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

Abstract

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 < 150 mm Hg in lower risk hypertensive adults aged 60 years or older.16 Irrespective of the definition, ample data suggest these targets are underachieved in routine clinical practice. In the United States, hypertension control rates (BP < 140/90 mm Hg) are currently not achieved in nearly 60% of all individuals with hypertension,3 irrespective of treatment. Although control rates approached 70% in 2014 among those prescribed medications, there has been a continual decline thereafter (Figure 1).3 Several reasons likely account for persistently low control rates. Although the effectiveness of pharmacotherapy varies between and within drug classes,17, 18 the lack of efficacious drugs is not perceived as the main problem. Physician inertia has long been recognized as a contributing factor: a national survey of ambulatory-care data from 2005 to 2012 on adults with BP > 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. The need to a or in the to for RDN, may not to these For this the panel that the term should be over treatment have been for need not be performed on every hypertensive However, when patients with hypertension as office ≥ 130/80 mm Hg despite prescription of antihypertensive medications at a if or a of medications to control for should be a The of primary in patients with hypertension is but largely among of patients with hypertension are for primary and remains patients with hypertension, it is also to evaluate in young hypertensive patients with or hypertension, and in patients with or findings a The presence of or will the need for BP hypertensive patients are by a primary care and are not for When are that are and on and among and are often to or who may have and of A of patients to hypertension Many of the factors uncontrolled hypertension lack of healthcare not a in the also the low of a will need to be up to access to also remains an There are approximately Hypertension Hypertension and to meet needs of a of more than million uncontrolled hypertensive in the United are and of the is currently at and large The of hypertension should not be a for the of patients with hypertension, and the panel that of BP often not require hypertension at primary care are to treatment physician inertia, and for RDN, should the option for such therapy should and patient for continuing medical on hypertension is A highly is to a with for example, by to BP on a regular to treatment A to medication intensification is to treatment and at For an interventional treatment such as RDN, for patients may be a patients to benefit from and the impact of TTR also the individual for BP and the of patient Although currently in hypertension, the panel that patient and will of major in treatment and individual risk would as not all patients will the or treatment which quality of life are being included in clinical For instance, RDN studies have the and and The that the of such measurements in RDN trials should be At however, standardized are for uncontrolled hypertension with medications alone, or an The primary outcome in hypertension trials is BP reduction but it is not clear if this represents the highest to patients for example, stroke avoidance or reduction. 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In with reductions in BP, several have also supported an between RDN and a need for antihypertensive In the medications in the RDN to the at more patients in the RDN no medications at than in the sham-controlled reduction in a medication has been reported to the SPYRAL RDN versus control in the presence of uncontrolled hypertension despite prescribed The the in a clinical trial to be in a which to the more clinically events in In this RDN more than on ambulatory office and in medication in of leading to a of The long-term impact of medication changes RDN was a interest among panel members. of in BP reduction is recognized as a to measure given changes in patient and conditions. the is from the a survey of RDN among a patient with uncontrolled hypertension. 3 years of RDN was associated with and significant reductions in both office and ambulatory BP independent of an in medication the reduction in BP is consistent across patients with risk and is a of In the a similar magnitude of BP reduction was observed RDN among patients with varying CV risk and Although RDN studies have not been to long-term clinical outcomes, a recent meta-analysis of randomized trials demonstrated that RDN is associated with a BP reduction at least similar to that of a and may to an relative reduction in risk of CV events and relative reduction in safety RDN, studies to have not any or In randomized trials have not demonstrated an risk of vascular decline in renal or of renal In a meta-analysis of trials that included a of patients and of the of renal renal denervation was a to the reported of events in an hypertensive no adverse events reported in the in the of patients from treated with radiofrequency RDN beyond the main In a of studies and using a of only one significant was that data over 3 years similarly no changes in renal and a of renal data in patients with are but studies have no reason for in this as recently When renal the panel that a 10 mm Hg reduction in BP may be expected to there is no on renal in the trials and regarding long-term safety and effectiveness given the current of of the currently is from the by has related to absence of a and potential for Finally, as with individual to RDN vary and the questions regarding how to measure and what may are being BP has been an to measure in the SPYRAL HTN-OFF MED reductions in ambulatory BP and office BP well for the changes with RDN, but there was no significant in the However, in RDN trials, in one of the not at least a 5 mm Hg SBP reduction over in BP, reductions in medications and adherence the assessment of these patients represent Several possible of to RDN have been but has been In SPYRAL HTN-OFF MED, ambulatory the was predictive of reduction in and office both renin activity and significantly RDN with higher baseline renin activity was associated with a significantly greater reduction in both office and systolic In RADIANCE-HTN baseline SBP and variability with low and the predictive value to be of Finally, given that no procedural measure to effective the to which denervation contributes to clinical is renal may the of the SBP and has the most sites in but it is time and The panel agreed that the availability of a reliable, method to treatment would have a large impact on the of RDN to of RDN has largely been limited to a patient with uncontrolled systolic and diastolic hypertension. as more data the clinical of what the most patient is of a for the most of BP, there may be a role for RDN as of the for hypertension The meaningful for the value of the would be to provide greater not to trials have for the but to a medication or other When considering RDN as an to hypertensive the benefit and risk be data that the main potential of an interventional therapy are and adherence Although current randomized trials have been limited to patients with combined hypertension, there was a lack of consensus among panel the threshold to consider RDN should be on both systolic and diastolic currently or systolic BP alone The panel also agreed that to to RDN may not be possible given the limited with of a standardized of would need to be A more should account for method and of BP relative versus absolute BP reductions and between and The panel also agreed that patient which has been largely in hypertension trials, Although of the is limited in RDN among hypertensive patients that approximately one-third of patients a catheter-based over of medications for uncontrolled Moreover, patient for RDN independent of medication or BP of for RDN was highest among those with hypertension who not taking medications. for RDN was associated with a greater to lower BP and a greater and understanding of the benefit of with the effects of BP and preferences. These results also that physician as has been in other of In however, a between patients and healthcare regarding for among healthcare of RDN is greatest for those patients taking multiple medications with hypertension. 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