Medication adherence in hypertension: lessons learned from renal denervation trials

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Control rates for hypertension are poor and stagnant. Of the many contributing factors, patients’ lack of adherence to medications ranks very high. Many causes contribute, ranging from perceived or real adverse effects, drug costs and pill burden, to patient-related factors including misunderstanding, mistrust, fear, cognitive impairment, and depression, and including poor physician–patient communication.¹ Available data to quantify adherence are imprecise, coming largely from studies using pill counts and questionnaires, and from refill audits in large prescription databases. We have a fresh source of direct evidence, from rigorous, controlled, randomized trials investigating renal denervation (RDN) in hypertension. These new generation studies, aimed to detect the blood pressure (BP) lowering efficacy of RDN compared with an invasive sham, have provided us with valuable insights into patient behaviour in closely monitored and strictly controlled research settings. One prominent feature of these newer RDN studies in hypertensive patients has been the assessment of medication adherence using highly accurate adherence testing of urine and/or plasma.

The DENERHTN trial confirmed the efficacy of RDN added to standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months.² The percent of completely or partly non-adherent patients at 6 months was high and not different in the RDN and control groups (50 and 53%). Regardless of adherence, RDN resulted in a greater decrease in BP when added to standardized antihypertensive treatment than medical therapy alone. In addition to excluding different levels of medication adherence as the cause of lower BP in the RDN group, this study quantified a discouraging low adherence rate.

The SPYRAL HTN-ON MED pilot trial enrolled patients with uncontrolled hypertension with ambulatory systolic blood pressure (SBP) 140–170 mm Hg despite treatment with one to three commonly prescribed antihypertensive drugs.³ Chemical adherence testing was performed in all patients. Roughly 40% were non-adherent, although all patients knew adherence was being tested. Individual patient adherence to prescribed drugs was dynamic and not consistent at different timepoints (adherence at baseline: sham 60%, RDN 66%; adherence at 6 months: sham 64%, RDN 60%). At 36 months, 77% of patients in the RDN group and 93% of patients in the sham control group adhered to medication; these optimistic values should be considered in light of a relatively small sample size in a highly controlled trial.⁴

SPYRAL HTN-OFF MED included patients with uncontrolled hypertension (trial inclusion ambulatory SBP 140–170 mm Hg). Patients were either drug-naïve or washed-out from previously prescribed antihypertensives.⁵ Drug testing was pre-planned and performed at baseline and 3 months. Overall compliance with the requirement to remain off antihypertensive drugs was 85% in this study, indicating that 15% of patients were taking drugs when they were not supposed to. Five percent even started to take drugs that were not prescribed.

The RADIANCE-HTN TRIO multicentre trial was designed to test the efficacy of RDN in true resistant hypertension. Patients with office BP ≥ 140 and ≥90 mm Hg despite three or more antihypertensive agents including a diuretic were switched to a once-daily, fixed-dose single-pill combining a calcium channel blocker, angiotensin receptor blocker and thiazide diuretic. After one month on the triple pill, if daytime ambulatory BP was ≥135 and ≥85 mm Hg, patients were randomized to RDN or sham procedure. Renal denervation was effective; it reduced daytime ambulatory SBP more than the sham procedure (−8.0 vs. −3.0 mm Hg; P = 0.02).⁶

Noteworthy findings related to adherence emerged from RADIANCE-HTN TRIO. A remarkably large number of patients initially on three or more meds with high office BP had to be excluded because ambulatory BP monitoring (ABPM) performed on the triple pill revealed their BP to be controlled. Of 819 patients enrolled with qualifying hypertensive office BP, 354 (43%) were excluded because daytime ambulatory BP was <135/85 mm Hg on the triple pill. This is likely an underestimate; many additional patients were excluded for other reasons (such as pandemic-related withdrawals) before ABPM could be performed. The dramatic gain in BP control is best interpreted as further evidence that pill count matters.⁷ Reducing pill burden from three or more to one helped achieve a high adherence at baseline, 79%. At the two-month primary endpoint, 82% of patients in both the sham and RDN groups were compliant with the triple pill. Hence, changes in adherence did not explain the BP changes observed following RDN.

Non-adherence to antihypertensive medication is one of the most significant obstacles to BP control, contributing to increased cardiovascular risk. Without an accurate understanding of exactly when and how often patients are taking prescribed medications, physicians practice in the dark. For hypertension specialists, the scenario of seeing a patient referred with uncontrolled BP despite being treated with four, five or six medications is not uncommon. The most typical explanation for apparent resistant hypertension is medication non-adherence. The reflex response of prescribing yet another pill is often not the best course of action, and is unlikely to address the underlying problem.

Data from recent RDN trials help illuminate the scope of the problem. Previous studies using less specific markers and measures have reported adherence floating around the 50% mark, and data from rigorous RDN studies support that value. These studies have also provided us with new information, including the dramatic improvement in adherence seen with a combination pill, as well as the dynamic nature of adherence.

Systematic efforts are underway in large health care systems, societies and guideline-writing agencies to improve global BP control. Efforts focusing on the education and engagement of patients in their hypertension management are critical. Providers need to be trained to solicit careful histories, to listen to patients’ reports about taking and tolerating their pills, to monitor refills, and to identify treatments based both on evidence and on each patient’s individual preferences, beliefs and values. Discussions with patients should emphasize the typical chronicity of a hypertension diagnosis, and the clear benefits of treatment.⁸ We should stack the deck in everyone’s favour by employing fixed-dose combination therapies, and once-daily, generic drugs.

Finally, the realization that some patients simply cannot or will not take medications should be factored into the decision tree for offering device-based therapy. Patient preference and shared-decision making studies have already demonstrated the strong interest of patients with hypertension in RDN. Studies in Western Europe and the US revealed that patients who experienced side effects attributed to their BP medications had a higher preference for RDN.^9,10 Similarly, in a Japanese survey of hypertensive patients, poor adherence to antihypertensive medication and the presence of side effects during treatment with antihypertensive drugs were significant predictors of preference for RDN.¹¹

Despite the widespread availability of multiple classes of antihypertensive medication for several decades, global control rates are poor. Fifteen years have passed since the last new class of anti-hpertensive medication was introduced. In that time period, critical advances have appeared in multiple realms, including a variety of digital care health solutions, community interventions, and new technologies. Renal denervation is not a replacement for either lifestyle modification or medication in the treatment of uncontrolled BP. But it is an ‘always on’ therapy that has been proven safe and effective in multiple randomized, sham-controlled trials,^3,5,6,12 and it works in conjunction with drugs. Even without data demonstrating improved clinical outcomes with RDN in individuals non-adherent to antihypertensive medications, we have a robust bank of evidence from multiple sham-controlled trials with RDN. The rate of non-adherence is high among patients interested in this treatment.

Key takeaways

• Adherence to hypertension medication in RDN hypertension trials has been discouragingly low during follow-up, even when patients knew testing would be performed.

• Switching from multiple single pills to a triple fixed-dose combination pill controlled BP in at least 43% of apparent resistant hypertensives.

• Adherence to a triple fixed combination was high and persistent (around 80%).

• In a trial setting where medications were washed-out, 15% of patients decided to reinitiate drugs; 5% started taking drugs they were never prescribed.

• A significant number of patients with hypertension are interested in RDN. Non-adherence to medication and side effects from medication have both been significant predictors of patient preference for RDN.

• Renal denervation is positioned to provide safe, effective antihypertensive therapy especially among those patients who cannot or will not take additional medications.

Author contributions

N.F. conceived the Commentary; both N.F. and F.M. contributed to the design and drafting of the manuscript. Both gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Acknowledgements

N.D.L.F. is a consultant for Recor Medical and Medtronic and receives research funding from ReCor Medical. This work is original by the two co-authors, does not duplicate any previously published work, and has not been published elsewhere, nor is it currently under consideration for publication elsewhere.

References

Author notes