Blood pressure lowering effect of renal sympathetic denervation or placebo? - building expectations for Symplicity-HTN 3

More than 10% of patients treated for hypertension have persistently uncontrolled blood pressure (BP) despite prescription of antihypertensive drugs (1). Renal sympathetic denervation is an old concept that has been re-introduced as a new treatment for hypertension that is apparently resistant to drug treatment (2). Patients considered eligible for this procedure populate the high end of the BP spectrum, where, for whatever reason, pharmacologic treatment has failed to produce adequate BP control. Recent data suggest that patients suspected of having “resistant hypertension” in fact represent a mixed group that includes those with white coat hypertension, secondary forms of hypertension, inadequate dosing of medication, and poor adherence to prescribed antihypertensive treatment, as well as true resistant hypertension (3). In the study by Verloop and coworkers, 2 out of every 3 patients referred for renal denervation because of apparent resistant hypertension did not have true resistant hypertension and therefore were not considered eligible for the procedure. Non- and poor adherence to prescribed treatment occurred frequently in this referral population, leading the authors to recommend careful screening of patients with apparent resistant hypertension before undertaking renal denervation procedures. The main aim of such a screening program is to confirm the persistence of uncontrolled hypertension despite adequate medical treatment and to exclude secondary forms of hypertension.

The Symplicity HTN-2 study (4) is the only randomized controlled trial of renal sympathetic denervation that has been reported to date. Symplicity HTN-2 randomized 106 patients with apparent treatment resistant hypertension to renal sympathetic denervation or control and followed them for 6 months. Office BPs were reduced by 32/12 mmHg in the intervention group at 6 months and remained unchanged in the control group. Reductions in ambulatory BP were much smaller, suggesting, a “white coat” effect. Further, drug adherence was not thoroughly investigated (4).

Poor drug adherence is a common problem among patients with apparent treatment resistant hypertension (5,6). For example, a recent study of 84 patients taking on average 5 antihypertensive drugs found no detectable blood levels of any antihypertensive drug in 34.5% of the patients, and that 65.5% of the patients fulfilled the criteria of non-adherence (7). It is not known to what extent the reduction in BP that is observed following renal denervation is caused by the denervation per se or by increased drug adherence. It is reasonable to postulate that patients with poor drug adherence who undergo renal denervation receive so much positive attention at follow-up that they become more adherent to their antihypertensive medications and thus have enhanced BP reductions. Some patients may even discontinue their antihypertensive drugs prior to qualification procedures for renal denervation and then resume their medication after the procedure. This could not be detected by the methods employed in Symplicity HTN-2 (4), and these deficiencies provided the impetus for the more tightly controlled Symplicity HTN-3 study in the USA, which includes a sham operated control group (8).

Drug adherence may be assessed in several ways, e.g. by electronic pill boxes, blood and urine measurements of prescribed drugs or by written patient's diaries. However, measurement of drugs in blood or plasma, can provide interesting information (7), but is not available in most clinical practices, and neither patient's diaries as used in Symplicity HTN-2 nor electronic pill boxes are reliable enough to ensure drug intake. The only method that fully ensures true drug intake and permits documentation of the effects of the drugs that are taken, e.g. BP reducing effects, is to observe the patient taking the medications. A recent study of 18 patients with apparent treatment resistant hypertension referred to a hypertension center for renal denervation required participants to bring their prescribed medication to the clinic visit and have the medication administered by the investigator and swallowed by the patient under continuous observation (10). A 24-hour ambulatory BP device was then placed on the patient and 24-hour monitoring was carried out. Strikingly, 5 of the participants had normalization of their ambulatory BP following witnessed intake of their medication and 7 others were excluded from the procedure because of various concomitant conditions. Thus, only 6 of 18 patients qualified for renal sympathetic nerve ablation procedure, and only 2 of the 6 experienced significant reductions in both office and ambulatory BP during 6 months of follow-up. The finding that only a minority of apparently treatment resistant hypertensive patients have true treatment resistance, are free of secondary forms of hypertension and have suitable renal arterial anatomy and thus are candidates for renal denervation has also been shown, and on a much larger scale, in other tertiary care hypertension centers (11). Similarly, other studies have reported minimal BP reductions in response to renal denervation (9).

In a recent 10-center multinational European study (12), BP was followed up 3 and 6 months after renal sympathetic denervation. Recruited patients (n = 109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. Office systolic/diastolic BP fell by 17.6/7.1 mm Hg, and 24-h, daytime and nighttime BP fell by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg (P ≤ 0.03 for all). In 47 patients (43%) with 3- and 6-month ambulatory measurements, systolic BP did not change between these 2 time points (P ≥ 0.08). Normalization was defined as a systolic BP < 140 mm Hg on office measurement or < 130 mm Hg on 24-h monitoring and improvement as a fall of ≥ 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9%, 59.6% and 22.9% of patients; for 24-h BP, these proportions were 14.7%, 31.2% and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up. Thus, BP responses to renal sympathetic denervation are likely to include substantial regression- to-the-mean effects and therefore remain to be confirmed in randomized trials based on ambulatory BP monitoring.

Symplicity HTN-3 is ongoing in the USA (8), and the Oslo RDN Randomized Study (ClinTrialGov ID: NCT01673516) is currently randomizing patients with true treatment resistant hypertension in a similar protocol, i.e. renal denervation with the Symplicity^™ Catheter System vs. intensified drug treatment guided by non-invasive hemodynamic assessments measured by impedance cardiography (13). A novel aspect of the Oslo RDN study is that patients can only qualify if ambulatory BP remains elevated after witnessed intake of the antihypertensive drugs.

The Oslo group has previously investigated the reproducibility of 24-hour BP in patients with newly diagnosed hypertension and found that reproducibility is reasonably high (14). Thus, there are reasons to believe that pseudo-resistant hypertension and poor drug compliance can be excluded with high precision despite only one qualifying measurement of ambulatory BP after witnessed drug intake prior to renal denervation.

Ongoing clinical studies are needed to shed further light on the clinical utility of renal sympathetic denervation in resistant hypertension. Although initial safety and efficacy studies have shown that renal sympathetic denervation has a potential therapeutic benefit in this patient group, the magnitude of the benefit needs to be firmly established by appropriately controlled studies. Clearly, randomized, controlled and un-biased studies with strict criteria for patient enrolment are necessary to confirm initial positive findings. Thus ultimate proof that catheter-based renal sympathetic denervation is a widely applicable therapy for the management of resistant hypertension remains to be demonstrated.

Disclosures

No relevant conflicts of interest to disclose related to this Editorial. SO is a consultant for Medtronic and on the Steering Committee of Symplicity HTN3.