Clinical Investigations Effects of Renal Denervation on Ambulatory Blood Pressure Measurements in Patients With Resistant Arterial Hypertension
Address for correspondence: Thomas Lambert, MD, Cardiovascular Division, Linz General Hospital Krankenhausstrasse 9, A-4020 Linz, Austria,
[email protected]
Thomas Lambert, MD; Hermann Blessberger, MD; Verena Gammer, MD; Alexander Nahler, MD; Michael Grund, MD; Klaus Kerschner, MD; Gunda Buchmayr, MD; Karim Saleh, MD; J¨ urgen Kammler, MD; Clemens Steinwender, MD Cardiovascular Division, Linz General Hospital, Linz, Austria
Background: The sympathetic nervous system is an important factor in hypertension. In patients suffering from resistant hypertension, transfemoral renal sympathetic denervation (RDN) reduces office blood pressure (BP) values. Hypothesis: Ambulatory BP measurement (ABPM) is a better predictor than office BP of cardiovascular morbidity and mortality. We thus believe that ABPM should be added to the systematic evaluation and follow-up protocol when treating patients with resistant hypertension with RDN. Therefore, we evaluated the effect of RDN on mean 24-hour BP by the use of ABPM. Methods: Patients with resistant hypertension (office systolic BP >160 mm Hg, or >150 mm Hg in patients with diabetes) have been treated with RDN. Ambulatory BP measurement was performed at baseline and at 3 and 6 months after RDN. Patients with a 24-hour systolic BP reduction of ≥5 mm Hg were classified as responders. Results: Of 86 patients initially enrolled in the study, 5 had to be excluded from the analysis because of 160 mm Hg (>150 mm Hg in patients with diabetes) after 3 measurements in our outpatient office. All patients had to be on ≥3 antihypertensive medications, including 1 diuretic. Secondary causes of hypertension had to be ruled out according to published literature.18,27 Renal parenchymal disease and Cushing syndrome were excluded through renal imaging. Aldosterone/renin ratio and free plasma levels of metanephrines were evaluated for screening for primary aldosteronism and for pheochromocytoma. Druginduced hypertension was ruled out by reviewing the patients’ medications. Patient-exclusion criteria included age 20 mm. Written informed consent was obtained from all patients, and the local ethics committee approved the study. The investigation was performed in accordance with the Declaration of Helsinki. Ambulatory BP measurement was performed in all patients before RDN, as well as at 3 and 6 months thereafter, using an ambulatory BP monitor, version 2.08.005 (Del Mar Reynolds Medical, Irvine, CA). Devices were preset so that 6 AM to 9:45 PM was defined as daytime (readings every 15 minutes) and 10 PM to 5:30 AM was defined as nighttime (readings every 30 minutes). The first BP reading in the morning (6 AM) was defined as the morning BP. Patients were told to follow their usual activities during the monitoring. The arm cuff was placed on the nondominant upper arm and patients were instructed to steady their arm during each measurement. According to the European Society of Cardiology/European Society of Hypertension guidelines, only recordings with >70% valid measurements
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Clin. Cardiol. 37, 5, 307–311 (2014) T. Lambert et al: BP measurement after RDN Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22269 © 2014 Wiley Periodicals, Inc.
were included in the analysis.18 Based on the recordings’ morning BP values, mean 24-hour BP, mean daytime BP, and mean nighttime BP were calculated. After RDN, antihypertensive medications could be changed at the physician’s discretion. Renal Denervation Both renal arteries were ablated using the Symplicity RDN System (Medtronic Inc., Minneapolis, MN) via transfemoral access. Point-to-point radiofrequency delivery (8-W maximum) lasted up to 120 seconds for each ablation point. In case of fluctuations in temperature or resistance, energy delivery was automatically stopped for safety reasons by the system. Depending on renal artery anatomy, ablation was performed at a maximum of 8 points in the right and left renal artery. Study Endpoints The primary endpoint was the change in systolic 24-hour BP levels. According to the results of the study of Mahfoud et al, responders were defined by a reduction of ≥5 mm Hg.17 As secondary endpoints, mean BP reductions in office, daytime, and nighttime BP and mean morning SBP were evaluated. Additionally, we analyzed the difference in the proportion of responders using the standard office-based definition (BP reduction of >10 mm Hg in office SBP) vs the ABPM criteria, defined above. Statistical Analysis Data were presented as mean ± standard deviation. For comparisons of variables between the groups and for comparison of BP measurements at each visit, a paired t test was performed. A 2-sided α level of 0.05 was considered statistically significant. The collected data were analyzed by per-protocol approach. For evaluation of the influence of antihypertensive medication on BP reductions, a statistical analysis of variance (ANOVA) was performed. All analyses were done with SPSS version 17.0 software (SPSS Inc., Chicago, IL).
Results Between June 2010 and December 2011, 86 patients were enrolled in the study. All patients underwent successful RDN without occurrence of periprocedural complications. Five patients were excluded from the analysis because they had 70
38.3
BMI, kg/m2 18.5–25
9.9
25–30
42.0
>30
48.1
CAD
35.8
DM
29.6
CVA
17.3
PAD
4.9
Hyperlipidemia
50.6
Abbreviations: BMI, body mass index; CAD, coronary artery disease; CVA, cerebrovascular accident; DM, diabetes mellitus; F, female; M, male; PAD, peripheral arterial disease.
Table 2. Medial Antihypertensive Treatment RAAS Ca++ αβAldosterone Blocker Diuretics Blocker Blocker Blocker Antagonists Baseline
100
6 months
100
100
48
18
74
30
100
59
18
72
36
++
Abbreviations: Ca , calcium; RAAS, renin-angiotensin-aldosterone system. Data are given as %.
3 months and to 139.9 ± 15.2 mm Hg after 6 months (P = 0.025, from baseline to 6-month follow-up). Six months after RDN, 49 patients showed a mean SBP reduction of ≥5 mm Hg in 24-hour BP and were classified as responders (60.5%). Responders had a mean SBP of 144.3 ± 16.2 mm Hg at baseline, of 142.8 ± 17.5 mm Hg after 3 months, and of 138.3 ± 14.3 mm Hg after 6 months (P = 0.025, from baseline to 6-month follow-up). Responders showed a mean SBP reduction in the 24-hour BP of −6 mm Hg 6 months after RDN. Office SBP increased from 150.2 ± 18.2 mm Hg at baseline to 168.7 ± 26.9 mm Hg after 6 months in nonresponders (P < 0.001). In nonresponders, 24-hour SBP decreased from 144.5 ± 16.7 mm Hg to 142.2 ± 16.4 mm Hg (P = NS). In the group of responders, we found a mean daytimeBP reduction from 146.6/89.7 mm Hg at baseline to 145.6/89.4 mm Hg after 3 months and to 140.1/89.5 mm Hg after 6 months (P = 0.014, from baseline to 6-month
follow-up). Nighttime BP in responders was 136/81.5 mm Hg at baseline, which decreased to 134.1/78.5 mm Hg after 3 months and to 129.8/79.6 mm Hg after 6 months (P = NS). Blood-pressure levels in the morning were 145.9/84.6 mm Hg at baseline, 147.9/84.4 mm Hg after 3 months, and 134.7/85.5 mm Hg after 6 months (P = 0.035). Table 3 illustrates BP levels in all patients. Based on the standard definition of response to RDN based on an office SBP reduction of >10 mm Hg, only 41 patients (50.6%) could be classified as responders. For evaluation of the influence of medical antihypertensive treatment on the effect of BP reductions in ABPM, a statistical ANOVA was performed. The results showed no statistical difference in medical antihypertensive treatment between responders and nonresponders.
Discussion The results of our study show a significant BP reduction in patients suffering from resistant arterial hypertension by performing RDN in addition to medical antihypertensive treatment. We were able to illustrate the effect of RDN on BP reductions in office BP as well as in ABPM. However, only 60.5% of patients had a mean SBP reduction of ≥5 mm Hg in 24-hour BP and were thus defined as responders. In responders, the impact of RDN on BP levels in ABPM also could be documented in different subsets, such as daytime and morning BP. Renal denervation is a new treatment option for patients suffering from resistant arterial hypertension.7 – 9,28 In most of the published studies on RDN, the treatment effect was evaluated by reduction of mean SBP, as evaluated by 3 office BP measurements. Patients with a reduction in mean SBP of ≥10 mm Hg were classified as responders.7,9 – 11,29 In our study we found a mean office SBP reduction of 25.9 mm Hg in responders, which is similar to the results published in previous trials.7 – 10 In the Symplicity-HTN 1 and Symplicity-HTN 2 trials, a mean SBP reduction of −11 mm Hg in ABPM was found.7,9 However, only 12 of 45 treated patients were evaluated by the use of ABPM in the Symplicity-1 trial.7 In the Symplicity-2 trial, 20 of 45 treated patients got ABPM at baseline and after 6 months.9 Compared with office BP measurements, ABPM is superior in predicting cardiovascular events.18 – 21 Therefore, the use of ABPM is considered to be crucial for BP control in hypertensive patients.30 – 32 Moreover, APBM provides a full BP profile and a high number of readings, resulting in a high reproducibility of BP levels.33 – 36 For this reason, all patients in our trial received APBM at baseline and at 3 and 6 months after RDN. Using ABPM, we identified 49 patients (60.5%) as responders. Compared with nonresponders, responders exhibited a significant decrease in the office SBP, the mean 24-hour SBP, the mean daytime SBP, and the mean morning BP at 6 months after RDN. Nevertheless, there was a significant discrepancy in BP-lowering effects between the office measurements and ABPM. We also found that the mean BP reduction in the 24-hour BP is only about 6 mm Hg in responders. A possible regression to the mean and other factors, like pseudoresistant hypertension, might be the reason for this phenomenon. Clin. Cardiol. 37, 5, 307–311 (2014) T. Lambert et al: BP measurement after RDN Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22269 © 2014 Wiley Periodicals, Inc.
309
Table 3. Office BP and Ambulatory BP in All Patients and in Responders Office BP
24-Hour BP
Daytime BP
Nighttime BP
Morning BP
161.9/87.8
144.3/86.0
146.6/88.0
136.8/78.9
144.1/85.3
± 20.0/± 14.4
± 16.3/± 13.5
± 16.6/± 13.7
± 18.2/± 14.0
± 21.2/± 14.5
164.4/93.5
142.4/85.2
145/87.4
134.1/77.6
144.9/85.3
± 25.0/± 14.6
± 18.6/± 15.2
± 19.1/± 15.6
± 19.4/± 14.7
± 26.7/± 16.8
153.5/86.3
139.9/84.0
141.7/85.8
131.6/76.6
137.5/82.3
± 23.3/± 16.2
± 15.2/± 12.5
± 15.5/± 12.8
± 20.0/± 14.2
± 23.8/± 16.1
SBP reduction
−8.4 (P = 0.009)
−4.4 (P = 0.025)
−4.9 (P = 0.016)
−5.2 (P = 0.041)
−6.6 (P = NS)
DBP reduction
−1.2 (P = NS)
−2.0 (P = NS)
−2.2 (P = NS)
−2.3 (P = NS)
−3 (P = NS)
169.6/90.3
144.3/84.7
146.6/89.7
136/81.5
145.9/84.6
± 17.2/± 13.6
± 16.2/± 12.2
± 16.6/± 14.7
± 17.7/± 15.8
± 21.1/± 13.7
159.8/89.0
142.8/83.6
145.6/89.4
134.1/78.5
147.9/84.4
± 25.6/± 16.4
± 17.5/± 14.7
± 18.4/± 17.7
± 19.2/± 15.7
± 25.3/± 16.7
143.7/79.7
138.3/81.5
140.1/89.5
129.8/79.6
134.7/85.5
± 13.5/± 18.1
± 14.3/± 11.4
± 14.7/± 13.9
± 18.7/± 15.9
± 22.3/± 14.6
SBP reduction
−25.9 (P < 0.001)
−6.0 (P = 0.025)
−6.5 (P = 0.014)
−6.2 (P = 0.074)
−11.2 (P = 0.035)
DBP reduction
−10.6 (P < 0.001)
−3.2 (P = 0.045)
−0.2 (P = NS)
−1.9 (P = NS)
+0.9 (P = NS)
150.2/84.0
144.5/84.7
146.4/86.9
137.9/77.2
141.5/85.8
± 18.2/± 12.0
± 16.7/± 14.7
± 16.9/ ± 13.0
± 19.2/12.7
± 21.6/15.1
171.3/100
141.9/83.6
144.1/86.1
134.2/77.1
140.5/85.9
± 22.5/± 13.2
± 20.5/± 13.7
± 20.5/± 14.1
± 19.9/± 14.1
± 28.5/±17.0
168.7/96.4
142.2/81.5
144.1/83.4
134.3/74.7
141.5/80.1
± 26.9/± 17.7
± 16.4/± 11.3
± 16.6/± 11.6
± 21.9/± 12.8
± 25.8/± 14.6
SBP reduction
+18.5 (P < 0.001)
−2.3 (P = NS)
−2.3 (P = NS)
−3.6 (P = NS)
−0.0 (P = NS)
DBP reduction
+12.4 (P = NS)
−3.2 (P = NS)
−3.5 (P = NS)
−2.5 (P = NS)
−5.7 (P = NS)
BP levels in all patients (N = 81), mm Hg Baseline SD 3 Months SD 6 Months SD
BP levels in responders (n = 49), mm Hg Baseline SD 3 Months SD 6 Months SD
BP levels in nonresponders (n = 32), mm Hg Baseline SD 3 Months SD 6 Months SD
Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; NS, not significant; SBP, systolic blood pressure; SD, standard deviation.
Though a significant BP-lowering effect of RDN could be shown for the group of responders, we also found a remarkable number of patients who did not benefit from RDN. Until now, no procedural factor or parameter is known to predict treatment success of RDN.7 – 10,29 In almost 40% of our patients, BP reduction was 10 mm Hg, only 41 patients (50.6%) could be classified as responders. This rate of response is much lower than others reported in recently published trials.7,9,10,29 In our patients, we found higher BP reductions through the use of ABPM. Although office BP
was measured after a 5-minute rest in sitting position, the influence of white-coat hypertension might be an important bias in this setting. In our opinion, this underlines the relevance of ABPM in evaluation of BP changes after RDN. One major limitation of our study is that it was not a randomized controlled trial. Another limitation is that there are no outcome data included in our analysis. Nevertheless, this study has important clinical implications. We were able to illustrate beneficial effects of RDN on different elements of ABPM in patients suffering from resistant arterial hypertension. Further randomized controlled trials are needed to prove the effect of RDN on ABPM.
Conclusion Through the use of RDN, office BP and ABPM levels can be significantly lowered in about two-thirds of patients suffering from resistant hypertension.
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Clin. Cardiol. 37, 5, 307–311 (2014) T. Lambert et al: BP measurement after RDN Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22269 © 2014 Wiley Periodicals, Inc.
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