COMMENTARY

Renal Denervation for Resistant Hypertension Is Not Back on Track

John Mandrola, MD

Disclosures

May 20, 2021

A systolic blood pressure (SBP) reduction of 4.5 mm Hg is not good enough—for an invasive procedure.

RADIANCE-HTN-TRIO Trial

At the virtual American College of Cardiology (ACC) 2021 Scientific Session, Ajay Kirtane, MD, from Columbia University in New York City, presented the results of RADIANCE-HTN TRIO. This global trial randomly assigned 136 patients (mean age, 52 years) with resistant hypertension to renal denervation with a novel ultrasound-based device or a sham procedure.

The primary endpoint, the change in daytime ambulatory SBP at 2 months, was reduced by about 8 mm Hg in the ultrasound group vs about 3 mm Hg in the sham arm. The median between-group change was –4.5 mm Hg. There were no safety issues.

Internal Validity Was Strong

The authors of RADIANCE-HTN TRIO learned a lot from the previous research on renal denervation. They took patients with resistant hypertension and first stabilized them on a fixed-dose combination pill containing 3 antihypertensive drugs. This enhanced medication adherence. The investigators reduced confounding by robust blinding procedures, use of imaging to plan ablation, and strictly limiting changes in meds after the intervention.

The strong methods isolated the effect of the procedure.

Two External Validity Concerns Emerge

The researchers screened nearly 1000 patients with "resistant hypertension" in order to enroll 136 patients. Most screened patients were excluded because blood pressures were too low.

RADIANCE-HTN TRIO confirms that most cases of resistant hypertension are not very resistant to proper medical treatment.

This is a major point because it speaks to the rarity of truly resistant hypertension. Notable also is that it took 4 years to recruit 136 patients from 53 centers. The trial enrolled its last patient in March 2020, so it's unlikely that the pandemic affected recruitment.

Another generalizability concern was the extremely short follow-up of 2 months. The authors emphasized this in the accompanying Lancet publication, but they also referenced two published papers that seemed to suggest optimism about the durable effects of renal denervation.

One was the 1-year follow-up of the RADIANCE-HTN SOLO trial, which used the same ultrasound-based system. This paper showed a sham-adjusted difference in daytime ambulatory blood pressure at 12 months of only –2.3 mm Hg. The other reference was the 3-year follow-up of an open-label registry of patients treated with renal denervation at 196 centers.  

Neither of those references persuades me. Durability remains a major question.

Is the Modest Drop in SBP Clinically Important?

In the case of RADIANCE-HTN TRIO, 5 factors argue against the clinical relevance of this modest decrease in SBP.

Presenter Kirtane noted that "although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure." The authors also mentioned the 8–mm Hg drop in BP from baseline in their report in The Lancet.

This should not be the message. The reason renal denervation trials have sham-control arms is to account for bias, such as regression to the mean. The effect of this treatment must be expressed as a sham-adjusted difference, which is –4.5 mm Hg. Anything else is pure spin.

The second concern is whether this more modest drop in SBP will reduce clinical outcomes, such as stroke, myocardial infarction, or kidney failure.

Blood pressure is not an outcome; it is a surrogate marker, a risk factor for future disease. This does not mean that treating severe hypertension isn't important. No one disputes that reducing very high blood pressure confers significant benefit.

The question for renal denervation proponents is whether an additional 4.5–mm Hg drop from baseline systolic blood pressures of 150 to 155 mm Hg will deliver a reduction in clinically relevant outcomes?  

The most recent meta-analysis of more than 344,000 patients from 48 randomized trials of BP-lowering medications found that a 5–mm Hg reduction in SBP reduced the risk for cardiac events by about 10% in relative terms.

That sounds strong, but the absolute risk reduction ranged from 3.7 to 6.0 fewer events per 1000 patient-years. That is a small difference.

My third concern is whether we can assume these modest gains would apply to patients with resistant hypertension. Are the highly selected patients in RADIANCE-HTN TRIO similar enough to everyday patients with hypertension? And do we even know the goal SBP in truly resistant hypertension?  

The SPRINT trial found that targeting a lower SBP (120 mm Hg vs 140 mm Hg) in patients at high cardiovascular risk lowered rates of major cardiovascular events. But SPRINT patients started at 140 mm Hg SBP, and most were taking only 1 to 2 antihypertensive agents. These patients were different from those in RADIANCE-HTN TRIO. As for the SBP goal, the benefits of lower blood pressure targets were not seen in patients with hypertension and diabetes in the ACCORD trial.

A fourth concern relates to the mechanism of BP lowering. Renal denervation likely works through reduction of sympathetic activity. β-Blockers also reduce blood pressure and sympathetic effects, but compared to other antihypertensive agents, they "have substantially less protective against stroke and overall mortality."

Finally, and perhaps most important, the addition of a generic diuretic, such as spironolactone or amiloride, might yield similar reductions in SBP in patients with resistant hypertension.

Patients enrolled in RADIANCE-HTN TRIO were receiving a combination of a calcium-channel blocker, an angiotensin-receptor blocker, and a thiazide diuretic. Before subjecting these patients to an invasive procedure, why not prescribe an inexpensive tablet?

J. Brian Byrd, MD, a hypertension expert at the University of Michigan, referred me to a paper in Annals of Internal Medicine that found biochemically proven primary aldosteronism in slightly more than 20% of patients with resistant hypertension. This could explain why spironolactone was far superior to placebo, bisoprolol, or doxazosin as an add-on drug in patients with resistant hypertension the PATHWAY-2 trial.

Byrd believes that the reason mineralocorticoid inhibition works so well for resistant hypertension is that many of these patients have relative (or milder) degrees of aldosteronism. He cited a substudy of PATHWAY-2 suggesting that resistant hypertension is commonly a salt-retaining state and responds to spironolactone and amiloride.

Conclusion

Recent studies of renal denervation alone (without medication) in patients with moderate hypertension using the same ultrasound-based system or a radiofrequency ablation–based strategy delivered about a 6.5–mm Hg decrease in SBP.

RADIANCE-HTN TRIO confirms these findings in patients with resistant hypertension.

But, of course, patients with moderate hypertension can achieve this degree of SBP reduction with an inexpensive tablet or perhaps weight loss and dietary changes.  For patients with resistant hypertension, RADIANCE-HTN TRIO reveals modest SBP reductions at 2 months. This is akin to page 1, chapter 1 of the entire story.

Proponents of renal denervation might argue that medications have side effects, lifestyle change is hard, and there is an unmet need in patients with resistant hypertension. All of which are true, but before we accept this invasive procedure as a substitute, we need much more evidence that short-duration drops in SBP of 4 to 6 mm Hg will actually reduce hard outcomes.

One thing that a career doing procedures makes clear: if renal denervation is approved and reimbursed, it will be heavily marketed and widely accepted by doctors and hospitals. Look to the vast expansion of left atrial appendage occlusion procedures as a guidepost.

And if this happens with renal denervation, we will spend limited healthcare dollars on yet another low-value therapy.

Societies cannot print money, so dollars spent on unproven procedures are dollars not available for providing basic care to everyone.

Byrd holds a National Institutes of Health grant investigating novel approaches to diagnosing excess mineralocorticoid receptor activation and has served on an advisory board for Phase Bio, which is developing an aldosterone synthase inhibitor.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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