从 timacs 研究结果再议 nsteacs 介入时机

从 TIMACS 研究结果再议NSTEACS 介入时机

福建医科大学附属协和医院心内科福建省冠心病研究所

陈良龙 MD PhD FACC

NSTE-ACS ： Pathogenesis Vulnerable

Plague

Not totally occlusive thrombosis

White thrombus

Yeghiazarians Y, et al. N Engl J Med. 2000;342:101-114.

背景 早期

尽早造影，明确病变，对后续治疗策略有指导意义； 减少等待期间不良事件的发生 [1] ； 缩短住院时间。

延迟 在积极抗血小板、抗凝、稳定斑块等治疗基础上，介入

治疗并发症少，安全系数更高 [2]; 等待期间可能发生不良事件乃至死亡 ; 延长住院时间 / 增加费用。

1.Neumann FJ, et al JAMA 2003;290:1593–9.2.Smith SC et al. Circulation 2001;103:3019–41.

目前指南 I 类推荐指征

UA/NSTEMI 患者 , 若有下列情况应早期介入 具有任何高危因素 病变适合 PCI 无影响 PCI 的严重合并症

问题与焦点 介入治疗的最佳时机尚不确定

早期：多早？ 延迟：多长？ 哪些患者需要尽早治疗？要多早？

目前的 RCT 研究结果不一致 [1,2] 。

1.Neumann FJ, et al JAMA 2003;290:1593–9.2. Riezebos RK, et al. Heart 2009;95:807-12.

Timing of Intervention in Patients with Acute

Coronary Syndromes (TIMACS)

Trial schema: TIMACS

UA/NSTEMI(3031)

Early Intervention（ 1593 ）

Delayed Intervention（ 1438 ）

angiographyafter 36 hrs （ 50h ）

angiography within 24 hrs （ 14h ）

Endpoint

Primary endpoint composite of death, MI, stroke at 6 m.

Secondary endpoints composite of death, MI, refractory ischemia

at 6m. composite of death, MI, stroke, refractory

ischemia, repeat revascularization at 6m.

End point HR (95% CI) p

Death, MI, stroke* 0.85 (0.68–1.06) 0.15

Death, MI, refractory ischemia

0.72 (0.58–0.89) 0.002

Death, MI, stroke, refractory ischemia, repeat intervention

0.84 (0.71–0.99) 0.039

Refractory ischemia

0.30 (0.17–0.53) <0.00001

Mehta SR, et al. N Engl J Med 2009;360:2165-75.

Primary and secondary outcomes in TIMACS, early vs delayed strategies

*Primary end point

Results: Primary endpoint

Results: Second endpoint

*Low/intermediate risk=GRACE score <140 High risk=GRACE score >140 *Prespecified analysis

Rates of death, MI, or stroke within six months according to GRACE score

Risk level by GRACE score*

Early (%)

Delayed (%)

HR (95% CI) p

Low/intermediate (n=2070)

7.7 6.7 1.14 (0.82–1.58) 0.43

High (n=961) 14.1 21.6 0.65 (0.48–0.88) 0.005

Kaplan–Meier Cumulative Risk of the Primary Outcome

High risk>140

Low-to- intermediate risk ≤140

High risk:>140; Low-to-intermediate risk: ≤140. （ GRACE Risk Score ）

Stratified According to GRACE Risk Score

Conclusion

与延迟干预相比，早期干预对于 NSTE-ACS患者 6 个月不良事件发生率没有显著差异 ;

NSTE-ACS 患者接受早期干预安全性良好 ; 高危患者（ GRACE 评分＞ 140 ）可从早期

干预策略获益； 早期干预可显著减少 NSTE-ACS 患者再发

心绞痛的发生率，且不增加出血风险；

其他随机临床试验 ABOARD

ISAR-COOL

OPTIMA

Trial Flow: ABOARD

352 Pts randomized

175 Randomized to receive immediateangiography

177 Randomized to receive delayedangiography

175 Included in primary analysis 177 Included in primary analysis

Primary endpoint Peak troponin value during hospitalizationSecond endpointDeath, MI, urgent revascularization, or recurrent ischemia at 1m

Montalescot G, et al. JAMA 2009;302:947-54.

ABOARD 研究结果

ImmediateN=175

DeferredN=177

P

Time To CAG 1h+ (0.51-2.03)

21h (17.30-24.36)

Peak cTnI(ng/mL)

2.1 (0.3-7.1) 1.7 (0.3-7.2) 0.70

Endpoint(at 1 m)

21.1% 21.5% 0.94

Montalescot G, et al. JAMA 2009;302:947-54.

结论

对于 NSTE-ACS 患者 , 即刻（ 1 小时）与延迟（次工作日）介入治疗策略比较 不能减少肌钙蛋白定义的 MI 不能减少 1 个月时的死亡、 MI 、紧急血运重建或 复发心肌缺血

Montalescot G, et al. JAMA 2009;302:947-54.

528 Pts Eligible

410 Randomized

203 early PCIReceive early intervention

207 Deferred PCIReceive Prolonged

Antithrombotic Pretreatment

Trial schema: ISAR-COOL

Endpoint: death, MI at 30d

ISAR-COOL 研究结果

EarlyN=203

DeferredN=207

P

Time To CAG < 6h 3-5 d

Endpoint(30d) 5.9%0 death12MI

11.6%3 death21MI

0.04RR 1.96

95%CI 1.01-3.82

Neumann FJ, et al JAMA 2003;290:1593–9.

This outcome was attributable to events occurring before catheterization;

after catheterization, both groups incurred 11 events each (P=.92).

结论

对于不稳定 ACS 患者 , 与早期介入治疗 +强化抗血小板比较， 延迟介入治疗 +延长抗栓治疗并不能改善临床

结局（死亡、 MI ）， 相反地，后者在等待期增加了约 50%的事件。

Montalescot G, et al. JAMA 2009;302:947-54.

Trial schema: OPTIMA

251 NSTEACS Pts 142 R

Immediate(< 24h) PCI 73

Deferred(24-48h) PCI69

Endpoint: death, MI, at 30d and 6m

Riezebos RK, et al. Heart 2009;95:807-12.

OPTIMA 研究结果 *

ImmediateN=73

DeferredN=69

P

Time To CAG < 24h 24-48h

Endpoint(30d)

60% 39% 0.004

Endpoint(6m) 66% 43% 0.008

*No deaths occurred in either group

Riezebos RK, et al. Heart 2009;95:807-12.

结论

对于 NSTE-ACS 患者，与延迟介入治疗（ 24-48H ）比较： 尽管有强化的抗栓治疗，早期介入治疗（ 24

H ）还是增加 MI 对于非顽固 NSTE-ACS 患者，介入治疗至少应

延迟至入院后 24H进行

Montalescot G, et al. JAMA 2009;302:947-54.

4 RCTs总结n early deferred

TIMACS 3031 14h 50h

ABOARD 352 1h 21h -

ISAR-COOL 410 6h 3-5d +

OPTIMA 251 24 24-48h -

For Pts with high risk, too early or too late intervention is harmful. 24 h may be the proper time window in setting of intensive antithrombotic therapy

The Answers 多早？

在有效抗栓基础上， 约在入院后 24H,是早期 PC

I 的最佳窗口

哪些患者早做？ 高危者 ( 包括血流动力学不

稳定 \ 恶性心律失常 ) 无禁忌者

感 谢！Fighting CVD

Reconsideration of Interventional

Therapeutic Time Window for NSTE-ACS

——Hint from the Result of TIMACS

Chen Lianglong MD, PhD, FACCCardiology, Union Hospital, Fujian Medical University

NSTE-ACS ： Pathogenesis Vulnerable

Plague

Not totally occlusive thrombosis

White thrombus

Yeghiazarians Y, et al. N Engl J Med. 2000;342:101-114.

Background Early intervention might prevent ischemic events that c

ould occur while the pts are awaiting a delayed procedure.

Alternatively, by treating pts with intensive antithrombotic therapy and delaying intervention for several days, procedure-related complications might be avoided with intervention on a more stable plaque.

Current CLASS-I recommendations

An early invasive strategy is indicated for pts with UA/NSTEMI

who have any of the high-risk features & who have coronary lesions amenable to PC

I & who have no serious comorbidities.

Uncertain

the optimal timing of such intervention

remains controversial. Early strategy: how early

delayed strategy: how prolonged

Timing of Intervention in Patients with Acute

Coronary Syndromes (TIMACS)

Trial schema: TIMACS

UA/NSTEMI(3031)

Early Intervention（ 1593 ）

Delayed Intervention（ 1438 ）

angiographyafter 36 hrs

angiography within 24 hrs

Endpoint

Primary endpoint composite of death, MI, stroke at 6 m.

Secondary endpoints composite of death, MI, refractory ischemia

at 6m. composite of death, MI, stroke, refractory

ischemia, repeat revascularization at 6m.

End point HR (95% CI) p

Death, MI, stroke* 0.85 (0.68–1.06) 0.15

Death, MI, refractory ischemia

0.72 (0.58–0.89) 0.002

Death, MI, stroke, refractory ischemia, repeat intervention

0.84 (0.71–0.99) 0.039

Refractory ischemia

0.30 (0.17–0.53) <0.00001

Mehta SR, et al. N Engl J Med 2009;360:2165-75.

Primary and secondary outcomes in TIMACS, early vs delayed strategies

*Primary end point

Results: Primary endpoint

Results: Second endpoint

*Low/intermediate risk=GRACE score <140 High risk=GRACE score >140

Rates of death, MI, or stroke within six months according to GRACE score

Risk level by GRACE score*

Early (%)

Delayed (%)

HR (95% CI) p

Low/intermediate (n=2070)

7.7 6.7 1.14 (0.82–1.58) 0.43

High (n=961) 14.1 21.6 0.65 (0.48–0.88) 0.005

Kaplan–Meier Cumulative Risk of the Primary Outcome

High risk>140

Low-to- intermediate risk ≤140

High risk:>140; Low-to-intermediate risk: ≤140. （ GRACE Risk Score ）

Stratified According to GRACE Risk Score

Conclusions

Early intervention did not differ greatly from d

elayed intervention in preventing the primary

outcome． but it did reduce the rate of the composite sec

ondary outcome of death, myocardial infarctio

n, or refractory ischemia

and was superior to delayed intervention in hi

gh-risk patients.

Other RCTs

ABOARD

ISAR-COOL

OPTIMA

Trial Flow: ABOARD

352 Pts randomized

175 Randomized to receive immediateangiography

177 Randomized to receive delayedangiography

175 Included in primary analysis 177 Included in primary analysis

Primary endpoint Peak troponin value during hospitalizationSecond endpointDeath, MI, urgent revascularization, or recurrent ischemia at 1m

Montalescot G, et al. JAMA 2009;302:947-54.

ABOARD-Results

ImmediateN=175

DeferredN=177

P

Time To CAG 1h+ (0.51-2.03)

21h (17.30-24.36)

Peak cTnI(ng/mL)

2.1 (0.3-7.1) 1.7 (0.3-7.2) 0.70

Endpoint(at 1 m)

21.1% 21.5% 0.94

Montalescot G, et al. JAMA 2009;302:947-54.

Conclusion

In pts with NSTE-ACS, a strategy of immediate intervention compared with a strategy of intervention deferred to the next working day (mean,21h) did not result in a difference in MI as defined by peak troponin level.

Montalescot G, et al. JAMA 2009;302:947-54.

528 Pts Eligible

410 Randomized

203 early PCIReceive early intervention

207 Deferred PCIReceive Prolonged

Antithrombotic Pretreatment

Trial schema: ISAR-COOL

Endpoint: death, MI at 30d

ISAR-COOL:Results

EarlyN=203

DeferredN=207

P

Time To CAG < 6h 3-5 d

Endpoint(30d) 5.9%0 death12MI

11.6%3 death21MI

0.04RR 1.96

95%CI 1.01-3.82

Neumann FJ, et al JAMA 2003;290:1593–9.

This outcome was attributable to events occurring before catheterization;

after catheterization, both groups incurred 11 events each (P=.92).

Conclusion

In pts with unstable coronary syndromes, deferred intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate （ early ） intervention accompanied by intense antiplatelet treatment.

Trial schema: OPTIMA

251 NSTEACS Pts 142 R

Immediate(< 24h) PCI 73

Deferred(24-48h) PCI69

Endpoint: death, MI, at 30d and 6m

Riezebos RK, et al. Heart 2009;95:807-12.

OPTIMA: Results*

ImmediateN=73

DeferredN=69

P

Time To CAG < 24h 24-48h

Endpoint(30d)

60% 39% 0.004

Endpoint(6m) 66% 43% 0.008

*No deaths occurred in either group

Riezebos RK, et al. Heart 2009;95:807-12.

Conclusions

Immediate PCI was associated with an increased rate of MI in comparison with a 24-48h deferred strategy, despite aggressive antithrombotic treatment.

The results suggest that PCI for high-risk patients with non-refractory NSTE-ACS should be delayed for at least 24h after hospital admission.

Riezebos RK, et al. Heart 2009;95:807-12.

Summary of RCTsn early deferred

TIMACS 3031 14h 50h

ABOARD 352 1h 21h -

ISAR-COOL 410 6h 3-5d +

OPTIMA 251 24 24-48h -

For Pts with high risk, too early or too late intervention is harmful. 24 h may be the proper time window

The Answers

How early? On aggressive anti-th

rombosis

24 h after hospital ad

mission

For Whom ？ Pts with high risk

Pts suitable for PCI

感 谢！Fighting CVD