Author + information
- Krishna J. Rocha-Singh, MD∗ ( and )
- Richard E. Katholi, MD
- ↵∗Reprint requests and correspondence:
Dr. Krishna J. Rocha-Singh, Prairie Vascular Institute at St. John's Hospital, Department of Cardiology, 619 East Mason, Springfield, Illinois 62701-1034.
Treatment-resistant hypertension (TRH), the persistent elevation of systolic blood pressure >140 mm Hg despite treatment with maximal or highest tolerated doses of at least three antihypertensive medications, one of which is a diuretic (1), remains a significant clinical challenge and a source of concern among patients, physicians, and public health policy makers. TRH patients face increased rates of cardiovascular-related morbid and mortal events that represent a significant burden on already constrained medical resources. Current estimates suggest that 10% to 15% of the patients referred for hypertension evaluation meet the TRH definition (2) and, until recently, had few therapeutic options. The Symplicity HTN-1 (3) and -2 (4) trials established the facts that percutaneous catheter-based radiofrequency renal sympathetic denervation (RDN) is a safe and effective therapy in highly selected patients with severe TRH (blood pressure: >160 mm Hg or >150 mm Hg in patients with type 2 diabetes and appropriate renal artery anatomy) and results in a significant blood pressure reduction through 30-month follow-up (5). However, the safety and effectiveness of RDN has yet to be defined in a potentially larger cohort of patients who meet the clinical definition of TRH (i.e., >140 mm Hg) but not the stricter blood pressure inclusion criteria of >160 mm Hg of the Symplicity trials.
In this issue of the Journal, Ott et al. (6) present a multicenter, prospective, open label, nonrandomized registry of 54 patients with moderate TRH (office blood pressure: ≥140/90 and ≤160/100 mm Hg, confirmed by 24-h ambulatory blood pressure monitoring of ≥130/80 mm Hg). The authors conclude, based on the results of baseline findings and of 6-month follow-up in 54 patients, that RDN using the Symplicity catheter (Ardian Medtronic, Mountain View, California) reduced office blood pressure by a mean of 13/7 mm Hg (n = 54) and 24-h ambulatory blood pressure by a mean of 14/7 mm Hg (n = 34) from a baseline value of 151 ± 6 mm Hg while receiving a mean of 5.1 medications, noting a positive 6-month “responder” rate (defined as a systolic blood pressure response of >10 mm Hg) of 61% with 51% achieving an office blood pressure of ≤140/90 mm Hg. This registry represents a pilot validation of RDN in patients with moderate TRH, in distinction to the severe TRH cohort evaluated in the Symplicity HTN-1 and -2 trials and the U.S. pivotal Symplicity HTN-3 trial, which recently completed enrollment. Importantly, this registry now sets the stage for the recently announced Symplicity HTN-4 trial, a randomized, controlled evaluation of RDN in this moderate TRH cohort.
The Symplicity HTN-1 and -2 trial results suggest that RDN in severe TRH patients lowers systolic blood pressure 27 mm Hg (1,2). This is the equivalent of the blood pressure-lowering effect of 2 1/2 classes of antihypertensive medications. However, as expected, the systolic blood pressure-lowering effect in patients with moderate TRH was lower, averaging approximately 13 mm Hg. Despite this, it must be recognized that the blood pressure-lowering effect of this degree has important potential socioeconomic consequences, with expected reductions in cardiovascular complications and the potential for reduced antihypertensive medications costs. A state transition model suggests that RDN in severe TRH patients is highly cost effective (7); however, whether the same can be said for treatment of moderate TRH awaits a larger, randomized controlled trial and long-term follow-up.
There is a strong argument for reconsidering in this moderate TRH cohort, and all future RDN trials, the use of the “responder” versus the “non-responder” endpoint definition, a pre-specified arbitrary systolic blood pressure lowering of ≥10 mm Hg compared to baseline, used to infer successful blood pressure response, and also used in the Symplicity HTN-1 and -2 trials. A 6-month successful “responder” rate of 90% was first reported in Symplicity HTN-1, which declined to 78.7% at 12 months in the RDN treatment arm of Symplicity HTN-2 (4). The terms are of little clinical utility, taking a continuous and dynamic variable (systolic blood pressure response) and converting it into a dichotomous, binary term. Furthermore, the actual systolic blood pressure values of these “non-responders” in the Symplicity HTN-1 and -2 trials have never been reported, preventing any potential valuable insights into the demographics of this patient cohort, leaving readers to hypothesize whether “non-responders” had a mean systolic blood pressure decline of 7 to 8 mm Hg, which would be considered a favorable response in any antihypertension drug trials, or whether it represented an actual worsening of systolic blood pressure. Importantly, Ott et al. (6) found that approximately 50% of patients experienced a systolic blood pressure reduction, reaching the “goal” of ≤140 mm Hg: a significant benchmark associated with a reduction in cardiovascular events (despite the reduction in the number of antihypertensive medications prescribed by referring physicians). This key therapeutic endpoint was reached even with a 38.9% “non-responder” rate; notably, the investigators observed a slight increase of 7 ± 13 mm Hg in systolic blood pressure at 6 months in these “non-responders.” While this blood pressure increase may represent a normal variation in blood pressure values in a small patient cohort at 6 months and/or patient medical noncompliance, the actual reporting of the “non-responder” blood pressure values is essential in future larger, randomized RDN trials; understanding whether nonresponse actually means “no response” or “worst response” post-RDN may assist in identifying patient-related pre-procedure predictors of clinical blood pressure response or the lack thereof.
In a pre-specified analysis of 10,705 patients in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial (8), which compared benazepril and amlodipine to benazepril and hydrochlorothiazide, treating patients with high-risk hypertension with the goal of lowering systolic blood pressure below 140 mm Hg, but no lower than 130 mm Hg, appeared to be the best therapeutic target. Every endpoint used to assess outcomes improved significantly if systolic blood pressure was brought to 130 to 139 mm Hg compared with higher pressures. Achieving a systolic pressure of 120 to 129 mm Hg was of minimal additional benefit to patients; however, a more aggressive reduction to 110 to 119 mm Hg was harmful to some patients. Reaching systolic blood pressures below 120 mm Hg reduced the risk of stroke but was associated with two coronary events for every stroke prevented. If these studies influence future guidelines, RDN as a therapeutic strategy in moderate TRH patients may likely increase the number of patients that could reach the ideal therapeutic goal.
As the RDN procedure evolves, the durability of its blood pressure-lowering effect and safety suggests that this therapeutic strategy and its clinical indications will continue to evolve and expand. Selection of patients with severe or moderate TRH, thus far, has required that the patients be receiving three or more antihypertensive medications at full or tolerated doses, including a diuretic. These patients have had maximal antihypertensive therapy directed at activity of the renin-angiotensin system and sodium volume-contributing factors. This has resulted in selection of patients who most likely have increased sympathetic nervous system activity as a contributing factor to their TRH. Future studies should define whether aldosterone receptor blocker agents should be initiated as part of the screening process, as increased aldosterone can contribute to TRH. Alternatively, if there is uncertainty as to whether increased sympathetic nervous system activity is contributing to a patient's TRH, prediction of which patients will respond to RDN may be made more specific by testing the blood pressure response to the administration of oral clonidine (0.1 mg every 12 h for 1 week). Clonidine, a central alpha agonist, reduces central sympathetic outflow, thus interrupting the sensory afferent renal nerve-central integration-increased peripheral sympathetic nervous system activity reflex arc. Our experience indicates that patients who responded to clonidine with a decline of ≥10 mm Hg in systolic blood pressure subsequently responded to RDN with even greater arterial pressure lowering. Thus, the positive predictive value of this screening test appears high. The greater blood pressure response to RDN than that to clonidine may reflect a limitation of the ability of clonidine treatment to reduce central sympathetic outflow without encountering its adverse drug side effects.
An important topic, which has received little attention, is the question of what post-RDN antihypertensive therapy should be advised long-term. Because RDN results in decreased central sympathetic outflow, therapy directed at activity of the renin-angiotensin-aldosterone system and sodium-volume factors would appear to be appropriate long-term antihypertensive choices. While reduction of the number of required antihypertensive medications in some patients is possible, the long-term strategy should be to attain antihypertensive goals that decrease long-term cardiovascular risks. Future studies should help develop long-term medication strategies to assist physicians in making thoughtful long-term adjustments in medications in RDN patients.
The Symplicity HTN-1 and -2 trials and the present registry used a 6-month primary time point at which to assess blood pressure by comparison to pre-RDN control values. However, longer-term follow-up in severe TRH patients is essential to identify a group of “slow responders” who do not manifest a blood pressure-lowering effect for up to a year (4). Thus, the reported 6-month blood pressure response by Ott et al. (6) may turn out to be more beneficial than reported and the maximal blood pressure reduction in this moderate-THR cohort may yet be fully realized.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Drs. Rocha-Singh and Katholi are consultants and investigators for Medtronic.
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