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A tale of two (disappointing) therapies
For years, the kidney has been a target of therapies to control hypertension, with the long-term hope of decreasing complications of heart disease, stroke, renal dysfunction and, possibly, mortality.
Renal artery (RA) stenting is straightforward, predictable and quite durable, with many reports suggesting a reduction in BP. Operators became proficient with the procedure, and many believed it was helpful and justified based on available data. Importantly, it was reimbursed. Subsequent results were disappointing, and these were hypothesized to be due to enrollment of excessively low-risk patients.
Timothy A. Mixon
The recently published CORAL trial was likewise disappointing, failing to show the expected benefits. Again, there was concern that excessively low-risk patients were enrolled and entry criteria were anatomic, not physiologic. One take-home message, however, was the impressive results of meticulous BP control. Whether credit goes to the expertise of hypertension (HTN) specialists, the effective armamentarium of available medications or simply the frequent and persistent follow-up, CORAL demonstrated that even patients with refractory hypertension were able to reach goal BP. Surely it would be difficult to improve CV outcomes vs. a cohort that achieves such excellent BP control.
Renal denervation (RDN), an entirely different approach to BP control that also involves interventional therapy in the RA, began to follow a similar course. Small, early, uncontrolled studies promised spectacular benefits. Hope and excitement in the interventional and HTN communities were high. Many envisioned the results of the large US pivotal trial as a foregone conclusion, a scientific “victory lap.” RDN became commercially available in Europe followed by widespread application (much like RA stenting had in the United States), including its use outside the narrow indication for three-drug refractory HTN in the early clinical trials.
SYMPLICTY HTN-3 was large, well designed and performed, and addressed prior trial design weaknesses. It included a control arm (receiving not only meticulous BP treatment, but also a sham procedure, mitigating a potential placebo effect), as well as better methods of BP evaluation (ambulatory monitoring). Although the full results have not been presented or published, an early statement (apparently designed to lower expectations) revealed the study had failed to meet the primary endpoint. Based on that limited information, it is unlikely that RDN will gain FDA approval in the near term, and the future of this technology in the United States is uncertain.
Here is what I think:
- There is great value to extensively studying procedures or medications before commercial use. Once therapies are commercially available, enrolling patients into clinical trials is more difficult, with potential enrollment bias.
- Adequate BP control can be achieved in many, despite the task being difficult. CORAL showed (and SYMPLICITY has hinted) that in fact, refractory HTN patients can be adequately controlled, albeit at the cost of multiple medications and close monitoring.
- RA stenting may not be “dead,” but it is critically ill. The onus is now fully on renal interventionalists to design and complete a trial with appropriate patients that demonstrates tangible benefits.
- RDN is not dead, but its future is uncertain. Many questions remain: Are we effectively denervating by “blind” ablation? What are the long-term benefits of altering sympathetic activity (eg, HTN control, renal function, HF)? Is it worthwhile (cost- and safety-wise) to perform in order to decrease medication usage?
That’s how I see it. What do you think?
Reference:
Cooper CJ. N Eng J Med. 2014;370:13-22.