3-year Efficacy Outcomes From the Spyral Htn-on Med Pilot Study: Long Term Effect of Renal Denervation On Blood Pressure Reduction in Patients on Antihypertension Medications
Reported from ACC 2022
Ali Nazmi Calik provides his take on the long-term results of the SPYRAL HTN-ON MED trial which demonstrated the durable efficacy and safety of RDN in patients who are already on one to three antihypertensive drugs.
Why this study? – the rationale/objective
Hypertension is the most frequent cause of death worldwide. Despite best efforts, lack of adherence to pharmacological blood pressure-lowering treatment is common and necessitates alternative therapy options.
Renal denervation (RDN) exhibits its blood pressure lowering effects by two pathophysiologic mechanisms. First, RDN inhibits efferent sympathetic nerves, leading to reduced tubular reabsorption of water and sodium and decreased vascular resistance and renin release (1). Second, RDN causes a decrease in sympathetic nerve activity of the central nervous system, peripheral resistance vessels, heart and kidneys by reducing afferent sensor signalling to the central sympathetic nervous system (2). The RDN system aims to deliver precisely controlled and targeted radiofrequency energy, ultrasound energy, or neurotoxic substances (alcohol) to the renal nerves to disconnect the sympathetic signal between the brain and the kidney.
Although the enthusiasm for the RDN was halted after the negative efficacy results of the SYMPLICITY HTN-3 trial (3), that did not preclude new studies from being initiated in the light of the limitations and the lessons taken from this trial. In this regard, the positive and encouraging results of SPYRAL HTN-ON MED, SPYRAL HTN-OFF MED, RADIANCE-HTN SOLO and RADIANCE-HTN TRIO trials helped to revitalize hopes for RDN therapy as a catheter-based treatment for hypertension by showing significant effects on both systolic and diastolic blood pressure.
The SPYRAL HTN-ON MED trial was designed to investigate the safety and efficacy of catheter-based RDN in patients with moderate, uncontrolled hypertension on antihypertensive treatment. The 6-month results of this study (4) showed that RDN extending into branch arteries was associated with significant and clinically relevant reductions in office and ambulatory blood pressure measures compared with a sham procedure. These promising results were achieved without procedural or intermediate-term adverse safety events associated with RDN. The current review will focus on the 3-year efficacy and safety outcomes of the SPYRAL HTN-ON MED study.
How was it executed? - the methodology
SPYRAL HTN-ON MED is a global, multicentre, blinded, randomised and sham-controlled trial. In summary, eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs. Patients meeting inclusion criteria and having suitable anatomy (confirmed via renal angiogram) were randomly assigned (1:1) to receive RDN or sham procedure. RDN procedures were performed with the Symplicity Spyral multielectrode renal denervation catheter (Medtronic, Galway, Ireland) by providing circumferential radiofrequency ablation treatments in a spiral pattern in the four quadrants of the renal artery and branch vessels.
Medications were required to be prescribed at 50% or more of the maximum manufacturer’s recommended dosage of a thiazide-type diuretic, a dihydropyridine calcium channel blocker, an ACE-inhibitor or angiotensin receptor blocker (ACE-I or ARB), or a β blocker. The protocol allowed changes in antihypertensive medications after 6 months at the discretion of the treating physician. All patients underwent urine and blood analysis for up to 6 months to assess adherence, defined as detectable levels of all prescribed antihypertensive drugs at each follow-up visit. Subsequently, the study protocol was updated to also include medication use assessment at 24 months and 36 months. Ambulatory blood pressure and office blood pressure were measured at 3, 6, 12, 24, and 36 months.
Besides long-term efficacy, long-term safety was compared between the renal denervation group and sham control group for up to 36 months using a composite endpoint of major adverse events, comprising all-cause mortality, end-stage renal disease, an embolic event resulting in end-organ damage, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis, and new renal artery stenosis greater than 70%.
What is the main result?
A total of 80 patients fulfilled the qualifying criteria and were randomly assigned to receive renal denervation (n=38) or a sham control procedure (n=42).
At 24 months and 36 months, there were significantly more significant reductions in mean 24-h, morning, daytime, and night-time systolic and diastolic blood pressure for patients in the renal denervation group than patients in the sham control group.
At 36 months, the ambulatory systolic blood pressure reduction was –18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and –8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference –10·0 mm Hg, 95% CI –16·6 to –3·3; p=0·0039). Treatment differences were –5·9 mm Hg (95% CI –10·1 to –1·8; p=0·0055) for mean ambulatory diastolic blood pressure, –11·0 mm Hg (–19·8 to –2·1; p=0·016) for morning systolic blood pressure and –11·8 mm Hg (–19·0 to –4·7; p=0·0017) for night-time systolic blood pressure. Safety events were rare and did not differ between the groups.
At 36 months, the number of prescribed antihypertensive medications in the renal denervation group was not different from the sham control group (3.03 vs 3.05, p=0.76). However, a higher medication burden was observed when accounting for medication classes and dosages for the sham control group compared with the renal denervation group.
Critical reading and the relevance for clinical practice
The long-term results of the SPYRAL HTN-ON MED trial demonstrated the durable efficacy and safety of RDN in patients who are already on one to three antihypertensive drugs. The RDN significantly reduced 24-h systolic and diastolic blood pressure at 24 and 36 months without any safety concerns.
Even though the efficacy and safety profile of the RDN treatment was in the previous trials, concerns emerged with the long-term sustainability of this treatment because of the probability of kidneys' reinnervation. Nevertheless, the sustained reductions in blood pressure observed up to 36 months after renal denervation in this study showed no significant functional reinnervation in this cohort of patients with hypertension. Notably, the sustained and significantly reduced lower blood pressure levels throughout the 24-h achieved by RDN treatment are clinically meaningful and associated with lower rates of cardiovascular events.
While implementing the current study's results into daily practice, it is noteworthy to keep in mind that the results are specific to radiofrequency renal denervation procedures and might not be generalizable to other renal denervation modalities. Further, the current study did not evaluate clinical data regarding patients' exercise, diet, or smoking habits, which could have influenced blood pressure measurements. Last but not least, the percentage of women enrolled in the study was relatively low.
Finally, the 3-year results of the current trial provide a satisfying answer to the concerns regarding the durability of the antihypertensive effect of RDN treatment and make it a reasonable conjunctive blood pressure-lowering therapy option in daily practice. The complete analysis cohort targets up to 340 randomized patients, and a six-month post-procedure follow-up for the entire cohort will be complete in the second half of the calendar year 2022.
References
- 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.
- Grassi G, Seravalle G, Brambilla G, et al. Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects. Hypertension. 2015;65:1209-16.
- Bhatt DL, Kandzari DE, O'Neill WW, et al. SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-401.
- Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018; 391(10137):2346-2355.
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