Prehospital Fibrinolysis in Concert with Rapid PCI

Clinical trials shows promising results for use of clot-dissolving agents in the field

 

 
 
 

David E. Persse, MD, FACEPJames J. McCarthy, MD, FACEPMary Vooletich, RN, BSNBonnie K. Richter, BS, EMT-PH. Vernon Anderson, MD, FACCAli E. Denktas, MD, FACCStefano M. Sdringola, MD, FACCRichard W. Smalling, MD, PhD, FACC | From the March 2008 Issue | Saturday, July 26, 2008


The Problemand the Controversy

Even with the many recent advances in cardiac care, acute myocardial infarction (AMI) remains a leading cause of death in the U.S. The estimated number of new or recurrent myocardial infarctions annually in the U.S. is estimated at 865,000, with ST-segment elevation myocardial infarction (STEMI) comprising approximately 500,000 of them (1,2).

Re-establishing blood flow through the infarct-related coronary artery using lytic agents or balloon angioplasty with or without stent placement, also known as percutaneous coronary intervention (PCI), as early as possible, has been the main focus of STEMI care (2-7). Research has shown that there_s a direct correlation between how soon an artery is re-opened and how quickly and completely a patient will recover (8).

Controversies have existed for several years over which therapy was superiorƒintravenous (IV) lytic therapy that could be administered quickly in the emergency department (ED), or PCI, which would take longer but potentially be more definitive and theoretically have less associated risk of hemorrhage.

The current ACC/AHA STEMI guidelines recommend PCI as the initial approach to STEMI management, contingent upon treatment at a center with a skilled PCI laboratory and rapid initiation of care (within 90 minutes of first medical contact).2 This recommendation is based on multiple randomized clinical trials demonstrating superiority of primary PCI over fibrinolysis alone in the treatment of STEMI (9-17).

The guidelines also suggest, however, that fibrinolysis may be the preferred treatment if the patient presents within the first two hours of symptomsƒparticularly if PCI can_t be performed within 60 minutes of presentation. As a result, the controversy continues.

In an effort to contribute to knowledge that could resolve this controversy, Houston Fire Department (HFD) EMS began a pilot study on reduced-dose prehospital fibrinolysis used with urgent PCI to assess the effects on STEMI patients. Before we discuss the early results of this original research, we should consider previous study conclusions and trends.

Time to Re-PerfusionIs the Real Issue

To date, more than 50,000 patients treated with fibrinolytics for STEMI have been analyzed, evaluating the importance of time from onset of symptoms to initiation of treatment on subsequent mortality.3 Patients treated within 30Ï60 minutes of the onset of pain have been shown to have a very low mortality. Researchers have suggested that if all patients could be treated within this cardiac ˙golden hourÓ of pain onset, 60Ï80 additional lives could be saved per 1,000 patients treated per year for STEMI.

In an analysis of nearly 30,000 STEMI patients treated with PCI, increased in-hospital mortality has been shown with longer door-to-balloon times (mortality rate of 3.0%, 4.2%, 5.7% and 7.4% for door-to-balloon times of < or = 90 minutes, 91Ï120 minutes, 121Ï150 minutes, and > 150 minutes, respectively) (18).

In an evaluation of primary PCI in STEMI patients, it has been demonstrated that patients who achieved reperfusion within two hours of onset of symptoms experienced a 4.3% mortality versus a 9% 30-day mortality for those treated beyond two hours (19). In fact, the mortality curve after two hours was flat, suggesting little correlation between time to reperfusion after two hours and 30-day mortality.

Another study demonstrated that patients treated within the first two hours with prehospital fibrinolysis had a 30-day mortality of just 2.2%, compared with patients treated with primary PCI within the first two hours who experienced a mortality of 5.7% (20).

It_s important to note there was a 55-minute advantage in terms of reduction in time to treatment in patients treated with prehospital fibrinolysis versus primary PCI. Additionally, patients treated with prehospital fibrinolysis had zero incidence of shock compared with 3.6% in the primary PCI group.

Strategic Approaches

Several studies have looked at different strategies to minimize delays to reperfusion. One approach was to provide fibrinolysis to those patients in whom PCI would be delayed due to a need to transfer the patient to another hospital. The PRAGUE-2 trial evaluated the strategy of fibrinolysis in a local hospital versus transfer to a PCI Center for primary PCI in 850 patients. They observed the mortality among those who actually underwent PCI was 6.0% versus 10.4% mortality in patients who finally received fibrinolysis. Among 299 patients randomized greater than three hours after symptom onset, the mortality of the fibrinolysis group reached 15.3%, compared with 6% in the PCI group.

Interestingly, patients randomized within three hours of symptom onset (n=551) had no difference in mortality whether treated by fibrinolysis (7.4%) or transferred to PCI (7.3%) (21). There was a higher incidence of re-infarction in the fibrinolysis group; however, the fibrinolysis group didn_t receive routine coronary revascularization (PCI balloon angioplasty) after hospital admission.

Prehospital Fibrinolysis

The presented scientific evidence suggests equivalent success between fibrinolysis and PCI when treated early in the course of a STEMI, and the lack of excessive bleeding when PCI followed fibrinolysis. Because time to reperfusion is obviously an important variable, several studies have looked specifically at the strategy of providing fibrinolysis in the prehospital setting in an attempt to gain the advantages of treating the patient at the earliest possible opportunity.

French researchers conducted a trial (CAPTIM) that evaluated prehospital fibrinolysis versus primary PCI (22). The rate of the primary end point (a composite of death, non-fatal re-infarction, and non-fatal disabling stroke at 30 days) wasn_t different, with 8.2% in the prehospital fibrinolysis group and 6.2% in the primary angioplasty group.

The mortality rate in the prehospital fibrinolysis group was lower (3.8%) compared with 4.8% in the primary angioplasty arm (22).In addition, shock was less frequent in the prehospital fibrinolysis group, suggesting that prehospital fibrinolysis and its attendant more rapid onset of reperfusion may be beneficial.

This same group of investigators demonstrated that randomization within two hours (n=460), or greater than or equal to two hours (n=374) after symptom onset, had no impact on the effect of treatment on the 30-day combined primary end point of death, non-fatal re-infarction and disabling stroke. However, patients randomized less than two hours after symptom onset had a strong trend toward lower 30-day mortality with prehospital thrombolysis compared to those randomized to primary PCI (2.2% versus 5.7%).

In the first two hours, cardiogenic shock was also less frequent with lytic therapy than with primary PCI, mostly because of a lower incidence of shock developing during transport to the hospital. In this subset, cardiogenic shock occurred between randomization and admission in 2.1% of patients randomized to PCI but in none randomized to prehospital thrombolysis.

A more recent study from Germany randomized STEMI patients to either ˙prehospital combination-fibrinolysisÓ (half-dose reteplase plus abciximab) with continued medical therapy (no planned PCI) care or prehospital combination-fibrinolysis PCI, followed by urgent PCIƒ˙facilitated PCI.Ó

Predefined criteria for rescue PCI were: persistent angina and/or incomplete ST-segment resolution (STR) of greater than 50% at 90minutes. In case of re-infarction or recurrent ischemia, urgent PCI was recommended and repeated fibrinolysis was discouraged. Otherwise, elective coronary angiography was recommended before hospital discharge, and the decision to undertake angioplasty was left to the discretion of the operator.

The primary end point was the infarct size assessed by delayed enhancement magnetic resonance. Secondary end points were ST-segment resolution at 90 minutes and a composite of death, re-myocardial infarction, major bleeding and stroke at six months. The infarct size was lower after facilitated PCI with 5.2% as opposed to 10.4% after prehospital combination-fibrinolysis.

Complete STR was 80.0% after facilitated PCI versus 51.9% after prehospital combination-fibrinolysis and there was a trend toward a lower event rate in the combined clinical end point (15% versus 25%) (23).

These same patients were later compared with a prospectively assessed group of patients treated with primary PCI in terms of time to complete STR as a proxy for better clinical prognosis. The percentage of patients with complete STR was highest in the group of PCI facilitated with prehospital fibrinolysis, with 80% versus 52% in the prehospital half-dose fibrinolysis group and 52% in primary PCI group (24).

Other researchers demonstrated that pursuing a strategy of initial fibrinolysis followed by urgent re-vascularization within 24 hours was preferable to delaying PCI until later into the hospital course, and then only in response to recurrence of symptoms or positive provocative stress testing (25). There was a trend toward reduced rate of death or re-infarction in patients treated with early re-vascularization after fibrinolysis, compared with those who had delayed or elective re-vascularization (7% versus 12%).

In summary, research has typically shown that the sooner an occluded coronary artery is reopened, whether by fibrinolysis or PCI, the better a patient will do. Patients who receive early fibrinolysis, but don't get PCI shortly afterwards, are likely to develop more problems over the next 30 days. Patients who can be treated early in the course of their STEMI followed by urgent PCI appear to do the best.

Original Houston ResearchCombines Two Therapies

With such extensive research in mind, the HFD EMS began conducting a pilot study known as PATCAR (Prehospital Administration of Thrombolytic Therapy with Urgent Culprit Artery Revascularization). The study was undertaken through a partnership with the University of Texas Health Science Center at Houston Medical School and the university_s teaching institution, Memorial Hermann Hospital.

The PATCAR pilot trial is currently evaluating the feasibility that reduced-dose prehospital fibrinolysis coupled with urgent PCI can reduce ischemic time in STEMI patients. One of the initial purposes of this pilot trial is to demonstrate the feasibility of urban paramedics to accurately and safely identify fibrinolytic-eligible STEMI patients and initiate therapy appropriately.

When an HFD paramedic arrives on scene and identifies a patient as experiencing a STEMI and a potential candidate for the administration of a fibrinolytic, the paramedic reviews the HFD Acute Myocardial Infarction Therapy Inclusion and Exclusion Criteria and enrolls the patient into the program.

Four STEMI patient groups are being evaluated:

  • Group A: Full-dose, prehospital initiated fibrinolysis (given half-dose in the ambulance and half-dose 30 minutes later) followed by treatment in the coronary-care unit;
  • Group B: Half-dose prehospital fibrinolysis followed by urgent PCI;
  • Group C: Patients who are ineligible for fibrinolysis; and
  • Group D: Patients not transported by participating EMS units.

Groups C and D are treated with primary PCI at the STEMI center. Although four groups of patients are evaluated, HFD paramedics simply classify each patient as either a patient to receive the fibrinolytic or one who met exclusion criteria. The decision to give or not give the fibrinolytic is made via on-line consultation with an emergency physician who had received a transmitted copy of the ECG.

Reperfusion is identified as greater than or equal to 70% STR on 12-lead ECG, with reduction in chest pain, or as Thrombolysis In Myocardial Infarction (TIMI) Flow Grade 2Ï3 (near normal or normal) in the infarct-related artery (IRA) on initial or post-PCI angiogram. Major bleeding was defined as bleeding resulting in substantial hemodynamic instability requiring intervention (GUSTO [Global Use of Strategies to Open Occluded Arteries] method).

Preliminary Results

The PATCAR trial has successfully revealed that urban paramedics can accurately identify STEMI patients prior to transporting them to a comprehensive cardiac-care center. A closer review of the data demonstrates that of 60 STEMI patients identified before entering the hospital, 46 were fibrinolytic eligible and treated in the ambulance with 10 units of reteplase, IV heparin and oral aspirin, and then randomized to either a second 10-unit dose of reteplase (Group A, n=22), or urgent catheterization with PCI (Group B, n=24).

Fibrinolytic-ineligible patients and patients brought in by non-participating EMS systems treated with primary PCI alone were prospectively analyzed for comparison (Group C+D non-transfer [NT], n=27). Four patients were excluded from analysis in Groups A and B because of inadvertent treatment delays or false-positive ECG results.

Group B (half-dose followed by PCI) experienced shorter ischemic times than Group A (two half-doses 30 minutes apart), (165 ± 54 minutes versus 270 ± 109 minutes) and Group C+D NT (221 ± 143 minutes) (see Table 1, p. 78). The time from contact (call to 9-1-1) to reperfusion (STR) was 114 ± 33 minutes for patients in Group B, compared with 168 ± 59 minutes in the patients in Group A, and 148 ± 94 minutes in the patients in Group C+D NT.

Eighty-two percent of Group B patients had TIMI Flow Grade 2 or 3 in the IRA on initial angiography, compared with 60% of Group A patients and 37% of primary PCI patients (see Figure 1, p. 79) (26).

No patients experienced an intracranial hemorrhage, and strokes were rare. One patient in Group B experienced a major bleed that occurred four days after admission and was not secondary to fibrinolytic therapy (see Table 1). Initial IRA TIMI flow grades of 2 to 3 are correlated with improved survival and were observed in 82% of Group B patients, compared with only 37% in Group C+D NT.

Sixty-eight percent of Group A patients crossed over to rescue PCI for persistent symptoms, ST-segment elevation or hemodynamic instability. Less than 50% of these had TIMI Flow Grade 2 or 3 IRA compared with 80% of the patients in Group B. This finding suggests that routine PCI immediately after prehospital fibrinolysis, irrespective of clinical setting, may be beneficial.

This sample is a relatively small feasibility study, not powered to detect a difference in major outcomes (i.e., mortality, stroke, reinfarction and major bleeding) among the groups. Groups A and B were randomized; however, Group C+D NT was an observational arm, which limits interpretation of the findings.

Curiously, Group A (half-dose fibrinolytic in the ambulance, half-dose 30 minutes later) had 0% mortality, compared with 3.8% for primary PCI and 4.8% for facilitated PCI. This group also had the longest ischemic time.

More Recent Data

Data has continued to be collected since randomization ended in the Houston trial study. The most current mortality and adverse events indicate a 30-day mortality rate of 2.7% in Group A, 3.1% in Group B and 6.0% in Group C (see Table 2, p. 79).

Although these data aren_t powered to detect a scientifically valid difference in mortality, it remains interesting that the fibrinolytic-only group continues to have the lowest mortality and fewest adverse events, trending away from the majority of the current literature, while the prehospital facilitated PCI group (Group B) is trending toward better mortality data than the primary PCI group (Group C).

It_s also important to note the reduction in door-to-balloon intervals as the number of HFD units trained and patient enrollment increased. This reinforces the current thinking that high-volume centers, including EMS provider agencies, will perform more efficiently than low-volume centers (see Figure 2, p. 80). (A copy of the inclusion/exclusion criteria is available at JEMS.com.)

Using data of primary PCI one-year mortality from previous studies (including CAPTIM and PRAGUE-2), a mortality versus time-to-treatment curve was constructed, which estimated a mortality rate among PATCAR patients to be 4.2%.

The measured mortality rate among all patients treated with prehospital fibrinolysis of 3.0% is more than 28% below the predicted level (see Figure 3, p. 82).

Conclusions

The strategy of diagnosing STEMI in chest-pain patients and administering reduced-dose fibrinolytic agents, heparin, aspirin and clopidogrel in the field by paramedics with simultaneous notification of the PCI team proved beneficial. It significantly reduced ischemic time, improved the quality of early myocardial reperfusion and wasn_t associated with excessive bleeding risks compared with full-dose prehospital fibrinolysis alone or primary PCI in an urban setting.

Patients with brief prehospital cardiac arrest, those in shock and elderly patients weren_t excluded, suggesting this strategy might be broadly applicable.

Our data, and those of others discussed in this article, suggest that reduced-dose prehospital fibrinolysis allows safe transport of STEMI patients to PCI centers for urgent culprit artery PCI, and may be a superior approach compared with transporting patients to the closest non-PCI hospital for fibrinolytic therapy.

Whether this strategy is superior to primary PCI remains to be determined. Further evaluation of the strategy of prehospital fibrinolytic acceleration of STEMI treatment, coupled with urgent PCI (FAST-PCI) in a large, multi-center, randomized trial compared with primary PCI, seems warranted.

References

1.
Rosamond W, Flegal K, Friday G, et al: ˙Heart disease and stroke statisticsƒ2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcomittee.Ó Circulation. 115:e69Ïe171, 2007.

2. Antman EM, Anbe DT, Armstrong PW, et al: ˙ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.Ó Circulation. 110:558Ï636, 2004.

3. Boersma E, Maas AC, Deckers JW, et al: ˙Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour.Ó Lancet. 348(9030):771Ï775, 1996.

4. Ribichini F, Ferrero V, Wijns W. ˙Reperfusion treatment of ST-elevation acute myocardial infarction.Ó Progress in Cardiovascular Disease. 47(2):131Ï157, 2004.

5. Boersma E, Mercado N, Poldermans D, et al: ˙Acute myocardial infarction.Ó Lancet. 361(9360):847Ï858, 2003.

6. De Luca G, Suryapranata H, Zijlstra F, et al: ˙Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty.Ó Journal of theAmericanCollege of Cardiology. 42(6):991Ï997, 2003.

7. De Luca G, Suryapranata H, Ottervanger JP, et al: ˙Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts.Ó Circulation. 109(15):1223Ï1225, 2004.

8. Kleinschmidt K, Brady WJ: ˙Acute coronary syndromes: An evidence-based review and outcome-optimizing guidelines for patients with and without procedural coronary intervention (PCI).Ó American Health Consultant. 21(25)286Ï295, 2000.

9. Zijlstra F, de Boer MJ, Hoorntje JC, et al: ˙A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction.Ó TheNew England Journal of Medicine. 328(10):680Ï684, 1993.

10. Grines CL, Browne KF, Marco J, et al: ˙A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction.Ó TheNew England Journal of Medicine. 328(10):673Ï679, 1993.

11. Ribichini F, Steffenino G, Dellavalle A, et al: ˙Comparison of thrombolytic therapy and primary coronary angioplasty with liberal stenting for inferior myocardial infarction with precordial ST-segment depression: Immediate and long-term results of a randomized study.Ó Journal of theAmericanCollege of Cardiology. 32(6):1687Ï1694, 1998.

12. Garcia E, Elizaga J, Perez-Castellano N, et al: ˙Primary angioplasty versus systemic thrombolysis in anterior myocardial infarction.Ó Journal of theAmericanCollege of Cardiology. 33(3):605Ï611, 1999.

13. ˙A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction.Ó TheNew England Journal of Medicine. 336(23):1621Ï1628, 1997.

14. Aversano T, Aversano LT, Passamani E, et al: ˙Thrombolytic therapy vs. primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: A randomized controlled trial.Ó JAMA. 287(15):1943Ï1951, 2002.

15. Keeley E, Boura JA, Grines C. ˙Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials.Ó Lancet. 361(9351):13Ï20, 2003.

16. Weaver WD, Simes RJ, Betriu A, et al: ˙Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review.Ó JAMA. 278(23):2093Ï2098, 1997.

17. Grines C, Patel A, Zijlstra F, et al: ˙Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: Six-month follow up and analysis of individual patient data from randomized trials.Ó American Heart Journal. 145(1):47Ï57, 2003.

18. McNamara R, Wang Y, Herrin J, et al: ˙Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction.Ó Journal of theAmericanCollege of Cardiology. 47(11):2180Ï2186, 2006.

19. Brodie BR, Stuckey TD, Wall TC, et al: ˙Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction.Ó Journal of theAmericanCollege of Cardiology. 32(5):1312Ï1319, 1998.

20. Steg PG, Bonnefoy E, Chabaud S, et al: ˙Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: Data from the CAPTIM randomized clinical trial.Ó Circulation. 108(23):2851Ï2856, 2003.

21. Widimsky P, Budesinsky T, Vorac D, et al: ˙Long distance transport for primary angioplasty vs. immediate thrombolysis in acute myocardial infarction: Final results of the randomized national multicentre trial PRAGUE-2.Ó European Heart Journal. 24(1):94Ï104, 2003.

22. Bonnefoy E, Lapostolle F, Leizorovicz A, et al: ˙Primary angioplasty vs. prehospital fibrinolysis in acute myocardial infarction: A randomized study.Ó Lancet. 360(9336):825Ï829, 2002.

23.Thiele H, Engelmann L, Elsner K, et al: ˙Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction.Ó European Heart Journal. 26(19):1956Ï1963, 2005.

24. Thiele H, Scholz M, Engelmann L, et al: ˙ST-segment recovery and prognosis in patients with ST-elevation myocardial infarction reperfused by prehospital combination fibrinolysis, prehospital initiated facilitated percutaneous coronary intervention, or primary percutaneous coronary intervention.Ó Journal of theAmericanCollege of Cardiology. 98(9):1132Ï1139, 2006.

25. Fernandez-Aviles F, Alonso JJ, Castro-Beiras A, et al: ˙Routine invasive strategy within 24 hours of thrombolysis versus ischemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): A randomized controlled trial.Ó Lancet. 364(9439):1045Ï1053, 2004.

26. Smalling RW, Giesler GM, Julapalli VR, et al: ˙Pre-hospital reduced-dose fibrinolysis coupled with urgent percutaneous coronary intervention reduces time to reperfusion and improves angiographic perfusion score compared with prehospital fibrinolysis alone or primary percutaneous coronary intervention: Results of the PATCAR pilot trial.Ó Journal of theAmericanCollege of Cardiology. 50(16):1612Ï1614, 2007.




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