Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF

Despite the availability of efficacious pharmacological treatments, hypertension remains the leading global cause of death and disability,1 and rates of blood pressure (BP) control are stagnant, if not modestly declining. In the United States alone, for example, more than one-half of individuals with hypertension do not meet societal or guideline-directed BP goals, representing more than 29 million people.2, 3 Although reasons are multifactorial, patient non-adherence, physician inertia, as well as barriers such as lack of social support, depression and complex polypharmacy regimens are major contributors to lack of BP goal achievement. Interventional strategies, such as catheter-based renal denervation (RDN) using radiofrequency energy, ultrasound, or perivascular injection of neurotoxic agents, are gaining increasing attention. The rationale for RDN is to interrupt the activity of afferent and efferent sympathetic nerves located in the perivascular space of the renal arteries, reducing the sympathetic nervous system's influence on renal vascular resistance and renin release and sodium reabsorption that contribute to the maintenance and progression of hypertension.4 Following a succession of promising exploratory trials, enthusiasm for the efficacy of RDN was tempered by the neutral results of the sham-controlled, randomized SYMPLICITY-3 HTN trial in 2014, which demonstrated the safety of RDN but not a significant BP reduction relative to control.5 Amidst persistent interest in the potential benefit of RDN and lessons learned regarding trial conduct, procedural technique and the study population6 a new generation of randomized, sham-controlled trials has been performed (SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, SPYRAL HTN-OFF MED PIVOTAL, RADIANCE-HTN SOLO and RADIANCE-HTN TRIO).7-11 Despite varying procedural techniques, these trials demonstrated consistent and clinically meaningful reductions in ambulatory and office BP with RDN in both the presence and absence of anti-hypertensive medications. Together, these studies have renewed interest in device-based therapies for hypertension, and additional trials are ongoing. While RDN is included as a therapeutic option in the latest ESC/ESH guidelines,12 it remains an investigational technology in the United States. Against this background, and given the potential for this procedure, there is a need to address questions regarding the possible role of RDN as a therapeutic option in addition to medical therapy and lifestyle interventions. The assessment needs to be multifactorial and take into account the current factors influencing poor hypertension control, healthcare stakeholders, and, importantly, patient preferences. The present communication represents considerations and consensus views from a roundtable discussion between leaders in hypertension and interventional cardiology. The consensus conference was supported by the National Kidney Foundation and the Society for Cardiovascular Angiography and Interventions; however, the content of this report represents solely the opinions of the consensus committee members. Hypertension guidelines vary in their precise definitions and terminology. The ACC/AHA 2017 recommendations consider a BP ≥ 120/80 mm Hg as “elevated” and ≥ 130/80 as “stage 1 hypertension”,13 whereas the ESC/ESH document classifies BP as normal up to 130/80 mm Hg and assigns the label “high-normal” to the segment SBP 130–139 mm Hg or DBP 80–89 mm Hg.12 The differences are more in degree than in kind, as there is almost universal agreement that reducing BP will lower the risk of CV disease and mortality, as demonstrated in several meta-analyses.14, 15 In practice, there is broad consensus that a range 130–140/80 mm Hg would be acceptable.12, 13 Nevertheless, targets have not been consistently defined across guidelines. For instance, the American College of Physicians and American Academy of Family Physicians Joint Guideline recommends an SBP target of 140/90 mm Hg found that only one out of six uncontrolled patients experienced intensification of their drug regimen during this period.19 Analyses of prescription records paint a similarly discouraging story.20 Complete or partial non-adherence to treatment regimens also contributes significantly to low rates of BP control. Analyses of prescription refills from national claims databases in the US suggest that around one-third of treated hypertensive individuals are nonadherent to their medication regimens.21 Many other countries show similar nonadherence rates.22 Nonadherence rates seem highest among young adults, and adherence improves with increasing age.3 Adherence rates also vary among drug classes, and it has long been known that escalating medication number, especially when combined with multiple daily doses, are major barriers to adherence.23-25 Furthermore, adherence to medications is dynamic, and patients may often be partially adherent (not taking all medications every day) rather than entirely non-adherent. For example, even among individuals who are 80% adherent to their medication regimens, the pattern of pill-taking can vary widely (Figure 2), with possibly relevant differences in clinical impact.22 Finally, aside from non-adherence to medical therapy, avoidance of lifestyle and dietary modifications (e.g., exercise, weight loss, modifying salt, and alcohol intake) also contribute to poor long-term BP control. The largely asymptomatic nature of hypertension adds to the difficulty of controlling BP. Disparities in care are particularly relevant for socio-economically disadvantaged groups. Among factors predictive of higher control rates are access to medical insurance and regular visits to healthcare centers.3 Not coincidentally, hypertension rates among African-American individuals are among the highest in the world, also perhaps partly due to genetic factors.13 Community outreach activities, combining trusted sites for BP interventions, physician-pharmacist collaboration, and the availability of effective and low-cost antihypertensive drug regimens have demonstrated promising results.26, 27 Still, a greater need is assuring access to medical coverage among these disadvantaged groups. When considering BP targets and reductions, the panel recognized that increasing understanding of the multifactorial nature, treatment and behavioral factors in hypertension has led to more sophisticated views on the topic. Visit-to-visit variability over time in systolic or diastolic BP has been shown to be associated with worse CV and renal outcomes, as well with a greater mortality risk. The associations hold for variations in the range of as little as 5–10 mm Hg.28-30 Furthermore, the long-term sustainability of BP reductions imparts significant clinical implications. It is becoming clear that time within or very close to BP target has benefits on cardiovascular (CV) risk reduction. Time spent in an SBP target range of 110–130 mm Hg (replacing the target value of 120 mm Hg) was recently shown to be associated with a lower risk of major adverse CV events.31 Such findings have led to the suggested introduction of time in target range (TTR) to take into account BP variability over time.31, 32 TTR was recognized by the panel as a possible endpoint in hypertension clinical trials. However, the consensus was that even though TTR seems to matter for outcomes, it is beyond the resources of most primary care physicians to measure and adjust this parameter in clinical practice. Further evaluation and a standardized method for evaluation are needed. As both TTR and BP variability are dependent, at least in part, on patient adherence to treatment,31, 33 these measurements deserve close scrutiny in trials of RDN or other device therapies. However, considering that the effects of these device-based interventions are independent of patient adherence to drug therapy, they may provide a unique and potentially meaningful advantage. A second, related question addressed by the panel constitutes a “meaningful reduction in BP” with any antihypertensive treatment. This has been similarly discussed in European consensus documents for RDN, in addition to an FDA Panel meeting.34 The panel agreed that the term is not easy to define; it is not a matter of setting an absolute threshold of systolic or diastolic BP reduction, but a “meaningful” reduction should also consider patient risk. In patients at higher baseline CV risk or with higher baseline BP, the absolute reduction in global CV and renal risk can be significant even with only modest reductions in BP (5–10 mm Hg SBP). It is also likely that a clinically meaningful BP reduction will vary between individuals depending on starting BP, risk profile and the specific therapy being administered, giving rise to complex evaluations of benefit versus risk. Accounting for individual patient risk will be very relevant when assessing the suitability of RDN candidates for the procedure. The panel considered it unhelpful to specify an absolute parameter that is highly dependent on the starting point and patient conditions. In recent meta-analysis of 51 randomized trials involving pharmaceutical therapies, an absolute systolic BP reduction of 5 mm Hg was achieved with a single antihypertensive drug,35 yet this seemingly modest difference translates into an approximately 5% relative reduction in CV death and 10%–15% reductions in CV events and stroke. Similarly, a 10 mm Hg reduction in systolic BP is associated with a 13% decline in CV mortality and 20%–30% reductions in CV and stroke events, independent of initial BP level or coexisting conditions.36 At least similar reductions in office systolic BP have been observed with RDN, and the panel agreed that there is no reason to suggest the BP reductions achieved with RDN would not convey similar benefit in outcome to what has been observed with medical therapies. In addition to the magnitude of BP reduction, it is also essential to take into account stabilization or decrease in BP medications and changes in patient reported quality of life (QoL). Specific therapies for treatment of hypertension require a thoughtful work-up of the patient with uncontrolled BP. The panel discussed how multidisciplinary hypertension centers might play a role in a treatment landscape that includes the option of an RDN procedure. Accurate BP measurements are crucial for risk assessment and to evaluate the effectiveness of antihypertensive therapies. Clinic BP interpretation is limited by the white coat effect, inter-measurement variability, and the inability to uncover masked or nocturnal hypertension. These deficiencies may lead to suboptimal accuracy, with an impact on treatment decisions.37-39 Home BP measurements and ambulatory BP monitoring are more reliable, but patients need careful instruction and periodic reinforcement regarding how to perform measurements. Moreover, despite initial adherence, performance of home BP monitoring often wanes when patients lose interest in continuing to measure BP. There is also a relevant financial impact of self-measurement devices among patients with lower socioeconomic status, who often are those who represent the greatest need for BP control. The rapid development of wearable devices is expected to contribute to more complete and patient-friendly monitoring in the future. The panel emphasized that most patients with hypertension encountered in routine clinical care will not have difficult-to-treat, let alone resistant, hypertension. In the large of and modifications and a in the of a as in can be expected to BP. 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