经导管双侧肾动脉消融对顽固性高血压疗效存疑（SYMPLICITY HTN-3研究）

美敦力公司在2014年1月7日宣布在美国的一项肾去神经化（经导管双侧肾动脉消融）治疗顽固性高血压的关键性试验-SYMPLICITY HTN 3，没有能够达到预期的有效性终点。此项研究的主要终点是从基线到治疗后6个月收缩压的差值，本试验达到了预期的首要安全指标，并且该实验的数据安全监测委员会得出结论：该实验中不存在安全性问题。

“SYMPLICITY HTN 3达到了重要安全终点的目标，即在随机化后的一个月内的重大不良事件及6个月的肾动脉狭窄的发生率，”美敦力常务董事、实验的共同研究者Deepak L. Bhatt, M.D., M.P.H讲到，“然而更重要的是，这个实验没有达到预期的主要有效性终点”

George Bakris, M.D，美国高血压协会前任主席，该实验的另一位共同研究者讲到：“实验没有达到预期的首要有效性指标是很让人失望的，这是到目前为止关于肾去神经化最严谨的临床试验，是第一个包括了盲法对照的实验，我们希望相关数据进一步提交同行审议并能够提交发表及在即将到来的一个科学会议上提交讨论”

鉴于产品安全性的相关文件，以及SYMPLICITYHTN 3的发现，没有证据表明需要对采用symplicity 系统进行肾去神经化的患者给予特殊的干预，病人如果关于治疗有任何问题应该和医生进行积极的沟通。

在审查期间，该公司将采取以下行动：
  1. 停止在另外三个国家进行的肾去神经话实验病人的纳入，等到进一步的审批（SYMPLICITY HTN-4 in the U.S., HTN-Japan and HTN-India）。

  2. 在通过市场准入的地区，医生继续谨慎决定病人使用symplicity系统的适用情况。

  3. 继续全球symplicity上市后的售后监督以及评估肾去神经化在高血压外的相关适用情况。

“对于实验没能达到它的主要有效性终点感到失望，”美敦力公司医疗官Dr. Rick Kuntz讲到，“我们相信这一实验室是很严谨的，并且将帮助我们更好的评估这些发现并帮助我们决定肾去神经化下一步该去向何方，再次我们要感谢参加到临床试验的病人和研究者，感谢他们对高血压领域研究的重要贡献”。

因为此项重大研究失败，国际上顶尖心脏病专家对此产生大量评论：

Cardiologists Respond to SYMPLICITY HTN-3

Initial results from the SYMPLICITY HTN-3 trial tempered enthusiasm for the use of renal denervation for treatment-resistant hypertension. The results showed that Medtronic's system -- though safe -- was no better than a sham procedure for reducing office systolic blood pressure through 6 months.
MedPage Today reached out to get the reactions of leading cardiologists about the news.

Cindy Grines, MD, Detroit Medical Center
"I do not think this is the end of renal denervation. This may just be the wrong approach and/or learning curve issues with rolling out the study to multiple operators. There is ample data that renal denervation reduces blood pressure in animal models and in smaller human trials, and there are at least 30 different methods being tested to denervate the renal arteries. As a participant in this trial, it was technically difficult to assure that the radiofrequency probe was oriented correctly and that it was touching the wall of the renal artery. This may have resulted in the energy being dissipated into the bloodstream instead of into the vessel. Also, the nerves are very deep and the energy level may not have been high enough to penetrate."

Gregg Stone, MD, Columbia University Medical Center/New York-Presbyterian Hospital
"This is a very surprising result, entirely unexpected. We must withhold judgment until we review the data in detail to gain insight as to whether any subgroups might benefit, and what this means for other renal denervation technologies. Most importantly, however, given the clear therapeutic effect renal denervation had in the earlier nonblinded SYMPLICITY studies, this result underscores that a sham-controlled trial is essential in this kind of investigation. The 'power of the placebo' cannot be overemphasized."

Robert Safian, MD, Beaumont Health System
"In addition to being a huge disappointment for Medtronic and for other companies that are invested in the arena of resistant hypertension, this is an enormous disappointment to physicians and patients, who believed that there might be a new emerging treatment approach for refractory hypertension. ... At this point, it isn't clear if the failure of HTN-3 reflects a failure of renal denervation itself, or whether it reflects a failure of Medtronic's device. In the meantime, other companies with other devices (radiofrequency, high-frequency ultrasound, hypothermia, local injection of chemicals to ablate renal nerves) will be reconsidering their own programs. It is possible that renal denervation with another device will be effective for treating hypertension, even though Medtronic's device appears less effective for this purpose."

Robert Califf, MD, Duke University Medical Center
"Of course, it's dangerous to speculate, but the fact that SYMPLICITY HTN-3 was so carefully done with blinding and scientific rigor could provide another example of why we need proper clinical trials. This seemed like a 'slam dunk,' but obviously when put to the true test, it hasn't yet made the grade. If the result stands up, imagine the implications of proliferation of the technology before finding out if the technology actually provides real benefit."

Carl "Chip" Lavie, MD , John Ochsner Heart and Vascular Institute
"This is important, as there was a great amount of initial enthusiasm that this treatment may allow blood pressure (BP) to be controlled with less medication. Obviously, besides lowering BP, this therapy would have to be shown to reduce cardiovascular events and be cost-effective before it could ever be used in routine practice."

Kirk Garratt, MD, Lenox Hill Heart and Vascular Institute of New York
"All new technologies have ups and downs, but this finding is very important. Since this was the first study in a North American population, and the first to use a sham procedure in control patients, the negative findings have to make U.S. physicians question whether this approach can really improve blood pressure the way we'd all hoped. This might also cause other companies to reconsider their plans for clinical trials of renal denervation. That would be a terrible shame. One company recently announced it's halting a trial that was about to start. This is a very clever and safe technique that should be studied fully, so we can understand how it might be used to help people."

Sanjay Kaul, MD, MPH, Cedars-Sinai Medical Center
"Implausibly large treatment effects observed in uncontrolled and unblinded studies are typically unreliable and seldom replicable in rigorously controlled randomized trials. That is the major lesson from the SIMPLICITY HTN-3 trial. If the data are too good to be true, they usually are! It is too soon to abandon this procedure. We need to scrutinize the data first. If the treatment effect is attributable entirely to a sham effect, then it is difficult to see a future for renal denervation."

Howard Weintraub, MD, NYU Langone Medical Center
"The field of renal denervation had promise in the background of 'resistant hypertension.' The failure of this trial may be due to several factors. One is the pharmacologic treatment of resistant hypertension. In many cases the patient could be successfully managed with adjustment of drugs or doses. The other issue is clearly that resistant hypertension may be due to a variety of factors that would not have a robust response to renal denervation. I believe that the issue may not be 'dead,' but rather its use more limited to patients who have truly not responded to an appropriate regimen of anti-hypertensive agents. The fact that it met the safety endpoint is encouraging."

Duane Pinto, MD, MPH, Beth Israel Deaconess Medical Center
"While the 'top-line results' are certainly a setback in the development cycle for renal denervation, there is no question that this therapy affects blood pressure in certain individuals. There is obviously more analysis of the data obtained in this study. The challenge will now be to identify the right patients for this therapy and to determine the technical predictors of success. Nonpharmacologic treatments that control blood pressure will still remain of considerable interest given the size of the hypertensive population who are at risk for stroke, heart attack, and kidney failure. We still need methods to control resistant hypertension. Nevertheless, a major contribution of SYMPLICITY HTN-3 will be clinicians learning that many of these patients can achieve blood pressure control with medications and adopting the best practice models used in this trial."

Jon Resar, MD, Johns Hopkins Hospital
"I am surprised by the news. Hard to comment expansively without seeing the actual data but certainly disappointing news, especially in light of the European data. Will obviously need to follow the patients beyond 6 months. Maybe the benefit will be seen at a later time period. Safety endpoint is good but efficacy is certainly paramount."

Roxana Mehran, MD, Mount Sinai Hospital
"It is obviously disappointing to hear this news, although I reserve judgment until the full data are presented. I still believe that we need to step back and better understand this trial and the results before we shut out so many patients who may benefit from this type of therapy."

Timothy Mixon, MD, Baylor Scott & White Healthcare
"I think the cardiology and hypertension communities will be surprised at the preliminarily presented findings, based on previously reported and published studies to date. It is not unprecedented that a therapy believed to be helpful fails in a clinical trial; this simply reiterates the importance of well-performed trials, adequately powered for relevant clinical endpoints. Compared to prior studies of renal denervation, SYMPLICITY HTN-3 was much larger, had very rigorous entry criteria, including the first time that ambulatory blood pressure was evaluated (instead of simply office-measured blood pressure), and perhaps, most importantly, had a control group that was blinded to whether they received the therapy or not. This finding argues for avoiding the premature dissemination of therapies (whether medications or procedures) until they are thoroughly studied. This is sometimes difficult when the expectation of benefit is so high, and particularly when patients are aware of a therapy and are even calling to request it. In the short term, this means that renal denervation, although performed frequently in Europe and other parts of the world, will not be approved or available in the U.S. for the foreseeable future. There is still much to learn, and it is certainly possible that it ultimately will be performed in the U.S.

相关文献：
Froeschl M, Hadziomerovic A, Ruzicka M.Percutaneous Renal Sympathetic Denervation: 2013 and Beyond.Can J Cardiol. 2014 Jan;30(1):64-74.

Kandzari DE, Bhatt DL, Sobotka PA, O'Neill WW, Esler M, Flack JM, Katzen BT, Leon MB, Massaro JM, Negoita M, Oparil S, Rocha-Singh K, Straley C, Townsend RR, Bakris G.Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012 Sep;35(9):528-35.