Unsolved issues in the treatment of hypertension and the era for renal denervation

Despite the availability of a large number and variety of antihypertensive drugs, hypertension remains uncontrolled in up to 60% of patients receiving dual antihypertensive therapy [398] . Furthermore, about 10–15% of patients with hypertension have resistant disease, defined as a lack of blood pressure (BP) control despite treatment with optimal dosages of three or more antihypertensive agents from different drug classes or the need for treatment with ≥4 drugs to achieve BP control [399, 400]. The proportion of treated patients achieving BP control is even lower when the lower BP targets mandated in the latest hypertension guidelines are used [178, 364]. Prescription of an adequate number of antihypertensive agents at optimal dosages and adherence to prescribed therapy are essential to ensure the effectiveness of drug therapy [401] . However, fewer than half of all patients are adherent with antihypertensive therapy one year after starting treatment [402, 403]. When serum or urinary drug levels are used as a measure of drug usage, 25–65% of patients with apparent treatment‐resistant hypertension are actually nonadherent to therapy [404–407].

Another weakness of medical treatment includes difficulty in controlling nighttime BP and the morning blood pressure surge (MBPS). Even if the office BP is well controlled, poorly controlled early morning and nocturnal hypertension, plus increased BP variability, increases the risk of cardiovascular disease [190, 221, 192].

Renal denervation is a new treatment approach that requires a single treatment, overcoming adherence issues, and partially blocks the renal sympathetic nervous system to reduce BP throughout the 24‐period to reduce cardiovascular risk. Denervation techniques currently under clinical investigation include radiofrequency, ultrasonic, and chemical ablation with alcohol, all of which are executed through transcatheter access to the renal artery. The first denervation technique was designed to deliver low‐level radiofrequency energy through the wall of the renal artery and is now improved to the spiral form with multielectrodes (Symplicity™ Spyral catheter‐based renal sympathetic denervation system) (Figure 6.1).

Hypothesis of perfect 24‐hour BP control by renal denervation

There is significant bidirectional interaction between the brain and kidney through the efferent and afferent sympathetic nervous system, resulting in the regulation of BP (Figure 6.2) [408] . As the mechanism of renal denervation, efferent denervation reduces renal catecholamine production and beta‐1 adrenergic renin production. These changes increase renal blood flow and reduce circulating volume, thus explaining the shift from non‐dipping to dipping of nighttime BP in patients with resistant hypertension. In addition, afferent denervation decreases central sympathetic activity in response to increased baroreceptor sensitivity, thus potentially explaining the reduced variability in BP (including MBPS) and reduction in 24‐hour BP, resulting from decreases in peripheral resistance and cardiac workload. It is hypothesized that renal denervation could achieve perfect 24‐hour ambulatory BP control consisting of a strict reduction in the 24‐hour BP level, a dipper pattern of nighttime BP, and an adequate morning BP surge (Figure 6.3). In addition, renal denervation inhibits neprilysin activity, resulting in increased circulating natriuretic peptides. This reduces myocardial fibrosis and improves left ventricular (LV) function in the setting of heart failure (HF) (Figure 6.4) [409] .

History

Surgical sympathectomy was being performed on patients with hypertension prior to the 1950s, but widespread use was limited by side effects such as perioperative complications and postoperative postural hypotension [411] . Figure 6.5 shows the Clinical trial history of renal denervation (RDN) [410] . In 2009, the first hypothesis‐testing SYMPLICITY HTN‐1 trial reported a significant antihypertensive effect in drug‐resistant hypertension using minimally invasive radiofrequency transcatheter renal denervation [412] . In this study, 12‐month postprocedural decreases in systolic (SBP) and diastolic blood pressure (DBP) in patients with drug‐resistant hypertension prescribed ≥3 antihypertensive medications (including diuretics) were −27 and −17 mmHg (n = 9) [412] .

The subsequent SYMPLICITY HTN‐2 (HTN‐2) trial, published in 2010, included 106 patients with treatment‐resistant hypertension randomized to pharmacotherapy plus renal denervation (52 patients) or conventional pharmacotherapy (54 patients) [413] . At six months, between‐group differences in the SBP/DBP change from baseline with renal denervation vs. control were −33/−11 mmHg. Twenty‐four‐hour mean BP in a subset of patients was also significantly decreased in the renal denervation group, although reductions were smaller than those for office BP (between‐group difference of about −8/−6 mmHg at 6 months).

The SYMPLICITY HTN‐J study was initiated in Japan in 2012. Renal denervation was performed in patients with treatment‐resistant hypertension using the first‐generation, single‐electrode radiofrequency (RF) Symplicity “Flex” catheter (Medtronic) and found to be highly effective upon initial investigation (Figure 6.6). However, in 2014, the SYMPLICITY HTN‐3 (HTN‐3) trial with a sham‐controlled comparison group found no significant difference in BP‐lowering level between the renal denervation and sham group [414] . Subsequently, several renal denervation trials, including the SYMPLICITY HTN‐J study, were stopped. However, we found that renal denervation tended to reduce 24‐hour SBP compared with the sham group (−6.2 mmHg, p = 0.087) (Figure 6.7) [415] , and that reductions in BP increased over time in the renal denervation group (Figure 6.8) [416] . Furthermore, subsequent pooled analysis combining data from the SYMLICITY HTN‐3 trial and interim analysis data from SYMPLICITY HTN‐J found that renal denervation clearly lowered the BP during the nighttime and early morning, when the effects of antihypertensive drugs are less likely to be seen (Figure 6.9) [281] .

In 2015, the French prospective randomized DENERHTN trial reported positive results using similar techniques and the same device as the SYMPLICITY HTN trial series [417] . The trial compared RDN (n = 53) with standardized stepped‐care antihypertensive treatment (n = 53) in patients with resistant hypertension and showed significant between‐group reductions in the primary endpoint of daytime SBP at 6 months (−5.9 mmHg; p = 0.0329); levels of drug nonadherence were high (about 50%) but were similar in the two groups [418] .

Advances in devices

Several renal denervation devices have been introduced clinically and, to date, serious procedure‐related complications are rare.

Symplicity spyral system (radiofrequency thermal ablation)

The SPYRAL HTN clinical trial program was designed to compensate for confounding factors in the SYMPLICITY HTN‐3 study, with a focus on patient selection, procedural details, and variability in patient drug nonadherence behavior [419, 420].

The first‐generation radiofrequency SYMPLICITY “Flex” ablation device used in the SYMPLICITTY HTN trial series had only one electrode and required rotation and repositioning between lesions, resulting in between‐operator variability. The subsequent SPYRAL HTN studies employed a second‐generation spiral‐shaped catheter device (Symplicity “Spyral”), which includes a four‐electrode array mounted on a 4F catheter that self‐expands into a helical configuration with electrodes located at 90° from each other circumferentially (Figure 6.10 upper panel) [421] . Radiofrequency energy treatment is delivered simultaneously to all four renal artery quadrants for 60 seconds. This device allows simultaneous independent ablation, and temperature and impedance monitoring, at four radially and longitudinally dispersed positions, ensuring electrode‐tissue contact and reducing the risk of stenosis. More complete denervation can be achieved by performing ablations in the distal portion of the main renal artery and in the branching vessels. In an experimental study, combination renal denervation treatment of renal artery branches and the main artery provided the best and most consistent reduction in norepinephrine levels (Figure 6.10 lower panel) [422, 423]. Clinical data showed an association between incrementally greater BP reductions with distal and branch ablation compared with main artery ablation only [424, 425].

In the SPYRAL HTN OFF‐MED and ON‐MED studies, ablations were performed in both the main renal arteries and vessel branches using a Spyral catheter. The primary endpoint was a change in 24‐hour mean SBP, measured using ambulatory BP monitoring (ABPM). These proof‐of‐concept trials showed impressive results, with significant differences in both office and ambulatory SBP and DBP with in the renal denervation group compared with sham control [283, 426

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