Multi-electrode Renal Denervation in Resistant Hypertension
Multi-electrode Renal Denervation in Resistant Hypertension
This is the first-in-human, multi-centre study to evaluate the safety and efficacy of a multi-electrode RF ablation catheter for renal artery sympathetic denervation in patients with drug-resistant HTN. A significant reduction in office and ambulatory BP was demonstrated at all follow-up time points through 6 months. No serious peri-procedural vascular events occurred and renal function remained within expected range for a hypertensive population following the procedure and up to 6-month post-renal denervation.
The EnligHTN I data set is the most complete of those published in the area of renal denervation with all patients remaining enrolled and followed through 6 months (no deaths, lost to follow-up, or exits for any reason). Only one visit was missed resulting in a 99.3% overall follow-up visit compliance rate. The overall reductions in office BP seen in the current study are comparable with those reported in two previous studies where single electrode RF catheters were used. Of interest, reductions in BP were recorded earlier in the current study (−28/10 by 1 month), whereas previous studies found that while BP was reduced at 1 month, a comparable reduction was not seen until 6 months. Arguably, the more rapid response seen in the current study may reflect more complete renal denervation acutely due to the use of a multi-electrode RF catheter system compared with a single electrode system. This variance may simply reflect the limited sample sizes being addressed. The reduction in office systolic BP was greater than the reduction in 24 h ABPM and is similar to the difference in the two measures as seen in other studies. One may argue this biases the endpoint however office systolic BP is the gold standard for the diagnosis, treatment, and monitoring of patients with HTN, therefore, the reduction in office systolic BP is clinically meaningful.
We found a reduction in HR over 6 months, which is consistent with previously published data, and consistent with a reduction in sympathetic activity. We also identified baseline HR as a predictor of reduction in office systolic BP, and change in HR over 6 months was correlated with office systolic BP reduction. Although this seems intuitive and consistent with the hypothesis that the reduction in sympathetic activity also drives the reduction in systolic BP, this is different to a previous study. Some reasons for this difference include the way heart rate was measured (in office HR assessment from the BP monitor vs. electrocardiogram), and the degree of baseline sympathetic activity as evidenced by the baseline HR (71 vs. 66 b.p.m.). Clearly, larger observational data sets will assist in clarifying such relationships.
The laboratory measures indicative of renal function vary slightly over time; however, there is no abrupt change in eGFR or serum creatinine immediately following the procedure. In addition, the cystatin C values improved over time, as did the urinary albumin-to-creatinine ratios, which suggest an improvement in renal function using these indices. Although changes in eGFR and serum creatinine reach statistical significance at 6 months, a shift of <6% is not considered clinically relevant, particularly in a population with normal renal function. These changes can be attributed to a number of reasons such as small sample size, excessive diuretic dosage including aldosterone antagonists, natural variability and progression over time, or contrast administration for the 6-month protocol specified CT angiogram. The protocol required a vascular image with contrast at 6 months, but it did not specify the timing in relation to renal function evaluation. It is possible that blood samples were collected after contrast administration when usually a small transient rise in serum creatinine may be noted. Nevertheless, renal function will be followed at 12 and 24 months and further assessment will be made. It is important to note that the total number of patients with an eGFR <60 was no different at baseline and 6 months (n = 3).
Additional studies with larger sample sizes and a randomized concurrent control group would be beneficial in further assessing benefits and risks of renal denervation therapy. A randomized trial comparing outcomes between single electrode and multi-electrode RF systems for renal denervation would allow more direct comparison of potential advantages/disadvantages of the two systems, in particular whether earlier reduction in BP is achieved with the use of a multi-electrode RF catheter. Current guidelines around clinical appropriateness and future directions with regard renal denervation have been very recently published.
In conclusion, renal artery sympathetic denervation was performed safely in patients with drug-resistant HTN, using the EnligHTN multi-electrode catheter, and resulted in a rapid and significant reduction in office BP as well as ambulatory BP that was sustained through 6 months. Thus, the EnligHTN multi-electrode system delivers a promising therapy for the treatment of drug-resistant HTN.
Discussion
This is the first-in-human, multi-centre study to evaluate the safety and efficacy of a multi-electrode RF ablation catheter for renal artery sympathetic denervation in patients with drug-resistant HTN. A significant reduction in office and ambulatory BP was demonstrated at all follow-up time points through 6 months. No serious peri-procedural vascular events occurred and renal function remained within expected range for a hypertensive population following the procedure and up to 6-month post-renal denervation.
The EnligHTN I data set is the most complete of those published in the area of renal denervation with all patients remaining enrolled and followed through 6 months (no deaths, lost to follow-up, or exits for any reason). Only one visit was missed resulting in a 99.3% overall follow-up visit compliance rate. The overall reductions in office BP seen in the current study are comparable with those reported in two previous studies where single electrode RF catheters were used. Of interest, reductions in BP were recorded earlier in the current study (−28/10 by 1 month), whereas previous studies found that while BP was reduced at 1 month, a comparable reduction was not seen until 6 months. Arguably, the more rapid response seen in the current study may reflect more complete renal denervation acutely due to the use of a multi-electrode RF catheter system compared with a single electrode system. This variance may simply reflect the limited sample sizes being addressed. The reduction in office systolic BP was greater than the reduction in 24 h ABPM and is similar to the difference in the two measures as seen in other studies. One may argue this biases the endpoint however office systolic BP is the gold standard for the diagnosis, treatment, and monitoring of patients with HTN, therefore, the reduction in office systolic BP is clinically meaningful.
We found a reduction in HR over 6 months, which is consistent with previously published data, and consistent with a reduction in sympathetic activity. We also identified baseline HR as a predictor of reduction in office systolic BP, and change in HR over 6 months was correlated with office systolic BP reduction. Although this seems intuitive and consistent with the hypothesis that the reduction in sympathetic activity also drives the reduction in systolic BP, this is different to a previous study. Some reasons for this difference include the way heart rate was measured (in office HR assessment from the BP monitor vs. electrocardiogram), and the degree of baseline sympathetic activity as evidenced by the baseline HR (71 vs. 66 b.p.m.). Clearly, larger observational data sets will assist in clarifying such relationships.
The laboratory measures indicative of renal function vary slightly over time; however, there is no abrupt change in eGFR or serum creatinine immediately following the procedure. In addition, the cystatin C values improved over time, as did the urinary albumin-to-creatinine ratios, which suggest an improvement in renal function using these indices. Although changes in eGFR and serum creatinine reach statistical significance at 6 months, a shift of <6% is not considered clinically relevant, particularly in a population with normal renal function. These changes can be attributed to a number of reasons such as small sample size, excessive diuretic dosage including aldosterone antagonists, natural variability and progression over time, or contrast administration for the 6-month protocol specified CT angiogram. The protocol required a vascular image with contrast at 6 months, but it did not specify the timing in relation to renal function evaluation. It is possible that blood samples were collected after contrast administration when usually a small transient rise in serum creatinine may be noted. Nevertheless, renal function will be followed at 12 and 24 months and further assessment will be made. It is important to note that the total number of patients with an eGFR <60 was no different at baseline and 6 months (n = 3).
Additional studies with larger sample sizes and a randomized concurrent control group would be beneficial in further assessing benefits and risks of renal denervation therapy. A randomized trial comparing outcomes between single electrode and multi-electrode RF systems for renal denervation would allow more direct comparison of potential advantages/disadvantages of the two systems, in particular whether earlier reduction in BP is achieved with the use of a multi-electrode RF catheter. Current guidelines around clinical appropriateness and future directions with regard renal denervation have been very recently published.
In conclusion, renal artery sympathetic denervation was performed safely in patients with drug-resistant HTN, using the EnligHTN multi-electrode catheter, and resulted in a rapid and significant reduction in office BP as well as ambulatory BP that was sustained through 6 months. Thus, the EnligHTN multi-electrode system delivers a promising therapy for the treatment of drug-resistant HTN.
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