 $\pm$ 16.5 mmHg (p = 0.577). At 1-month post RDN, the 24-hour systolic BP decreased from 132.5 $\pm$ 17.7 mmHg to 136.3 $\pm$ 14.0 mmHg. Numerically, the decline in 24-hour systolic BP was greater in group B at 3–6 months (–9.4 $\pm$ 19.6 mmHg vs. –18.3 $\pm$ 12.3, p = 0.330) and 12 months (–8.9 $\pm$ 17.0 mmHg vs. –12.5 $\pm$ 5.3, p = 0.693), respectively (Table 2).

The percentage of drug classes in use by each group is depicted in Fig. 1; the proportion of patients in group B prescribed at least four classes of drug decreased from 95% to 73% within three months and to 62% at 12 months. Compared to group A, the number of drug classes continued to decrease to 12 months in group B.

Fig. 1.

Percentage of drug class number distribution. Group A: triad (–); Group B: triad (+). The percentage of drug classes in use is depicted at baseline and 1, 3, 6, 12 months. The percentage of patients taking less than four classes of drug increases till 12 months only in group B.

Overall, nineteen patients (41%) had response to RDN in the first month. Thirty (65%) and thirty-one (67%) of all patients responded to the RDN procedure in six months and twelve months, respectively. The response rate was significantly greater in group B at 3 months (48.1% vs. 84.2%, p = 0.016); and (48.1% vs. 89.5%, p = 0.005) at 6 months. The proportion and timeline of response in two groups are depicted in Fig. 2.

Fig. 2.

Response rate to renal denervation (RDN) by groups. Group A: triad (–); Group B: triad (+). The change in proportion of responders in both groups during 12 months after RDN.