对STEMI患者的非梗死冠脉实施PCI有益

阿姆斯特丹——一项纳入465例患者的随机多中心试验显示，在急性ST段抬高性心肌梗死(STEMI)患者中，对未引起梗死的狭窄冠脉和导致梗死的病变血管均置入支架，结局明显优于仅对梗死相关狭窄实施支架置入术。

这一结果似乎反驳了各心脏病学会的建议——在急性STEMI治疗过程中应限制经皮冠脉介入(PCI)的使用，仅用于梗死相关病灶，尤其是在次要病灶并未明确导致持续血液动力学不稳定的情况下。

英国伦敦大学玛丽皇后学院Wolfson预防医学研究所的David S. Wald博士在欧洲心脏病学会(ESC)年会上报告称，这一新发现明确了“对于顽固性心绞痛或随后发生心肌梗死的患者而言，预防性PCI是比限制进一步干预更好的策略”。该研究同时发表在《新英格兰医学杂志》在线版上(N. Engl. J. Med. 2013 [doi:10.156/NEJMoa1305520])。

现行的STEMI治疗指南建议仅对梗死相关动脉实施PCI(Eur. Heart J. 2012;33:2569-619；Circulation 2013;127:529-55)，主要原因是迄今为止尚无充分证据表明其他策略对患者更有益。“这种不确定性已导致临床实践中的做法不一致，一些心脏科医生不依从指南而实施即刻预防性PCI，一些医生等患者度过急性期之后再实施预防性PCI，其他医生则仅对反复出现症状或有缺血证据的患者进行这一操作。”

这项名为急性心肌梗死中的预防性血管成形术(PRAMI)的临床试验从5家英国医院连续招募了2008年4月~2013年1月的所有年龄患者。该研究主要针对STEMI患者，原因是NSTEMI患者常常并无明显可识别的梗死相关动脉。而且，入组患者还必须满足以下条件：梗死相关动脉已经被PCI成功治疗，至少有1条可接受PCI治疗、狭窄程度小于50%的其他冠脉。排除冠脉解剖学更适宜旁路手术治疗的患者。入组患者的平均年龄为62岁，约3/4为男性，约18%合并糖尿病。大约2/3的患者有狭窄程度超过50%的第二条冠脉，其余患者有两条冠脉存在明显病变。

在成功治疗梗死相关动脉之后，有适宜接受PCI治疗的其他明显病灶的患者被随机分组，在同一次PCI术中处理其他的明显病灶，或者不接受进一步干预。结果在被随机分至积极干预组的234例患者中，人均有1.36条额外动脉接受了PCI治疗。

在PCI术后，所有患者均接受标准内科治疗：每日服用阿司匹林和另一种抗血小板药物——氯吡格雷(波立维)、普拉格雷(Effient)或替卡格雷(Brilinta)。两组中均有约95%的患者还使用了一种他汀类药物，约90%使用了一种β受体阻断剂和一种血管紧张素转换酶抑制剂(ACEI)。

在平均23个月的随访期间，心源性死亡、非致死性心肌梗死或顽固性心绞痛的复合发生率——该研究的主要终点——在立即接受非梗死相关狭窄冠脉PCI的患者中为9%，在对照组231例患者中为23%，差异有统计学意义。两组间14%的绝对差异相当于65%的相对差异。接受额外PCI 的患者在心导管室中发生心源性死亡或非致死性心肌梗死的比例为5%，仅治疗梗死相关动脉的患者为12%，也具有统计学差异。

进一步分析还显示，同时治疗多支冠脉的患者发生非致死性心肌梗死和顽固性心绞痛的比例均明显更低，而且有心源性死亡更少的强烈趋势。

上述结果实质上并不受患者年龄、性别、糖尿病状态、梗死部位或明显狭窄冠脉数量的影响。而且，并发症(包括操作相关卒中、需要输血或手术的出血，以及需要透析的造影剂诱导性肾病)发生率在两组中相似。

这一结果与既往两项随机试验的结果一致，后者也评估了预防性PCI对急性STEMI患者的价值，不过患者数较少。其中一项研究共纳入了69例患者(Int. J. Cardiovasc. Intervent. 2004;6:128-33)，另一项共纳入了214例患者(Heart 2010;96:662-7)，二者均不具有统计学效力，而且均将再次血管重建作为一项终点，Wald博士指出这可能会引起偏倚。

不过Wald博士也承认，这项研究并未解决“采用分阶段处理方法，对明显的非梗死相关狭窄延迟实施预防性PCI治疗，是否对患者更有益？”、“是否应当将治疗范围扩大至闭塞不到50%的非梗死性狭窄冠脉？”以及“相似的治疗策略是否对非ST段抬高性心肌梗死(NSTEMI)患者也有益？”等问题。

Wald博士承认自己是Polypill公司的一名主管并且是该公司持股人。

随刊述评：扩大PCI治疗STEMI的范围是有希望的

Laura Mauri医生评论指出：根据这篇来自PRAMI试验的报告，我们不能再假定急性心肌梗死中的次要病灶是无辜的了(N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1309383])。

“对非梗死病灶实施PCI不能预防死亡或心肌梗死”一直是介入心脏病学的一个核心观点。心脏科医生已经习惯于只积极治疗梗死病灶，而且在患者出现症状之前通常不会给予进一步治疗。但是与稳定型心绞痛患者相比，急性STEMI患者早期出现复发事件的风险明显增高。为什么？冠脉疾病往往伴随着凝血、炎症和内皮功能障碍等全身性异常，有多处炎性病灶。急性冠脉综合征(ACS)患者在这些方面有显著的全身性紊乱。PRAMI试验中采用的积极早期治疗策略或许可使这些不那么无辜的病灶趋于稳定。

PRAMI试验的结果提示，急性STEMI患者体内并不存在健康的冠脉。这是否意味着这些患者需要接受更大范围的血管重建治疗呢？来自非梗死病灶的风险似乎是独立于其血液动力学严重性的。

这项研究采用的策略迥异于当前临床实践。指南已经告诫我们在急性STEMI过程中不要同时治疗多条血管，尤其是当次要部位并未明确导致当前的血液动力学不稳定时。PRAMI结果提示，对急性STEMI患者扩大介入治疗范围是一条有希望的途径。

Mauri医生是布里格姆妇女医院的介入心脏科医生、哈佛大学的内科学教授、哈佛临床研究所的首席医学官。她担任了Biotronik和圣裘德公司的顾问，接受了另外7家药物或器械生产商提供的研究资助。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

AMSTERDAM – In patients with acute ST-segment elevation myocardial infarction, stenting of significant coronary stenoses not responsible for the infarction as well as the infarct-producing lesion led to substantially better outcomes than an intervention that only targeted the infarct-related stenosis in a randomized, multicenter trial with 465 patients.

The results appeared to refute the prevailing recommendation from cardiology societies to limit the percutaneous coronary intervention (PCI) done during acute treatment of ST-segment elevation myocardial infarction (STEMI) to the infarct-related lesion, especially when the secondary lesions are not clearly causing ongoing hemodynamic instability.

The new findings "make it clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction," Dr. David S. Wald reported on Sept. 1 at the annual congress of the European Society of Cardiology. Simultaneous with Dr. Wald’s report, the results appeared in an article published online (N. Engl. J. Med. 2013 [doi:10.156/NEJMoa1305520]).

Current guidelines on management of STEMI recommend PCI for the infarct-related artery only (Eur. Heart J. 2012;33:2569-619; Circulation 2013;127:529-55), primarily because, until now, scant evidence existed that a different strategy helped patients. "This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia," noted Dr. Wald, an interventional cardiologist at the Wolfson Institute of Preventive Medicine of the Queen Mary University of London.

Dr. Wald acknowledged, however, that his study did not address whether patients would be better served by a staged approach that delayed preventive PCI of significant, noninfarct related stenoses in a second PCI procedure, whether the benefits extend to treating noninfarct stenoses that occlude less than half of a coronary artery, and whether a similar strategy would help patients with non-ST–elevation MI (NSTEMI).

The Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial enrolled consecutive patients of any age at five U.K. centers during April 2008 to January 2013. The study focused on STEMI patients because patients with a NSTEMI often do not have a clearly identifiable infarct-related artery. In addition, to qualify for entry, the patient’s infarct-related artery had to have been successfully treated by PCI and they had to have at least one other coronary artery with at least 50% stenosis judged treatable by PCI. Patients with coronary anatomy more appropriately treated with bypass surgery were excluded. The enrolled patients averaged 62 years of age, about three-quarters were men, and about 18% had diabetes. Roughly two-thirds had a second coronary artery with a greater than 50% stenosis, and the remaining patients had two coronary arteries with a significant lesion.

After successful treatment of the infarct-producing artery, patients with additional, significant lesions judged appropriate for PCI were randomized to either have their other significant lesions treated during the same procedure or to undergo no further intervention. This resulted in an average of 1.36 additional arteries undergoing PCI in the 234 patients randomized to the more aggressive protocol.

Following the PCI procedures, all patients received standard medical treatment: daily treatment with aspirin and a second antiplatelet drug, clopidogrel (Plavix), prasugrel (Effient), or ticagrelor (Brilinta). About 95% of patients in both study arms also received treatment with a statin, and about 90% received a beta-blocker and an angiotensin-converting enzyme inhibitor.

During an average follow-up of 23 months, the combined rate of death from cardiac causes, nonfatal MI, or refractory angina – the study’s primary endpoint – occurred in 9% of the patients randomized to immediate PCI of their noninfarct-related stenoses and in 23% of the 231 patients in the control arm, a statistically significant difference. The 14-percentage-point absolute reduction in endpoints translated into a 65% relative risk reduction. The rate of cardiac death or nonfatal MI was 5% in the patients who received added PCI while in the catheterization laboratory and 12% among those only treated in their infarct-related artery, also a statistically significant difference.

Additional analyses also showed statistically significantly lower rates of both nonfatal MI and refractory angina in the patients treated in multiple arteries when these endpoints were tallied individually and a strong trend toward fewer cardiac deaths in these patients as well. Kaplan-Meier analysis showed that the risk reduction in the preventive-PCI group was evident after 6 months of follow-up and then increased with continued follow-up.

These results were not materially affected by patient age, sex, diabetes status, infarct location, or the number of coronary arteries with significant stenoses. In addition, the complication rates, including procedure-related strokes, bleeding requiring transfusions or surgery, and contrast-induced nephropathy requiring dialysis, were similar in the two study arms.

The results were consistent with reports from two prior randomized trials that also assessed the value of preventive PCI in patients with acute STEMI, but in fewer patients. One of these prior studies involved a total of 69 patients (Int. J. Cardiovasc. Intervent. 2004;6:128-33), and the second enrolled a total of 214 patients (Heart 2010;96:662-7); both were limited by a lack of statistical power, and both relied on repeat revascularization as an endpoint, which may be subject to bias, Dr. Wald said.

Dr. Wald said that he a director for and shareholder in Polypill Ltd.

Commentary – Broadening scope of STEMI PCI holds promise

Dr. Laura Mauri comments: Based on this report from the PRAMI trial, we can no longer assume that secondary lesions in acute myocardial infarction are innocent until proven guilty.

It has been a core belief in interventional cardiology that percutaneous coronary intervention in noninfarct lesions does not prevent death and MI. Cardiologists have refrained from treating anything but the infarct lesion acutely, and they usually withhold further treatment unless a patient is symptomatic.

But patients with acute ST-segment elevation MI have a substantial risk for early, recurrent events, in contrast to patients with stable angina. Why? Coronary artery disease is accompanied by systemic abnormalities in coagulation, inflammation, and endothelial function, with multiple inflamed lesions. Patients with acute coronary syndrome have prominent, systemic derangements in these processes. The aggressive, acute treatment used in PRAMI may have stabilized these not-so-innocent lesions.

The PRAMI findings suggest that there are no healthy coronary arteries in a patient with acute STEMI. Does this mean that these patients need extensive revascularization? It is plausible that the risk from noninfarct lesions is independent of their hemodynamic severity.

The strategy employed in this study differs markedly from current practice. Guidelines have cautioned against treating multiple vessels during acute STEMI, particularly when the secondary sites are not clearly causing ongoing hemodynamic instability. The PRAMI results suggest that widening the scope of interventional therapy in acute STEMI patients is a promising new approach to management.

Dr. Mauri is an interventional cardiologist at Brigham and Women’s Hospital, professor of medicine at Harvard University, and chief scientific officer of the Harvard Clinical Research Institute in Boston. She has been a consultant to Biotronik, has been on an advisory board of St. Jude, and she has received research grants from seven other drug or device-manufacturing companies. She made these comments in an editorial that accompanied the published version of the PRAMI report (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1309383]).