In this expert analysis we present information regarding three trials related to vascular medicine presented at the 2022 Transcatheter Cardiovascular Therapeutics (TCT) Scientific Sessions held in Boston, Massachusetts, September 16-19.

RADIANCE II
An ultrasound-based renal denervation system, Paradise™ by ReCor Medical, Inc., has demonstrated some benefit in two small randomized controlled trials: RADIANCE-HTN SOLO for hypertensive patients (146) not taking anti-hypertensive medication,¹ and RADIANCE-HTN TRIO for hypertensive patients (136) on triple combination therapy.² RADIANCE II recently evaluated the reduction in daytime ambulatory systolic blood pressure (ABP) over two months (primary efficacy endpoint) in patients with mild-to-moderate hypertension (ABP ≥ 135/85 and < 170/105 mmHg) and a history of using zero to two antihypertensive medications. The randomized controlled trial was conducted at 37 centers in the United States (US) and 24 centers in Europe and enrolled 224 patients with a 2:1 randomization to ultrasound-based renal denervation versus a sham procedure that included renal angiography. Patients had no prior cardiovascular or cerebrovascular events, no type 1 or uncontrolled type 2 diabetes, and an eGFR ≥ 40 mL/min/m2. The average age was 55 years and women represented a minority of the patients enrolled (29%). The primary efficacy endpoint was met (p value < 0.0001) with a 6.3 mmHg greater reduction in the treatment arm versus the sham arm over a 24-hour circadian cycle. The mean home and office systolic blood pressure (SBP) differences were also significant between the two arms, with a reduction of 6.8 mmHg (p <0.001) and 6.7 mmHg (p<0.001) respectively in the renal denervation group. Denervation was successfully delivered to 98.7% of patients and there were no major procedural or device-related adverse events observed at 30 days. Renal function remained unchanged in both arms of the trial. Of the participants treated with renal denervation, 64% of patients achieved at least a 5 mmHg reduction in ABP and 48% achieved a 10 mmHg reduction. Consistent with findings from prior studies, about one-third of the patients did not respond to renal denervation. Future studies may evaluate whether the reduction of BP achieved with renal denervation will translate into a reduction of cardiovascular events, with a goal to identify patients who would benefit most from renal denervation.

SYMPLICITY HTN-3: 3-year Follow-Up
Designed as the largest prospective, single-blind, randomized, sham-controlled trial of patients with severe resistant hypertension undergoing renal denervation, SYMPLICITY-3 enrolled 535 patients and had a negative primary efficacy endpoint at 6 months.³ Patients were enrolled in the randomized controlled trial at 99 centers in the US and were on maximally tolerated doses of three or more medications (including a diuretic), with a SBP of 160 mmHg or higher and a 24-hour ABP of 135 mmHg or higher. The difference in SBP at 6 months between the radiofrequency based renal denervation (first generation Flex catheter) procedure and the sham-procedure was 2.39 mmHg and was not statistically significant (p = 0.26), with no significant change in 24-hour ABP (p = 0.98). The 3-year follow-up of this study, initially presented in 2014, demonstrated an adjusted treatment difference in office BP of 22.1 mmHg (p < 0.0001) and a 24-hour SBP difference of 16.5 mmHg (p < 0.0001). Of the 535 patients enrolled in the original randomized trial, 219 patients from the original renal denervation group, 63 crossover patients, and 33 patients from the non-crossover group were available for follow-up at 36 months. At the 3-year follow-up, there was reduction in the medication burden (drug doses per day) prescribed in the renal denervation group, but no difference in the number of medication classes prescribed to patients. While the large benefit at 36 months of follow-up is of similar order of magnitude as that reported in the original SYMPLICITY HTN-1⁴ and SYMPLICITY HTN-2⁵ trials, the authors note the limitations of un-blinding at this stage of follow-up and the potential introduction of biases. The BP in the non-crossover group was initially reduced when masked and subsequently increased after unmasking, suggesting the contribution of a placebo effect and a Hawthorne effect. The long-term follow-up confirmed no significant difference in safety signal between the two groups. While the long-term follow-up suggests a favorable signal for renal denervation in patients with severe resistant hypertension, these results have to be interpreted with caution, as the primary outcome for the trial was not met.

The UNIVERSAL Randomized Clinical Trial – Routine Ultrasonography Guidance for Femoral Vascular Access for Cardiac Procedures
While bleeding and major vascular complications are significantly reduced with radial access as compared to femoral access,⁶ femoral access is still indicated for cardiac procedures when radial access is not possible or for large-bore access. A total of 621 patients undergoing coronary angiography and/or percutaneous coronary intervention (PCI) at two Canadian centers were enrolled in this randomized, open-label clinical trial comparing femoral access with ultrasonography guidance with fluoroscopy versus fluoroscopy alone. Operators were required to have completed at least 10 observed ultrasonography-guided femoral access procedures. The primary outcome was the composite of Bleeding Academic Research Consortium (BARC) 2, 3, and 5 bleeding or major vascular complications (pseudoaneurysm, AV fistula, RP bleed, hematoma > 5 cm or ischemic limb requiring intervention/surgery) at 30 days. The key secondary outcome was BARC 2, 3, or 5 major bleeding. The mean age was 71 years, and a minority of patients were female (25.4%). PCI was performed in 42% of the procedures and most procedures utilized 6 French sheaths, with closure devices used in 52.1% of patients. The primary composite outcome occurred in 12.9% of the patients in the ultrasonography group and 16.1% of patients without ultrasonography (p = 0.25). The rates of BARC 2, 3, or 5 bleeding and major vascular complications were similar between the two groups (10% vs. 10.7%, p = 0.78 and 6.4% vs. 9.4%, p = 0.18 respectively). In the pre-specified subgroup of patients who received a closure device, the primary composite outcome was significantly reduced (p = 0.004) in the ultrasonography group (11.8%) as compared to the no ultrasonography group (23.4%). One of the limitations of the trial was that micropuncture needle kits were not used for femoral access, although the only randomized clinical trial evaluating the bleeding reduction associated with micropuncture use was underpowered and did not meet its primary end point.⁷ The combined use of ultrasonography and micropuncture, two techniques to reduce bleeding risks, may have been an interesting hypothesis to evaluate in this study. Despite this trial being underpowered for the primary outcome, the authors found that ultrasound guidance reduced the composite of major bleeding and vascular complications (RR 0.58; 95% CI 0.43-0.76) and the risk of major vascular complications (RR 0.49; 95% CI 0.34-0.69) when combining this study with eight prior randomized clinical trials as part of a meta-analysis.

References

1. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 2018;391:2335–45.
2. Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN Trio): a randomised, multicentre, single-blind, sham-controlled trial. Lancet 2021;397:2476–86.
3. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–1401.
4. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622–29.
5. Esler MD, Böhm M, Sievert H, et al. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the Symplicity HTN-2 randomized clinical trial. Eur Heart J 2014;35:1752–59.
6. Jolly SS, Yusuf S, Cairns J,  et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409-20.
7. Ambrose JA, Lardizabal J, Mouanoutoua M, et al. Femoral micropuncture or routine introducer study (FEMORIS). Cardiology 2014;129:39-43.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Vascular Medicine, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging, Hypertension

Keywords: Transcatheter Cardiovascular Therapeutics, TCT22, Antihypertensive Agents, Diabetes Mellitus, Type 2, Random Allocation, Denervation, Goals, Angiography, Coronary Angiography, Diuretics, Placebo Effect, Maximum Tolerated Dose, Prospective Studies, Follow-Up Studies, Single-Blind Method, Hypertension, Catheters, Percutaneous Coronary Intervention, Aneurysm, False, Hemorrhage, Punctures, Hematoma, Fluoroscopy, Fistula

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