On Monday, 28 August 28 2017 at 11 am, in the late breaking clinical trial session of the European Society of Cardiology (ESC) in Barcelona, the results of the SPYRAL HTN-OFF MED trial were reported and simultaneously published in the Lancet. Not surprisingly, the findings elicited a high level of interest because they stood in sharp contrast to those of SYMPLICITY HTN-3, a sham-controlled renal artery denervation (RDN) trial, which was sponsored by the same company (Medtronic) and published 3 years ago. As one may remember, this 535 patient blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after RDN as compared with a sham control. Irrational exuberance came to a grinding halt, ‘ugly facts refuted beautiful hypotheses’. We were invited to comment on these disappointing results and concluded our Editorial with ‘the SYMPLICITY studies merely document the natural history of resistant hypertension in clinical trials, and the time has come to turn the page on renal denervation for hypertension but by all means, let us not close the book’. Fortunately, the sponsor was committed to keep the book open and embarked on the SPYRAL HTN-OFF MED and ON MED studies. These studies were designed to address the potentially confounding factors identified in SYMPLICITY HTN-3 such as procedural variability, inconsistent patient drug adherence, and inclusion of patients less likely to benefit. Of note, the positive results reported at the ESC meeting were based on a pre-specified interim analysis on the first 80 randomized patients at the 3-month follow-up in the OFF MED study. The hypothesis of the SPYRAL HTN-OFF MED study was to confirm that RDN lowers blood pressure in untreated hypertension. Obviously, the most reliable method to control for the confounding effects of antihypertensive medications is to exclude them entirely. However, since in this preliminary report the sample size is small, the results have to be interpreted with great caution and by all means should not be extrapolated to patients who would not have fulfilled the rather strict inclusion criteria of SPYRAL HTN trials. What then are the major differences between SYMPLICITY HTN-3 and SPYRAL HTN-OFF MED trial? (Table 1). Based on the blood pressure inclusion criteria, patients with isolated systolic hypertension were virtually excluded in SPYRAL HTN. Also, since patients had to be taken off their antihypertensive drugs, they did not have resistant or accelerated hypertension. In fact, many patients were drug naı̈ve and wished to participate in the study in the hope that drug therapy could be avoided altogether. Not surprisingly, therefore, the study population of SPYRAL HTN-OFF MED was substantially younger than in SYMPLICITY HTN-3 and had much less severe hypertensive cardiovascular disease, presumably with less target organ damage. Sympathetic overactivity has been documented to occur in the early phases of hypertension as well as in the advanced stages with hypertensive heart disease. The present working hypothesis pertaining to the underlying mechanisms of RDN is that the procedure interrupts sympathetic fibres and reduces norepinephrine levels. One should also consider that irreversible changes may have occurred in a vascular tree that has been exposed to the ravages of hypertension for years and decades. Attesting to this are the findings of REGARDS; normotensive patients (systolic blood pressure <120 mmHg) on triple antihypertensive therapy exhibit a higher risk of stroke than those with stage 1 hypertension (systolic blood pressure 140–159 mmHg) on no medication. A young population with little or no target organ disease as in SPYRAL HTN-OFF MED should therefore be particularly susceptible to benefit from RDN. Conceivably when applied early, RDN may allow us to postpone pharmacological treatment for hypertension or at least to mitigate it. Of note, the achieved decrease in BP in SPYRAL HTN-OFF MED has to be seen in proper context. When compared to antihypertensive efficacy of standard drug classes as measured by 24-hour ambulatory BP monitoring the decrease of 5.5/4.8 mmHg seems to be rather paltry (Figure 1). Importantly, safety data of the procedure have been satisfactory; subsequent renal artery stenosis has been reported, but overall renal function has been found to be stable after 12 months. However the benefits of RDN, if any, have so far only been defined by the not infallible surrogate endpoint of blood pressure. Only a prospective randomized trial looking at the

中文翻译：

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肾去神经支配：凤凰涅槃重生？

2017 年 8 月 28 日星期一上午 11 点，在巴塞罗那欧洲心脏病学会 (ESC) 的最新临床试验会议上，SPYRAL HTN-OFF MED 试验的结果被报告并同时发表在《柳叶刀》上。毫不奇怪，这些发现引起了高度的兴趣，因为它们与 SYMPLICITY HTN-3 的结果形成鲜明对比，SYMPLICITY HTN-3 是一项由同一家公司（美敦力）赞助并发表了 3几年前。正如人们可能记得的那样，这项 535 名患者的盲法试验并未显示与假对照相比，RDN 后 6 个月顽固性高血压患者的收缩压显着降低。非理性的繁荣戛然而止，“丑陋的事实驳斥了美丽的假设”。我们受邀对这些令人失望的结果发表评论，并以“SYMPLICITY 研究仅记录了临床试验中顽固性高血压的自然病程，现在是时候翻开高血压肾神经支配的一页了，但无论如何，让我们我们不合上书'。幸运的是，赞助商承诺让这本书保持开放状态，并着手进行 SPYRAL HTN-OFF MED 和 ON MED 研究。这些研究旨在解决 SYMPLICITY HTN-3 中确定的潜在混杂因素，例如程序变异性、患者药物依从性不一致以及纳入不太可能受益的患者。值得注意的是，在 ESC 会议上报告的阳性结果是基于对 OFF MED 研究中 3 个月随访时前 80 名随机患者的预先指定的中期分析。SPYRAL HTN-OFF MED 研究的假设是确认 RDN 可降低未经治疗的高血压患者的血压。显然，控制抗高血压药物混杂作用的最可靠方法是完全排除它们。然而，由于本初步报告中的样本量很小，因此必须非常谨慎地解释结果，并且无论如何不应将其外推到不符合 SPYRAL HTN 试验相当严格的纳入标准的患者。那么 SYMPLICITY HTN-3 和 SPYRAL HTN-OFF MED 试验之间的主要区别是什么？（表格1）。根据血压纳入标准，SPYRAL HTN 实际上排除了单纯收缩期高血压患者。此外，由于患者不得不停用抗高血压药物，他们没有抵抗性或加速性高血压。事实上，许多患者未接触药物，希望参与研究，希望可以完全避免药物治疗。因此，毫不奇怪，SPYRAL HTN-OFF MED 的研究人群比 SYMPLICITY HTN-3 中的研究人群要年轻得多，并且高血压心血管疾病的严重程度要低得多，可能靶器官损伤也更少。交感神经过度活跃已被证明发生在高血压的早期阶段以及高血压心脏病的晚期阶段。目前关于 RDN 潜在机制的工作假设是该过程中断了交感神经纤维并降低了去甲肾上腺素水平。人们还应该考虑到，多年来一直受到高血压蹂躏的血管树可能已经发生了不可逆转的变化。REGARDS 的调查结果证明了这一点；接受三联降压治疗的血压正常患者（收缩压 <120 mmHg）比未接受药物治疗的 1 期高血压患者（收缩压 140-159 mmHg）具有更高的卒中风险。因此，像 SPYRAL HTN-OFF MED 中很少或没有靶器官疾病的年轻人群应该特别容易从 RDN 中受益。可以想象，在早期应用时，RDN 可以让我们推迟对高血压的药物治疗或至少减轻它。值得注意的是，在 SPYRAL HTN-OFF MED 中实现的血压降低必须在适当的背景下看到。与通过 24 小时动态血压监测测量的标准药物类别的抗高血压功效相比，5.5/4.8 mmHg 的下降似乎微不足道（图 1）。重要的是，该程序的安全数据令人满意；有报道随后出现肾动脉狭窄，但发现 12 个月后整体肾功能稳定。然而，到目前为止，RDN 的好处（如果有的话）仅由血压这一并非绝对可靠的替代终点来定义。只有一项前瞻性随机试验研究 但已发现 12 个月后整体肾功能稳定。然而，到目前为止，RDN 的好处（如果有的话）仅由血压这一并非绝对可靠的替代终点来定义。只有一项前瞻性随机试验研究 但已发现 12 个月后整体肾功能稳定。然而，到目前为止，RDN 的好处（如果有的话）仅由血压这一并非绝对可靠的替代终点来定义。只有一项前瞻性随机试验研究