第一部分 左主干冠状动脉介入治疗术后围术期心肌生物标志物升高和围术期心肌梗死的预后价值

 

摘要

背景: 左主干（Left main，LM）病变患者经皮冠状动脉介入治疗（Percutaneous coronary intervention, PCI）术后常发生围术期心肌生物标志物升高（即围术期心肌损伤）和围术期心肌梗死 （Periprocedural myocardial infarction, PMI）。PMI的发生率依赖于心肌生物标志物和PMI定义的选择。目前关于PCI相关PMI的争议点存在于: 1）最优的心肌生物标志物选择（肌酸激酶同工酶或心肌肌钙蛋白）；2）最优的具有临床预后意义的术后心肌标志物升高阈值；3）心电图，造影，和影像学等新发心肌缺血证据在判定PMI中的价值；4）何种PMI定义具有远期心血管死亡及全因死亡的预测价值。

 

目的: 本研究旨在探讨左主干病变患者接受PCI术后，1）术后肌酸激酶同工酶（Creatine kinase-myocardial band，CK-MB）和心肌肌钙蛋白（Cardiac troponin，cTn）升高的不同阈值与远期心血管死亡及全因死亡事件的关联性；2）不同的PMI定义对远期心血管死亡及全因死亡的预测价值。

 

方法: 研究前瞻性连续入选从2004年1月至2016年12月，就诊于中国医学科学院阜外医院接受左主干PCI的患者。常规收集术前和术后8至48小时内的心肌标志物（CK-MB和cTnI），以及患者术前及术后心电图，冠脉造影和心脏影像学检查的数据。将CK-MB分成间隔为（<1×，≥1×至<3×，≥3×至<5×，≥5×至<10×，和≥10×正常参考值上限[Upper reference limit, URL]），cTn分成间隔为（<1×，≥1×到<5×，≥5×到<35×，≥35×到<70×，和≥70×URL），应用单因素和多因素Cox比例风险模型，进行生存分析，并计算风险比（Hazard ratio, HR）和95%可信区间（Confidence interval, CI）。PMI定义依据美国心血管造影和介入学会（Society for Cardiovascular Angiography and Interventions，SCAI），学术研究联合会（Academic Research Consortium-2, ARC-2），和第四版心肌梗死通用定义（Universal Definition of Myocardial Infarction , UDMI）进行判定。研究的主要终点是变量调整的3年心血管死亡事件率，次要终点是变量调整的3年全因死亡事件率。

 

结果：本次分析共纳入4013例LM PCI患者，平均年龄60.1岁，80.6%的患者为LM分叉病变，分别有4008（99.9%）和2038（50.8%）的患者有术前和术后连续测量的CK-MB和cTnI数值，根据SCAI，ARC-2，和第四版UDMI定义的PMI发生率分别是1.3%，3.1%，和5.1%。3年心血管死亡率随着 CK-MB 峰值的升高而逐渐增加（log-rank P<0.001）。以术后CK-MB峰值＜1×URL当做参照，术后CK-MB峰值升高到3-5×URL时，与3年心血管死亡有独立的相关性（校正后HR：2.93；95% CI：1.02-8.40）。术后CK-MB峰值升高到5-10×URL（校正后HR：4.12；95% CI：1.55-10.93）和≥10×URL（校正后HR：5.46；95% CI：2.08-14.37）的患者3年心血管死亡风险更高。术后CK-MB峰值升高到≥10×URL可预测3年全因死亡风险（校正后HR：3.25；95% CI：1.37-7.70）。相比之下，术后 cTnI 峰值升高水平与3年心血管死亡和全因死亡无关。SCAI定义的PMI与3年心血管死亡（校正后HR：4.93；95% CI：1.92-12.69）和全因死亡（校正后HR：3.11；95% CI：1.33-7.27）显著相关，而ARC-2和第四版UDMI定义的PMI则不能预测远期心血管死亡和全因死亡风险。

 

结论：连续入组的大型LM PCI队列显示，CK-MB≥3×URL即可预测3年心血管死亡风险，CK-MB≥10×URL可以预测3年全因死亡风险，而术后cTnI则不能有效预测3年心血管死亡和全因死亡。SCAI定义的PMI可以预测LM PCI术后远期心血管死亡和全因死亡事件，而ARC-2和4th UDMI定义预测价值不足。

 

 

第二部分 高危急性冠脉综合征患者冠状动脉介入治疗术后

最佳抗血小板时长探索

 

摘要

背景: 最近的研究发现经皮冠状动脉介入治疗（Percutaneous coronary intervention, PCI）术后缩短双联抗血小板治疗（Dual antiplatelet therapy，DAPT）时长可在不影响疗效的情况下降低出血风险。然而目前欧美及中国指南推荐根据临床表现，患者出血与缺血风险来优化DAPT时长。缩短DAPT时长的方案可能忽视了急性冠脉综合征（Acute coronary syndrome，ACS）患者远期再次发生自发性动脉粥样硬化血栓形成事件的残余风险。

 

目的: 本研究旨在分析延长（>12个月）DAPT疗程相比缩短或标准DAPT时长（≤12个月）方案在真实世界接受PCI治疗的高危“TWILIGHT样”ACS患者队列中的疗效和安全性。

 

方法: 研究前瞻性连续入选从2013年1月至2013年12月，就诊于中国医学科学院阜外医院接受药物洗脱支架（Drug-eluting stent，DES）置入的PCI患者。根据TWILIGHT研究的入选标准（至少1个临床危险因素[年龄≥65岁，女性，慢性肾脏病，ACS，既往确诊的动脉粥样硬化血管疾病病史，或需要治疗的糖尿病]和至少1个造影危险因素[多支血管病变，支架总长度>30 mm，血栓性靶病变，分叉病变置入2个支架，左主干或前降支近端病变，或接受冠状动脉斑块旋磨术的钙化病变]），共计8358例患者符合TWILIGHT研究入选标准，判定为高危（高缺血或高出血风险）PCI人群，其中5404例为高危ACS患者。主要研究终点为主要不良心脑血管事件（Major adverse cardiac and cerebrovascular events，MACCE），定义为30个月内的全因死亡、心肌梗死或卒中构成的复合终点。关键次要终点为30个月内的出血学术研究联合会（Bleeding Academic Research Consortium，BARC）定义的2、3或5型出血。采用多因素Cox比例风险模型和倾向性匹配评分方法（Propensity score-matching，PSM）计算风险比（Hazard ratio, HR）和95%可信区间（Confidence interval, CI）。

 

结果：本次分析共纳入4875例PCI术后12个月内没有不良心血管事件的ACS人群。研究中位随访时间为28.8个月（四分位间距：26.5-31.0个月），其中68.4%（n=3335）的ACS患者延长DAPT超过12个月。延长DAPT疗程超过12个月相比DAPT≤12个月显著降低了主要不良心脑血管事件终点（1.5% vs. 3.8%；校正后HR：0.374；95% CI：0.256-0.548；匹配后HR：0.361, 95% CI: 0.221-0.590）。延长DAPT时长方案降低了心血管死亡风险，在心肌梗死和支架内血栓方面保持一致的获益趋势，其中心血管死亡的HR为 0.049（95% CI：0.007-0.362），心肌梗死的HR为 0.45（95% CI：0.153-1.320），明确或可能的支架内血栓HR为 0.296（95% CI：0.080-1.095）。BARC 2、3或5型出血风险（0.9% vs. 1.3%；校正后HR：0.668；95% CI：0.379-1.178；匹配后HR：0.721, 95% CI: 0.369-1.410）在两组中未达到统计学差异。

 

结论：在接受PCI的高危ACS患者中，与DAPT时长 ≤12个月相比，延长DAPT超过12个月降低了主要不良心脑血管事件，且不增加安全性出血事件风险，表明对于具备高缺血且低出血风险的ACS患者可以考虑延长DAPT时长的方案以达到最优的临床净获益。

 

 

第三部分 复杂经皮冠状动脉介入治疗与高出血风险

对患者远期预后的影响

 

摘要

背景: 复杂经皮冠状动脉介入治疗（Percutaneous coronary intervention，PCI）与高出血风险（High bleeding risk，HBR）对冠状动脉药物洗脱支架（Drug-eluting stents，DES）置入后患者远期不良心血管事件的影响尚未完全阐明。

 

目的: 本研究旨在分析1）与非复杂PCI相比，接受复杂PCI手术（complex PCI）患者远期缺血和出血事件风险，2）探讨HBR对复杂PCI与远期临床结局的影响。

 

方法: 研究前瞻性连续入选从2013年1月至2013年12月，就诊于中国医学科学院阜外医院接受DES置入的PCI患者。复杂PCI定义为至少具有以下特征之一：处理3支血管病变、置入 ≥3个支架、处理 ≥3个病变、分叉病变置入2个支架、支架总长度>60 mm、处理慢性完全闭塞病变、无保护左主干 PCI、靶病变为支架内再狭窄、接受冠状动脉斑块旋磨术的严重钙化病变。HBR患者定义为PARIS出血评分 ≥8分。主要缺血终点为主要不良心血管事件（Major adverse cardiovascular events，MACE），定义为心原性死亡，心肌梗死，支架内血栓，和靶病变血运重建构成的复合终点。主要缺血终点为出血学术研究联合会（Bleeding Academic Research Consortium，BARC）定义的2、3或5型出血。

 

结果：本研究中位随访时间为 29 个月。在多因素Cox回归分析中，与非复杂PCI 相比，接受复杂PCI手术的患者发生MACE事件的风险更高（7.7% vs. 4.5%；校正后风险比[Hazard ratio，HR]：1.63，95%置信区间 [Confidence interval, CI]：1.38-1.92；P<0.001），风险差异主要由心肌梗死（校正后HR：2.16，95% CI：1.62-2.87），支架内血栓（校正后HR：2.71，95% CI：1.66-4.41），和靶血管血运重建（校正后HR：1.59，95% CI：1.29-1.95）事件驱动。相反，接受复杂PCI手术的患者不增加临床相关BARC 2、3或5型出血的风险（2.4% vs. 2.9%，校正后HR：0.86，95% CI：0.86-1.11；P=0.238）。无论是否存在HBR，复杂PCI对远期MACCE事件（调整后的交互作用P值=0.388）和临床相关出血事件（调整后的交互作用P值=0.279）的影响保持一致，没有统计学显著的交互作用，但复杂PCI合并HBR患者缺血和出血事件发生率均最高。

 

结论：接受复杂PCI手术的患者远期MACE，心肌梗死，支架内血栓，再次血运重建等缺血事件发生风险更高，而不会增加临床相关出血事件风险，提示强化的抗血小板治疗可能在接受复杂PCI手术的患者中获益。

Part I Prognostic Significance of Periprocedural Myocardial Biomarker Elevations and Periprocedural MI in Patients Undergoing PCI for Left Main Disease

 

Abstract

Background: Periprocedural myocardial injury occurs frequently in the complex setting of percutaneous coronary intervention (PCI) in left main (LM) lesions. To date, there is conflicting evidence on the magnitude for post-procedural biomarker elevations representing a clinically meaningful periprocedural myocardial infarction (PMI) in patients after LM PCI. Despite several diagnostic criteria and revisions of PMI have been proposed over the years, the preferred post-PCI cardiac biomarker (creatine kinase myocardial band [CK-MB] or cardiac troponin [cTn]) after LM PCI representing periprocedural myocardial injury related to worsening prognosis has not been settled, and whether varying definitions of PMI have differing prognostic implications in real-world LM PCI patients remains unknown.

 

Objective: We sought to 1) evaluate the association of different thresholds of CK-MB or cTnI with long-term mortality risk and 2) assess the differential prognostic significance of PMI according to various MI definitions from a large contemporary cohort of LM PCI patients.

 

Methods: The study prospectively enrolled 4,013 consecutive LM PCI patients at a single center from January 2004 to December 2016. Levels of CK-MB and cTnI were routinely collected at baseline and every 8 hours for 24 hours after PCI, and daily thereafter. Supporting electrocardiographic, angiographic, and imaging evidence new myocardial ischemia were independently assessed. PMI was adjudicated by the Society for Cardiovascular Angiography and Interventions (SCAI), Academic Research Consortium-2 (ARC-2), and fourth Universal Definition of Myocardial Infarction (UDMI) definitions. The primary and secondary endpoints were cardiovascular and all-cause death at 3 years, respectively. Cox proportional hazards regression was used to estimate unadjusted and adjusted hazard ratios of 3-year cardiovascular and all-cause death according to different cutoff values of CK-MB (<1, ≥1 to <3, ≥3 to <5, ≥5 to <10, and ≥ 10× URL) and cTnI (<1, ≥1 to <5, ≥5 to <35, ≥35 to <70, and ≥ 70× URL). The relationship between each SCAI, ARC-2, and fourth UDMI-defined PMI type and long-term mortality was examined.

 

Results: Among 4,013 LM PCI patients, 4,008 (99.9%) had serial CK-MB measurements and 2,038 (50.8%) had serial cTnI values. The 3-year rate of cardiovascular mortality progressively increased with higher peak CK-MB values, in which intermediate post-procedural CK-MB (3 to 5× upper reference limit [URL]) levels predicted cardiovascular death (adjusted hazard ratio [HR]: 2.93; 95% CI: 1.02 to 8.40, P=0.045), with an adjusted HR of 4.12 (95% CI: 1.55 to 10.93, P=0.005) in those with post-procedural CK-MB levels of 5 to 10× URL and 5.46 (95% CI: 2.08 to 14.37, P=0.001) in ≥10×URL. In contrast, no level of peak post-procedural cTnI was associated with cardiovascular death. Extensive myonecrosis (post-procedural CK-MB ≥10×URL, adjusted HR: 3.25; 95% CI: 1.37 to 7.70, P=0.007), instead of cTnI ≥70×URL, was prognostic for all-cause mortality at 3 years. The rates of PMI by SCAI, ARC-2, and 4th UDMI criteria were observed in 53 (1.3%), 125 (3.1%), and 203 (5.4%) patients, respectively. Compared with ARC-2 and fourth UDMI definitions of PMI, SCAI-defined PMI was more accurate and clinically relevant for predicting 3-year cardiovascular death (adjusted HR: 4.93; 95% CI: 1.92 to 12.69, P=0.001) and all-cause death (adjusted HR: 3.11; 95% CI: 1.33 to 7.27, P=0.009).

 

Conclusions: In this large-scale LM PCI cohort, lower levels of peak post-procedural CK-MB elevations (CK-MB ≥3×URL) provided prognostic implication for 3-year cardiovascular death and substantial myonecrosis (CK-MB ≥10×URL) was independently associated with increased 3-year all-cause mortality. Even large degrees of post-procedural cTnI elevation was not prognostically significant. For several definitions of PMI in widespread use, SCAI-defined PMI was most accurate and clinically relevant for predicting hard endpoints at 3 years.

 

Part II Optimal Duration of Dual Antiplatelet Therapy Among High-risk Patients with Acute Coronary Syndrome undergoing PCI

 

Abstract

Background: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor is necessary to prevent thrombotic events in culprit lesions and recurrent atherothrombotic events being related to nonculprit lesions among patients undergoing PCI. However, there is concern of an increased risk in major bleeding with extended DAPT. A heightened predisposition to atherothrombotic events following an acute coronary syndrome (ACS) may persist more than 1 year. Abbreviated DAPT strategy after PCI irrespective of indication for PCI may increase the substantial residual risk of de novo atherothrombotic lesions in the entire coronary arterial bed in ACS patients.

 

Objective: The main objective of this study was to determine the efficacy and safety of prolonged-term (>12-month) DAPT versus ≤12 months of DAPT with regard to ischemic and bleeding events in high-risk “TWILIGHT-like” patients undergoing PCI for an ACS in a large and contemporary PCI cohort.

 

Methods: We conducted this retrospective analysis using the data from the prospective Fuwai PCI registry of 10,167 consecutive patients undergoing PCI with drug-eluting stents (DES) implantation. High-risk patients (n = 8,358) fulfilling the “TWILIGHT-like” criteria were defined by at least one clinical and one angiographic feature according to TWILIGHT trial inclusion criteria. Of these, 5,404 high-risk “TWILIGHT-like” patients with ACS were analyzed for this study. The primary ischemic end point was major adverse cardiac and cerebrovascular events (MACCE) at 30 months, defined as a composite of all-cause death myocardial infarction, or stroke. The 30-month Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was key secondary end point. The impact of duration of DAPT on adverse events was evaluated using multivariable Cox proportional hazards regression and propensity score-matching analysis.

 

Results: Of 4,875 high-risk patients with ACS who were event-free within 12 months after implantation of DES, 68.4% of patients remained on DAPT beyond 12 months. Continuation of DAPT beyond 12-month was associated with a lower risk for MACCE (1.5% vs. 3.8%; adjusted HR: 0.374, 95% CI: 0.256-0.548, P<0.001; matched HR: 0.361, 95% CI: 0.221-0.590, P<0.001) without a concomitant increase in in clinically meaning bleeding events (0.9% vs. 1.3%; adjusted HR: 0.668, 95% CI: 0.379-1.178, P=0.164; matched HR: 0.721, 95% CI: 0.369-1.410, P=0.339) compared with short-term DAPT. The risk reduction on MACCE was driven by lower rates of all-cause death (0.2% vs. 2.4%; adjusted HR: 0.069; 95% CI, 0.029-0.165, P<0.001; matched HR: 0.051, 95% CI: 0.012-0.211, P<0.001), without a significant difference in MI (0.4% vs. 0.6%; adjusted HR: 0.596; 95% CI, 0.264-1.348; P=0.214; matched HR: 0.450, 95% CI: 0.153-1.320, P=0.146) and stroke (1.0% vs. 1.3%; adjusted HR: 0.738; 95% CI, 0.421-1.293; P=0.289; matched HR: 0.780, 95% CI: 0.403-1.509, P=0.461). DAPT>12-month had lower 30-month incidences of cardiovascular death in comparison with DAPT≤12 months (0.1% vs. 1.3%; adjusted HR: 0.066; 95% CI, 0.019-0.223; P<0.001; matched HR: 0.049, 95% CI: 0.007-0.362, P=0.003). Definite/probable stent thrombosis occurred more frequently in the short-term DAPT group than long-term DAPT group (0.2% vs. 0.6%, P=0.045).

 

Conclusions: Among high-risk patients who underwent PCI for ACS, long-term (>12-month) DAPT was associated with reduced risk of ischemic events without any measurable increase in BARC type 2, 3, or 5 bleeding compared with shorter (≤12-month) DAPT, suggesting that extended DAPT can be considered in ACS patients who are carefully assessed to be at particularly higher risk for thrombotic complications and low bleeding risk, and have tolerated antiplatelet therapy without a major bleeding during 1 year of DAPT.

 

 

Part III Complex Percutaneous Coronary Intervention, High Bleeding Risk, and Adverse Events in Patients Receiving Drug-Eluting Stents

 

Abstract

Background: The concept of complex percutaneous coronary intervention (PCI) has recently been proposed to describe PCI on lesions with challenging anatomical and procedural characteristics. Patients with high bleeding risk (HBR) who underwent PCI portended an elevated risk of thrombotic and bleeding complications. The relationship between complex PCI, HBR, and clinical outcomes among patients receiving drug-eluting stents (DES) have not been well studied.

 

Objective: The aim of our study was to 1) evaluate the prevalence, clinical characteristics, and clinical outcomes of patients undergoing PCI complex lesions compared with noncomplex PCI and (2) examine whether the underlying risk of HBR, as defined by the PARIS bleeding risk score, influences the associations between complex PCI and adverse events after PCI with DES implantation in an all-comer real-world cohort.

 

Methods: A total of 10,167 consecutive patients undergoing PCI between January 2013 and December 2013 were prospectively enrolled. Complex PCI procedures were defined when having at least one of the following features: three coronary vessels treated, unprotected left main PCI, ≥ 3 stents implanted, a total stent length of 60 mm or longer, ≥ 3 lesions treated, bifurcation lesions with at least two stents implanted, treatment of a chronic total occlusion, in-stent restenosis target lesion, and heavy calcified lesions treated with rotablator system. The primary ischemic outcome was major adverse cardiovascular events (composite of cardiac death, myocardial infarction, definite/probable stent thrombosis, and target lesion revascularization). The primary bleeding outcome was major bleeding, which was determined as Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.

 

Results: Median duration of follow-up was 29 months (interquartile range: 26.5 to 31.1 months). Overall, complex PCI was performed in 3,651 (35.9%) patients and the most common components of complex PCI were ≥ 3 stents implanted (23.5%). By multivariable Cox regression, patients who had complex PCI procedures were associated with increased risks of major adverse cardiovascular events (adjusted hazard ratio [aHR]: 1.63, 95% confidence interval [CI]: 1.38-1.92; P<0.001), myocardial infarction (aHR: 2.16, 95% CI: 1.62-2.87; P<0.001), definite/probable stent thrombosis (aHR: 2.71, 95% CI: 1.66-4.41; P<0.001), and target lesion revascularization (aHR: 1.59, 95% CI: 1.29-1.95; P<0.001) compared with patients undergoing noncomplex PCI. Conversely, the risk of BARC type 2, 3, or 5 bleeding was statistically similar between the two groups (adjusted HR: 0.86, 95% CI: 0.66-1.11; P=0.238). There was a graded risk increase for major adverse cardiovascular events (0: 4.5%; 1 to 2: 7.4%; and ≥3: 8.3%; P<0.001), whereas there was a numerically gradual risk decrease for BARC type 2, 3, or 5 bleeding (0: 2.9%; 1 to 2: 2.4%; ≥3: 2.2%; P=0.223) as a function of the number of complex PCI features. The incidences of major adverse cardiovascular events among patients with both complex PCI and HBR, complex PCI alone, HBR alone, or neither complex PCI nor HBR were 8.9%, 7.8%, 6.9%, 4.4%, respectively (log-rank P<0.001). The rate of BARC major bleeding was higher in patients with HBR, although PCI complexity showed a nonstatistically significant low incidence of BARC major bleeding (log-rank P=0.003). The incidences of BARC major bleeding across these same four groups were 5.6%, 2.2%, 4.6%, 2.9%, respectively. Associations between complex PCI and adverse events were uniform across HBR strata (PARIS bleeding score ≥8 or <8) without evidence of interaction (all P_interaction>0.05), suggesting that the presence of HBR did not emerge as a modifier of risk for adverse events after complex PCI.

 

Conclusions: Patients who had undergone complex PCI resulted in substantially more ischemic events, without an increase in clinically relevant bleeding risk; and theses associations did not seem to be modified by HBR status. Complex PCI is an important parameter to take into account in practice for clinical decision-making regarding the duration of DAPT and choice of P2Y₁₂ inhibitors.