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Although patients with ST-segment elevation myocardial infarction (STEMI) who receive facilitated percutaneous coronary intervention (PCI) initially achieve greater vessel patency than those treated with primary PCI alone, thrombolytic therapy is more likely to leave them with a large residual thrombus burden, according to an observational study published in the May 10, 2011, issue of the Journal of the American College of Cardiology. Moreover, that thrombus is associated with less efficient myocardial reperfusion and a worse clinical outcome.

In the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) trial, STEMI patients randomized to PCI preceded by full-dose tenecteplase (facilitated PCI; n = 829) experienced a higher rate of the clinical primary endpoint of death, congestive heart failure, or shock within 90 days than those assigned to primary PCI (n = 838; 19% vs. 13%; RR 1.39, 95% CI 1.11-1.74; P = 0.0045). 

For the substudy, investigators led by Frans Van de Werf, MD, of Katholieke Universiteit Leuven (Leuven, Belgium), assessed the angiograms of 1,342 patients from ASSENT-4 PCI to correlate infarct-related thrombus burden with reperfusion efficiency and clinical outcome.

Primary PCI Still Comes Out Ahead

At 90 days, rates of the clinical primary endpoint and reinfarction were higher in the facilitated PCI group than the primary PCI group. The individual endpoints of death, congestive heart failure, and shock also tended to be more common in facilitated PCI patients (table 1). 

Table 1. Clinical Outcomes at 90 Days

In the angiographic assessment, after fibrinolytic therapy, the facilitated PCI group showed higher rates of low TIMI thrombus grade (0-3), while the highest TIMI thrombus grade (5) was more frequent in the primary PCI group (P < 0.0001 for trend). In addition, during PCI, more patent vessels without thrombus were found in the facilitated PCI arm, whereas more arteries with medium-size thrombus (grades 2/3) were present in the primary PCI group (P < 0.0001 for trend). 

After the procedure, differences in TIMI thrombus grade were no longer evident between the treatment groups. Rates of slow flow also were similar. However, trends emerged toward more distal embolization and large residual thrombus (TIMI thrombus grade ≥ 2) in the facilitated PCI group. And thrombus burden was significantly higher in these patients (table 2).

Table 2. Angiographic Results

 

Multivariable regression analysis identified several independent preprocedural predictors of a large residual thrombus after PCI, including:

• Post-fibrinolytic therapy TIMI thrombus grade ≥ 3
• No PCI vs. stent implantation
• Angioplasty vs. stenting
• Tenecteplase administration
• Older age
• Longer time from symptom onset to first balloon inflation

On the other hand, a loading dose of clopidogrel or ticlopidine and prior PCI predicted lower risk of large residual thrombus. 

Sixty minutes after fibrinolysis, ST resolution was more common in patients receiving facilitated PCI than primary PCI (median 38.6% vs. 28.6%; P = 0.002). However, by 180 minutes rates were similar for the 2 groups (71.4% and 71.2%, respectively; P = 0.95). There was a strong relationship (P < 0.0001) between post-fibrinolytic therapy and post-PCI TIMI thrombus grades and rates of ST resolution in both groups

Residual Thrombus the Culprit

At 90 days, the presence of residual thrombus after PCI in patients treated with facilitated PCI was associated with a higher risk of the primary endpoint (P = 0.023), though not of death (P = 0.407). Interestingly, the absence of a residual thrombus burden (TIMI grade 0) was tied to a higher risk of reinfarction (P = 0.020).

On multivariable regression analysis, the strongest factors correlated with 90-day mortality were Killip class 3/4 (OR 6.12; 95% CI 2.30-16.3; P = 0.0003) and facilitation with tenecteplase in women (OR 5.31; 95% CI 1.69-16.7; P = 0.0050). Other predictors included:

• Age
• Loading dose of clopidogrel/ticlopidine
• Facilitation with tenecteplase in men (reduced risk)
• Thrombus burden
• Anterior infarct
• Glycoprotein IIb/IIIa inhibitor

The authors suggest that “[t]he well-known prothrombotic effects of fibrinolytic agents, the suboptimal antithrombotic cotherapy in this trial and, as a consequence, the presence of residual thrombus resistant to lytic therapy, might be responsible for the unexpected failure of facilitated PCI.”

In an accompanying editorial, Robert J. Applegate, MD, of Wake Forest University School of Medicine (Winston-Salem, NC), writes that the study findings “provide important insights into the potential mechanisms responsible for the lack of benefit overall of the facilitated PCI strategy in ASSENT-4 PCI.”

However, he questions the validity of the researchers’ characterization of the composition and role of so-called resistant thrombi, concluding that “we have a long way to go before we achieve adequate understanding of the dynamics of functional and effective reperfusion in the setting of an acute myocardial infarction.”

Improving Thrombolysis—For When It’s Needed

In a telephone interview with TCTMD, Ron Waksman, MD, of Washington Hospital Center (Washington, DC), said that facilitated PCI has long been controversial. However, it is something of a moving target, he observed, because in addition to a thrombolytic agent it involves different types of antiplatelet agents.

In addition, although the literature clearly does not support broad use of facilitated PCI, there may be a subgroup of patients who do benefit from the strategy, Dr. Waksman said, adding, “In large trials with broad inclusion criteria, that benefit may be so diluted that it disappears. In that respect, I think we need to be careful not to completely write off facilitated PCI.” 

Even though the number of patients undergoing lytic therapy is declining, there always will be some patients for whom it is needed due to lack of timely access to the cath lab, Dr. Waksman pointed out. For that reason, exploring the optimal cotherapy with antiplatelet agents to counterbalance lytics’ prothrombic effect remains worthwhile, he commented.

“It’s very tricky, however, and there is no free lunch—you may pay the price of more intracranial bleeds,” Dr. Waksman cautioned. To mitigate this problem, some clinicians use half-dose lytics, while others choose a short-acting agent or avoid long infusions, he said, adding that in general thienopyridines seem to be more forgiving in terms of the risk of intracranial bleeding.

Another potential candidate for use in conjunction with lytic therapy is bivalirudin, Dr. Waksman noted. “We have looked at our own data on patients who were pretreated in the field with thrombolysis and then given bivalirudin in the cath lab and we’re submitting a paper on this combination, which could be safer in terms of bleeding,” he said.

Why Bother? 

On the other hand, Jeffrey W. Moses, MD, of Weill Cornell Medical College (New York, NY), when asked about the potential for improving the safety of thrombolysis, responded, “Why bother?” In a telephone interview with TCTMD, he questioned whether the patients who may need lytics for acute MI because they fall outside the range of PCI centers represents a large enough population to justify the effort. “Why not expedite PCI instead, either by regional organization or expanding the PCI capability of local facilities?” he asserted. 

Addressing the larger picture, Dr. Moses said that the ASSENT-4 PCI study “shows why we do clinical trials. Translating the hypothesis-generating observation of improving TIMI 3 flow—which was the logic behind all [the focus on] facilitation—gave a totally unanticipated outcome.” 

The current substudy has drilled down, and its findings are fascinating, Dr. Moses said. “It fulfills a lot of our preconceived notions of thrombolytics being thrombogenic because of platelet activation,” he observed. “And this in the face of [an era of] more potent antiplatelet drugs. It may not be the whole story, but it gives us a very interesting insight into some of the mechanisms that lead to higher mortality” with facilitated PCI. 

Study Details 

Facilitated and primary PCI patients had similar median times from symptom onset to first balloon inflation. Significantly more patients underwent an intervention in the primary PCI group. A clopidogrel loading dose after the procedure and glycoprotein IIb/IIIa inhibitors both before, and after PCI were more frequently administered to primary PCI patients. All patients received 150-325 mg aspirin and a single IV bolus of unfractionated heparin.

Thrombus burden was defined angiographically as the composite of residual thrombus (TIMI thrombus grade of at least 2) after PCI or evidence of distal embolization or slow flow during or immediately after the procedure.

 

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Sources:
1. Zalewski J, Bogaerts K, Desmet W, et al. Intraluminal thrombus in facilitated versus primary percutaneous coronary intervention. An angiographic substudy of the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) trial. J Am Coll Cardiol. 2011;57:1867-1873.

2. Applegate RJ. Optimal therapy for ST-segment elevation myocardial infarction. The role of residual thrombus. J Am Coll Cardiol. 2011;57:1874-1876.

 

 

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