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January/February 2010
Fibrinolytic Therapy for STEMI
The role of this treatment in the era of primary percutaneous intervention.
By Troy A. Weirick, MD, and H. Vernon Anderson, MD, FACC, FSCAI
The role of fibrinolytic therapy as a sole means of reperfusion in ST-elevation myocardial infarction (STEMI) is becoming increasingly limited, whereas the roles played by primary and facilitated percutaneous coronary intervention (PCI), especially the role of prehospital or pretransfer fibrinolytic administration, are continuing to grow. For most STEMI patients, the safety and efficacy of PCI is superior compared to treatment with fibrinolysis. Furthermore, the availability of qualified interventional cardiologists and the number of primary PCI-capable hospitals continues to grow, expanding access to primary PCI. In addition, contemporary methods of mechanical reperfusion, including thrombectomy, drugeluting stents, and improved adjuvant pharmacotherapy, have led to a reduced bleeding risk and improved patient outcomes with primary PCI. Taken together, these factors limit the role of primary fibrinolytic-based therapy in STEMI and expand the roles of primary PCI and, as we will discuss, facilitated PCI.
BLEEDING RISK AND EFFICACY
BLEEDING RISK AND EFFICACY
Issues of safety and efficacy limit the role of primary
fibrinolysis as a sole means of reperfusion in STEMI. In
carefully selected patients, full-dose fibrinolysis does
have an acceptable risk-benefit ratio. In large randomized
trials, the overall risk of major bleeding with thirdgeneration
fibrinolytics varies according to bleeding
definition; however, the risk of the most serious bleeding
(intracranial hemorrhage [ICH]) is relatively uniform
at approximately 0.9%.1,2 The list of absolute and relative
contraindications to fibrinolytic therapy is substantial
(Table 1).3 Although the risk of ICH may seem
acceptably low, the consequences of ICH are dramatic
and often deadly, and thus, extra vigilance is necessary
to avoid this complication. Making matters worse,
essential historical data are often unobtainable at the
time of STEMI treatment. In a 2006 review of the
National Registry of Myocardial Infarction database,
Pinto et al found that nearly 20% of STEMI patients
who were eligible for reperfusion therapy did not
undergo either PCI or fibrinolysis.4 The inability to accurately
assess the bleeding risk of a patient, along with
the seriousness of a potential adverse outcome, may
lead to treatment delays or failure to provide appropriate
therapy in some cases.
Although the issue of fibrinolytic safety is fundamental, there are also very real concerns regarding efficacy and durability. Ninety-minute patency rates for tenecteplase and reteplase vary between 60% and 75%, and TIMI grade 3 flow is only 60% to 65% (Table 2).5 This means nearly one-third of fibrinolytic-treated patients will have suboptimal results after therapy. In addition, the 30-day rate of recurrent angina is 19% to 28% with third-generation fibrinolytics. One-quarter of lytic-treated patients will require mechanical intervention after having failed fibrinolysis.1,2 In our experience, and in multiple randomized and nonrandomized studies, the procedural success rate with drug-eluting stents in STEMI is greater than 93%, and the 12-month target lesion revascularization rate is less than 7%. Therefore, both angiographic results and efficacy endpoints are superior with mechanical intervention. With an aging population, the risks associated with primary fibrinolytic therapy are considerable. When this is coupled with the relative uncertainty of success, mechanical reperfusion is frequently a more attractive option.
PRIMARY PCI AVAILABILITY
In regions where primary PCI resources are limited,
fibrinolytic therapy may remain relatively popular; however,
training programs in the United States are graduating
an increasing number of qualified operators to staff
a growing number of primary PCI-capable hospitals.
This increase in operators and facilities expands the
availability of primary PCI for STEMI treatment. From
2008 to 2009, there were 134 Accreditation Council for
Graduate Medical Education-accredited interventional
cardiology training programs, and these programs
trained nearly 300 new interventional cardiologists. This
total nearly doubles the number of interventional cardiologists
trained in the academic year of 2001 to 2002.
Commensurate with this increase in the number of
interventional cardiologists, the number of primary PCI
laboratories has increased. Approximately 25% of acutecare
hospitals in the United States have primary PCI
capability. From 2005 to 2009, the number of these hospitals
in the United States increased from nearly 5,000
to more than 5,800, which means a potential additional
200 primary PCI-capable facilities. Further expanding
the availability of primary PCI, recent data suggest that
primary PCI for STEMI without on-site surgical backup
in well-staffed facilities with quality-control programs
achieves similar outcomes when compared to primary
PCI performed at sites with on-site surgical backup.6
Given that primary PCI is generally preferred over fibrinolysis
and recognizing an overall increase in the availability
of primary PCI resources, the role of primary fibrinolysis
for STEMI is likely to diminish even further.
PHARMACOINVASIVE THERAPY
Primary fibrinolytic therapy for STEMI is far from
optimal and may not be appropriate for some individuals.
Additionally, although the availability of primary PCI
continues to grow, many patients living outside major
population centers still do not have access to primary
PCI within the American College of
Cardiology/American Heart Association (ACC/AHA)
recommended 90-minute window. So, how do we offer
safe and timely reperfusion to all patients, especially in
high-risk patients and when transfer times may be
longer than desired? The natural choice is facilitated PCI.
However, the data on facilitated PCI are equivocal and
may suggest harm. Or do they?
Historically, facilitated PCI trials are small, and study design varies considerably, making it difficult to draw sound conclusions from these trials. For the basis of this article, facilitated PCI is considered to be any combination of pharmacological reperfusion therapy followed by planned early revascularization. Theoretically, facilitated PCI is very attractive, combining the speed and accessibility of fibrinolysis with the efficacy and durability of mechanical intervention. Multiple combinations of drugs and devices have previously been explored. Early pharmacological strategies have included regimens with full-dose and half-dose fibrinolytics, combinations of fibrinolytics and IIb/IIIa inhibitors, and programs with IIb/IIIa antagonists alone. The timing and method of revascularization also varies among trials, with planned revascularization taking place as soon as possible in most studies to as late as 24 hours after hospital admission. Similarly, the means of revascularization differs between older and more recent trials, with earlier programs employing balloon angioplasty as opposed to the more modern use of drug-eluting stents. In an excellent review of facilitated PCI that included both recent and older data, Keely et al determined that facilitated PCI offered no additional advantage over primary PCI.7 However, their conclusions were heavily influenced by the ASSENT-4 trial results, which comprised more than one-third of the patients in the 13 trials they analyzed. Furthermore, therapeutic options were not well balanced in this meta-analysis. The third-generation fibrinolytic, reteplase, was used in only 4.3% of fibrinolytic-treated patients and in only 3.2% of the total population.
Although previous pharmacoinvasive trials have been equivocal, recent data support a much more substantial role for facilitated PCI. In a multicenter collaborative effort, the AMICO registry trialists demonstrated a significant reduction in death, and in the combined endpoint of death, reinfarction, and stroke when patients are treated with a facilitated approach. The AMICO registry was composed of 2,869 STEMI patients treated at five high-volume centers in the United States and Europe. Of these, 1,200 patients were treated with facilitated PCI. Thirty-day mortality in the facilitated PCI group was 3.8% versus 6.4% in the primary PCI group (P = .002).8 Complementing these findings, in a subset of patients at our center undergoing cardiac magnetic resonance imaging after STEMI, we found that patients treated with prehospital, reduced-dose fibrinolytics prior to urgent PCI developed smaller infarcts when compared to patients treated with primary PCI (9.5% vs 12.7%; P = .04) (Figure 1). Similarly, a recent subgroup analysis from the FINESSE trial showed improved outcomes when high-risk STEMI patients presenting to non-PCI hospitals were treated with a combination of abciximab and half-dose retevase before transfer to a tertiary care center.9
Although primary fibrinolysis may not be the optimal means of reperfusion in many situations, time to any reperfusion is critical in limiting infarct size and improving outcomes, especially in the precious first hours after symptom onset (Figure 2).10 A pharmacoinvasive approach combines the speed of primary fibrinolysis with the durability of mechanical intervention. Perhaps in recognition of these issues, the 2007 ACC/AHA STEMI guidelines revised the 2004 class III indication for facilitated PCI to a class IIb recommendation. 3 However, the writers limit this recommendation to programs using other than full-dose thrombolytics, and only if patients are high risk, primary PCI is not immediately available, and patient bleeding risk is acceptable. Additional research into which patients will benefit most from a facilitated approach is warranted, and further investigation into the best combination of drugs and devices is also needed.
CONCLUSIONS< br/>
In general, there is a strong preference for primary PCI over fibrinolytic therapy in STEMI treatment. This preference is largely due to the superior safety and efficacy of primary PCI compared to fibrinolysis. Improved access to skilled interventionists and the growing availability of primary PCI facilities will further add to the popularity of primary PCI. Additionally, enhanced methods of mechanical reperfusion and improved adjuvant pharmacotherapy further reduce bleeding risk and improve patient outcomes with primary PCI. Finally, emerging data from facilitated PCI programs demonstrate improved outcomes in high-risk STEMI patients. Thus, in an era of primary PCI, the role of fibrinolysis alone for STEMI treatment is decreasing, whereas the role of primary PCI is firmly established, and the role of facilitated PCI continues to take shape.
Troy A. Weirick, MD, is from the University of Texas Health Science Center in Houston, Texas. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein.
H. Vernon Anderson, MD, FACC, FSCAI, is Professor of Medicine, Cardiology Division at the University of Texas Health Science Center in Houston, Texas. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Anderson may be reached at (713) 500-6575; h.v.anderson@uth.tmc.edu.
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