Is There Any Role for Device Therapies in Resistant Hypertension? PRO

In the text to follow, I focus on the role of renal-denervation therapies to address the debate topic. This is because so much of the data accumulated on resistant hypertension, at least in the last 10 years, have centered on this approach. I acknowledge there are studies of other device therapies such as baroreflex amplification (¹) and barostimulation (²) in this space, but in the interest of maximally using my word allotment I am deferring discussion of these areas to (hopefully) future debates.

The presence of drug-resistant hypertension represents a public health hazard (³). When BPs persist in an elevated state despite prescription of—and adherence to—a reasonable antihypertensive regimen consisting of diuretic, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocker, the likelihood of target organ damage is magnified by the persistent increase in BP (⁴,⁵).

When faced with a patient on a multitude of hypertensive agents, who has persistent elevations of BP, what options are available? A standard recommendation is to reduce sodium intake, which can have impressive reductions in BP, but is challenging to implement outside the confines of a research study where the meals are provided for the patient by a clinical research center kitchen (⁶). Additional medication is typically recommended; for instance in the PATHWAY-2 study, investigators observed that when adding either a β-blocker or an α-blocker or spironolactone to a standardized triple-therapy regimen, spironolactone had the greatest additional BP-lowering effect (⁷).

Sermons are a means to persuade an audience (or congregation) to either amend or reinforce a particular behavior. Sermons typically have three points. A good preacher typically starts their sermon by stating all three points, developing each one, and then reviewing all three again in the summary. This is my intent for this topic.

Can I Hear an Amen?

The three points I plan to make are as follows:

1. Device-based therapies for hypertension produce a BP reduction similar to drug monotherapies.
2. Device-based interventions have a reasonable safety record and the BP reduction appears durable.
3. A sizable portion of patients with high BP on three or more drugs have a BP that is not controlled at the level of a prevailing guideline (i.e., resistant hypertensives).

Point 1: Device-Based Therapies for Hypertension Produce a BP Reduction Similar to Antihypertensive Drugs

Here we begin by asking “how much BP reduction occurs in a patient with hypertension when started on a single agent, titrated to a reasonable dose?” Every oral agent indicated for use in managing hypertension has been subjected to such scrutiny. In the Veterans Affairs Cooperative Trial of antihypertensive agents, six agents from six different classes of BP medications were randomly assigned as monotherapy to a group of mainly men with hypertension. The typical BP reduction associated with each agent, given to about 200 veterans in each group, ranged from as little as 7 mm Hg of systolic BP in office-based measurements to as much as 17 mm Hg (⁸). Excluding placebo, an office reduction of 10–12 mm Hg systolic was a common magnitude of systolic BP reduction from monotherapies in this large, blinded trial.

When a regimen of two antihypertensive drugs is compared with a regimen of single-agent therapy, a recent meta-analysis of 33 randomized trials in 13,095 participants observed that the presence of the second antihypertensive agent provides about 5 mm Hg more systolic pressure reduction in the dual arm (⁹). When a regimen of three antihypertensive drugs is compared with a regimen of dual-agent therapy, a recent meta-analysis of 14 randomized trials in 11,457 participants observed that the presence of the third antihypertensive agent provides, again, about 5 mm Hg more systolic pressure reduction in the triple arm (¹⁰).

When used as “monotherapy,” in the absence of antihypertensive drug usage, renal denervation is associated with an office systolic BP reduction of 10–11 mm Hg (¹¹,¹²), similar to single antihypertensive medications. When renal denervation is used as an adjunct to a regimen of one to three antihypertensive medications, the additional office systolic BP reduction was 9 mm Hg (¹³), which is similar—if not slightly more than—the effects seen in trials that assessed the effect on one additional antihypertensive drug.

Point 2: Device-Based Interventions Have a Reasonable Safety Record and the BP Reduction Appears Durable

The requirements for a femoral-artery puncture, selective renal angiograms, and the need for conscious sedation during the denervation procedure expose the patient to significant procedure-related risks. Moreover, although the BP-lowering effects of renal denervation appears to last for at least 3 years (¹⁴), intercurrent illnesses (such as vomiting, diarrhea, or both) and the use of medications which could have effects on renal blood flow or renal function (such as nonsteroidal anti-inflammatory drugs) might have greater toxicity in the absence of an intact renal nervous supply. Fortunately, the safety record of renal-denervation interventions to date, no matter which method of denervation is used, has been favorable and complications have been at a lower level than those found in other invasive studies (such as those using renal angioplasty) (¹⁴,¹⁵). To date, the peri-procedural significant adverse event rates surrounding renal denervations is <2% (¹⁶).

In a nonrandomized renal-denervation intervention in patients with existing CKD, kidney function appeared stable when followed for the next 2 years (¹⁷). In the Global SYMPLICITY Registry, with enrollment currently at about 2600 people who have undergone a radiofrequency ablation in the renal artery, no significant safety signal in terms of renovascular anatomy (i.e., unanticipated renal artery stenosis) or greater-than-expected kidney function decline has been noted.

Point 3: a Sizable Portion of Patients with High BP on Three or More Drugs Have a BP that Is Not Controlled at the Level of a Prevailing Guideline (i.e., Resistant Hypertensives)

Whether using a highly monitored health care system like Kaiser Permanente (¹⁸) or stalking the wilds of a National Health and Nutrition Examination Survey (¹⁹), the prevalence of treatment-resistant hypertension ranges from 2% to 16% of patients with hypertension. Perhaps the most-worrisome finding in antihypertensive-treatment resistance is the well documented occurrence of medication nonadherence among these patients. Studies have shown that up to almost half of patients with treatment-resistant hypertension either have no antihypertensive medication, or less than the expected number of antihypertensive medications, present in their blood or urine (²⁰). One of the defining features of renal-denervation therapy is that nonadherence is not an issue, because it is not characterized by the need for daily medication taking by the recipient once the procedure has been undertaken.

So where does one turn, in a debate, to find additional support beyond single published studies for one’s side of the discussion? Especially with word count, or time, limits we often turn to reviews of the topic favorable to our point of view. If we are really scrupulous (and lucky), we might find systematic reviews that have thoroughly covered the published literature in a particular area. Fortunately, just such a review appeared this year (²¹). It covered, in rigorous fashion, >3000 articles that touch on the topic of renal denervation and found 12 randomized clinical trials with 1539 people studied. To be fair, the investigation centered on uncontrolled hypertension, of which resistant hypertension is a subset. Their bottom line, using the best efficacy measure we have (ambulatory BP monitoring over 24 hours), showed that—compared with nondenervation therapy—renal denervation was associated with a 7–8 mm Hg greater systolic BP reduction over 24 hours.

Two other items regarding denervation approaches are worthy of consideration in this last point. The first is that a recent review comparing current costs of renal denervation therapy with standard of care for treatment-resistant hypertension found that renal denervation “would be cost-effective among patients with [treatment-resistant hypertension]” (²²). The second is that specifically intervening on resistant hypertension through sympathetic nerve ablation holds promise for reducing the complications of heart failure and arrhythmia, which are important problems for patients who are treatment resistant (²³).

Summing up, let’s revisit the debate question. Is there any role for device therapies in the treatment of resistant hypertension? The key is the use of the word “any.” I submit that the following simple points are reasonable arguments for considering the use of device therapies in resistant hypertension:

• they lower BP, similar to medications;
• they appear reasonably safe, for at least up to 3 years of follow-up; and
• unlike medications, these interventions do not need to be repeated in a daily fashion.

Let us also revisit the time period after the publication of SYMPLICITY HTN-3. Some thought the device-based intervention approach was dead on publication. However, a perhaps-optimistic look at the SYMPLICITY HTN-3 data showed that renal denervation effectively lowered systolic BP in the office and by ambulatory BP monitoring. The problem was the sham procedure also did, although not quite to the same degree. During the time after the publication of HTN-3 we revisited not only the putative effectiveness of the therapy, but also how well we managed the sham control group. The result was a series of more stringent protocols that are active in the current era. The most important modifications included an improved catheter design and protocol-driven antihypertensive drug testing to identify off-protocol medication usage. Fortunately, with respect to the current results, as the lawyers say, res ipsa loquitur.

Lastly, for our closing hymn, please turn with me to https://clinicaltrials.gov and use the search term “resistant hypertension,” applying the filters of “recruiting,” “not yet recruiting,” and “active not recruiting.” As of November 13, 2019 you will find, after applying these filters, 53 studies. Of these, 25 are using a device approach, seven are medication related, and the rest are a variety of lifestyle and other behavioral interventions. Resistant hypertension continues to be a significant public health problem and many of the current investigations into the area are using device-based approaches. Just sayin’.

Brothers and Sisters, the PROsecution rests its case.

Disclosures

R. Townsend reports consultant fees from Medtronic during the conduct of the study.