Other thrombolytic agents in STEMI

Alteplase

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Study design

  • This study evaluated the safety and efficacy of a pharmaco-invasive strategy (using half-dose alteplase) vs. routine PPCI in patients (18-75 years) with STEMI, with an expected PCI-related delay, presenting within 6 hours of symptom onset.
  • A total of 344 STEMI patients were enrolled from 7 Chinese centres between January 2014 and September 2016 and randomised 1:1.
  • For 328 patients, primary endpoint data are available (pharmaco-invasive group, n=161; PPCI group, n=167).
  • Complete epicardial reperfusion (defined as TFG* 3) and myocardial reperfusion (defined as TMPG§ 3) after PCI, and complete (≥70%) reperfusion 60 minutes after PCI were the primary endpoint criteria.

*TFG: thrombolysis in myocardial infarction flow grade; §TMPG: thrombolysis in myocardial infarction myocardial perfusion grade

Results

EARLY-MYO Primary Endpoint Results Table

Conclusions

In STEMI patients presenting within 6 hours of symptom onset and with an expected PCI-related delay, a pharmaco-invasive strategy provided a more complete reperfusion (epicardial and myocardial) than PPCI.

References:

  1. Pu J, et al. Efficacy and safety of a pharmaco-invasive strategy with half-dose alteplase versus primary angioplasty in ST-segment-elevation myocardial infarction. EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment–Elevation Myocardial Infarction). Circulation 2017;136:00-00. DOI:10.1161/CIRCULATIONAHA.117.030582.

Primary percutaneous coronary intervention (PCI) has been shown to be superior to fibrinolysis in the treatment of ST-segment elevation myocardial infarction (STEMI) patients when it can be delivered in a timely manner by an experienced team. However, the advantages of primary PCI are less certain when there are delays associated with its administration. The DANish Acute Myocardial Infarction 2 (DANAMI-2) study compared fibrinolysis within hospitals with transfer to invasive-treatment centres for PCI. The average distance between referring hospitals and invasive-treatment centres was 50 km and up to 150 km.

Study design

The DANAMI-2 study randomly assigned 1,572 patients with acute ST-elevation myocardial infarction (symptoms present for ≥30 min but <12 h) to treatment with primary PCI or fibrinolysis (accelerated treatment with intravenous alteplase). Patients were enrolled at either 1 of 24 referral hospitals (n=1,129) or 1 of 5 invasive-treatment centres (n=443).

The primary endpoint was a composite of death from any cause, clinical evidence of re-infarction, or disabling stroke within 30 days of follow-up.

Results

Recruitment of patients to the DANAMI-2 trial was stopped ahead of schedule when the third interim analysis showed a significant benefit of PCI in the subpopulation of patients from referring hospitals.

The 30-day clinical outcomes support primary PCI over fibrinolysis for STEMI patients, even when the patients have to be transported from a local hospital to an invasive-treatment centre. The superiority of PCI over thrombolysis was driven by a 75% reduction in re-infarction, whereas the reductions in death and stroke did not reach statistical significance.

DANAMI-2: Clinical outcome at 30 days (n=1572)

DANAMI  2  Clinical  outcome  at  30  days The 30 day clinical outcomes supported superiority of primary PCI over fibrinolysis.

At long-term follow-up (median time 7.8 years), the benefit of primary PCI over fibrinolysis was maintained. There was a statistically significant reduction in re-infarction, whereas the reduction in death did not reach statistical significance.

(N.B. Stroke was not considered in the long-term follow-up as a clinical diagnosis could not be extracted from the registries.)

DANAMI-2: Clinical outcome at long-term follow-up (median time 7.8 years)

DANAMI  2  Clinical  outcome  at  long  term  follow  up The benefits of primary PCI over fibrinolysis was maintained in the long term follow up.

Conclusion

  • The clinical benefit of primary PCI over fibrinolysis was seen at both 30 days and at long-term follow-up, largely due to a reduction in the risk of re-infarction.
  • If the transfer of a patient to an invasive-treatment centre can be completed within 2 h, primary PCI is superior to on-site fibrinolysis.

References:

  1. Nielsen, PH, Maeng, M, Busk, M, et al. Primary Angioplasty Versus Fibrinolysis in Acute Myocardial Infarction. Circulation 2010;121:1484-1491.
  2. Andersen, HR, Nielsen, TT, Rasmussen, K, et al. A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction. N Engl J Med 2003;349:733-742.

The Comparison of primary Angioplasty and Pre-hospital fibrinolysis In acute Myocardial Infarction (CAPTIM) study was a randomised, clinical, multi-centre trial comparing pre-hospital thrombolysis with transfer to an interventional facility (and, if necessary, percutaneous coronary intervention [PCI]) with primary PCI in patients with ST-segment-elevation myocardial infarction (STEMI).

Through the collaboration between the CAPTIM and the WEST trialists more than 300 similarly randomised STEMI patients were added to the initial CAPTIM enrolment. The CAPTIM-WEST study examined the relationship between reperfusion strategy and time from symptom onset on 1-year mortality.

Study design

In CAPTIM 840 patients who presented within 6 h of onset of symptoms of acute myocardial infarction (characteristic pain lasting for at least 30 min, not responsive to nitrates, with ECG ST-segment elevation of ≥0.2 mV in two or more contiguous leads, or left bundle-branch block) were randomly assigned to either pre-hospital fibrinolysis with accelerated alteplase (n=419) or primary angioplasty (n=421). All patients were then transferred to a centre with access to emergency angioplasty. The trial took part in 27 tertiary hospitals and their affiliated mobile emergency care.

The primary endpoint was a composite of death, non-fatal re-infarction or non-fatal disabling stroke at 30 days.

Secondary endpoints included cardiovascular mortality, refractory recurrent ischaemia, cardiogenic shock, severe bleeding, or emergent revascularisation (angioplasty or CABG).

In CAPTIM-WEST 221 patients from the WEST trial were added to the fibrinolysis arm of CAPTIM and 107 patients were added to the primary PCI arm of CAPTIM. A total of 1168 STEMI patients were examined in the combined analysis.

The primary endpoint was all-cause mortality within 1 year.

CAPTIM/ CAPTIM-WEST: study design

CAPTIM  CAPTIM  WEST  study  design     In CAPTIM patients within 6h of onset of symptoms of acute myocardial infarction were randomised to either pre-hospital fibrinolysis or primary angioplasty. In CAPTIM-WEST, patients from WEST trial were added to both the treatment arm of CAPTIM.

Results

There was no significant difference in the composite primary endpoint between the pre-hospital fibrinolysis group and the primary PCI group at 30 days (8.2% versus 6.2%; risk difference 1.96; 95% confidence interval [CI] -1.53 to 5.46; p=0.29).

There were some differences in benefit between the two groups when the time elapsed from treatment onset was considered.

  • Randomisation within 2 h (n=460) or beyond 2 h (n=374) of symptom onset had no impact on the effect of treatment on the 30-day composite primary endpoint. However, patients randomised within 2 h had a strong trend toward lower 30-day mortality with pre-hospital fibrinolysis compared to those randomised to primary PCI (2.2% versus 5.7%, p=0.058) whereas patients randomised after 2 h had similar mortality (5.9% versus 3.7%, p=0.47).
  • Patients randomised 2 h to receive pre-hospital fibrinolysis had a lower incidence of cardiogenic shock than patients receiving primary PCI (1.3% versus 5.3%, p=0.032) whereas incidences were similar for patients randomised >2 h.
  • The differences in cardiogenic shock were mainly driven by lower incidences of shock developing in <2 h pre-hospital fibrinolysis patients during transport to the hospital.

CAPTIM: 30-day survival, patients treated within and after 2 hours of symptom onset

CAPTIM  30  day  survival  patients  treated  within  and  after  2  hours  of  symptom  onset     Patients randomised within 2h show lower mortality and incidence of cardiogenic shock with pre-hospital fibrinolysis in comparison with primary PCI

Overall 1-year mortality in CAPTIM-WEST was not significantly different between thrombolysis and primary PCI (4.6% vs. 6.5%, p=0.263).

CAPTIM-WEST: Kaplan-Meier curve of 1-year survival according to treatment

CAPTIM  WEST  Kaplan  Meier  curve  of  1  year  survival  according  to treatment      No significant difference is observed between thrombolysis and primary PCI in overall mortality.

The interaction between treatment and time from symptom onset to randomisation was statistically significant (p = 0.043).

  • Patients randomised < 2 hours of symptom onset benefited from treatment with thrombolysis compared to those receiving primary PCI (2.8% vs 6.9%, p = 0.021, HR 0.43, 95% CI 0.20- 0.91).
  • Beyond 2 hours, no treatment difference in 1-year mortality was observed (6.9% vs 6.0%, p = 0.529, HR 1.23, 95% CI 0.61-2.46).

CAPTIM-WEST: 1-year mortality, patients treated within and after 2 hours of symptom onset

CAPTIM  WEST  1  year  mortality  patients  treated  within  and  after  2  hours  of  symptom  onset   Thrombolysis treatment had improved outcome in comparison with primary PCI on treatment before 2 hours but no difference is observed after 2 hours.

CAPTIM 5-year follow-up

Data from the CAPTIM 5-year follow-up largely support the findings from the 30-day clinical outcome data.

  • Mortality at 5 years was similar for the pre-hospital fibrinolysis group and the primary PCI group (9.7% versus 12.6%; HR 0.75; 95% CI 0.50 to 1.14; p=0.18).
  • However, for patients randomised within 2 h of symptom onset, mortality was lower in the pre-hospital fibrinolysis group than the primary PCI group (5.8% versus 11.1%; HR 0.50; 95% CI 0.25 to 0.97; p=0.04).
  • For patients randomised after 2 h, mortality was similar.

CAPTIM: 5-year follow-up patient treated within 2 hours

CAPTIM  5  year  follow  up  patient  treated  within  2  hours  Mortality was lower in the pre-hospital fibrinolysis group in comparison with primary PCI with patients randomised within 2 hrs.

Conclusion

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  • Both, the 1- year follow-up of CAPTIM-WEST and the long-term follow-up of the CAPTIM study confirm that in reference to mortality, a strategy of pre-hospital fibrinolysis with immediate transfer and rescue angioplasty if needed appears to yield similar long-term survival benefits to primary PCI in STEMI patients managed within 6 h of symptom onset.
  • In patients managed within 2 hours, the pre-hospital fibrinolysis strategy reduced long-term mortality
  • The data underline that different reperfusion strategies might bring similar results at the acute phase of a myocardial infarction when an appropriate pre-hospital organisation is operative.

CAPTIM/ CAPTIM-WEST: study design -  In CAPTIM patients within 6h of onset of symptoms of acute myocardial infarction were randomised to either pre-hospital fibrinolysis or primary angioplasty. In CAPTIM-WEST, patients from WEST trial were added to both the treatment arm of CAPTIM.

References:

  1. Bonnefoy, E, Lapostolle, F, Leizorovicz, A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomised study. The Lancet 2002;360:825-829.
  2. Bonnefoy, E, Steg, PG, Boutitie, F, et al. Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up. Eur Heart J 2009;30:1598-1606.
  3. Steg, PG, Bonnefoy, E, Chabaud, S, et al. Impact of Time to Treatment on Mortality After Prehospital Fibrinolysis or Primary Angioplasty. Circulation 2003;108:2851-2856.
  4. Westerhout, CM, Bonnefoy, E, Welsh, RC, et al. The influence of time from symptom onset and reperfusion strategy on 1-year survival in ST-elevation myocardial infarction: A pooled analysis of an early fibrinolytic strategy versus primary percutaneous coronary intervention from CAPTIM and WEST. Am Heart J 2011;161(2):283-290.
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Reteplase

The Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial was designed to test the hypothesis that PCI that is facilitated with the use of a combination of abciximab and reduced-dose reteplase would be more effective than primary PCI, in which abciximab is administered in the catheterisation laboratory immediately before PCI. A group for whom PCI was facilitated by abciximab alone was included to help clarify the contribution of this component of the combination therapy to the clinical outcome.

Study design

FINESSE: Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events

Patients were randomised in a 1:1:1 fashion to 3 treatment arms:

  1. Facilitated PCI with reduced-dose reteplase and abciximab bolus doses administered in the emergency department;
  2. Facilitated PCI with abciximab bolus administered in the emergency department;
  3. Primary PCI with abciximab initiated in the cardiac catheterisation laboratory.

FINESSE: Study design

FINESSE  Study  design  Acute patients with STEMI or new LBBB were randomised into three treatment arms: primary PCI, Abciximab coupled PCI and Reteplase plus abciximab coupled PCI

The primary endpoint was a composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomisation, cardiogenic shock, and congestive heart failure requiring rehospitalisation or an emergency room visit through 90 days.

Secondary endpoints were complications of MI through 90 days, death from all causes through 90 days, and ST-segment resolution of more than 70% from baseline as assessed at 60 to 90 minutes after randomisation.

Results

The 90-day primary composite endpoint occurred in 9.8% of the patients in the combination-facilitated PCI group, 10.5% of the patients in the abciximab-facilitated PCI group, and 10.7% of the patients in the primary PCI group (hazard ratio in the combination-facilitated PCI group as compared with the primary PCI group, 0.91; 95% confidence interval [CI], 0.67 to 1.23).

Complications of myocardial infarction occurred in 7.4%, 7.5%, and 9.0% of patients in the three groups, respectively, with no significant differences.

The individual components of the primary endpoint did not differ significantly among the combination facilitated PCI, abciximab-facilitated PCI, and primary-PCI groups.

FINESSE: Kaplan-Meier curves for the primary endpoint at 90 days

FINESSE  Kaplan  Meier  curve  for  the  primary  endpoint  at  90  days  Primary endpoints did not siginificantly differ in the PPCI, Abciximab PCI, and Reteplase/Abciximab PCI

All-cause mortality at 1 year was, 6.3%, 7.4%, and 7.0% in the combination- facilitated PCl, abciximab-facilitated PCI, and primary PCI with in-Iab abciximab groups, respectively (p=non-significant), which represented a 1.1%, 1.9%, and 2.5% increment from the initial 90-day endpoint (p=0.053 for combination vs. primary PCI).

FINESSE: All-cause mortality at 1 year

FINESSE  All  cause  mortality  at  1  year   All cause mortality was not significantly different in combination facilitated PCI, Abciximab facilitated PCI and primary PCI

Conclusion

  • The primary endpoint did not differ significantly between the treatment groups.
  • Neither of the facilitated PCI strategies provided a clinical benefit compared with primary PCI with in-lab abciximab.
  • Reteplase/abciximab facilitation, and to a lesser extent abciximab facilitation, increased bleeding compared with the in-lab administration of abciximab.
  • Primary PCI with in-lab abciximab provides a better benefit-to-risk ratio than the two facilitated strategies in patients with STEMI who can undergo PCI within 4 hours of the first medical contact.
  • 1-year follow-up survival data confirms the overall lack of significant clinical benefit with either of the treatment regimens tested for non-high-risk patients.
  • ln a subgroup of patients identified as high risk on the basis of a modified TIMI risk score ≥3, presentation to a spoke site without PCI capability, and with a symptom-to-randomisation time ≤4 h, facilitation of PCI with early administration of a combination of abciximab and half-dose reteplase or abciximab alone may reduce 90-day clinical outcomes compared with abciximab given just before PCI.
  • Furthermore, combination-facilitated PCI significantly reduced 1-year mortality as compared with primary PCI.

References:

  1. Ellis SG, et al. Facilitated percutaneous coronary intervention versus primary percutaneous coronary intervention: design and rationale of the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial. Am Heart J 2004;147:684.
  2. Ellis SG, et al. Facilitated PCI in Patients with ST-Elevation Myocardial Infarction. N Eng J Med 2008;358:2205-2217.
  3. Ellis SG, et al. 1-Year Survival in a Randomized Trial of Facilitated Reperfusion. JACC 2009;2(10):909-916.
  4. Herrmann HC, et al. Benefit of Facilitated Percutaneous Coronary Intervention in High-Risk ST-Segment Elevation Myocardial lnfarction Patients Presenting to Nonpercutaneous Coronary Intervention Hospitals. JACC 2009;2(10):917-924.
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Streptokinase

The aim of the PRAGUE-2 study was to compare the therapeutic effects of intravenous streptokinase with the immediate transport for primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI), admitted to hospitals without PCI facilities in the Czech Republic, where the distance between primary hospitals and tertiary PCI centres does not exceed 120 km.

Study design

In the PRAGUE-2 study, 850 patients with acute STEMI presenting within 12 h of symptom onset to the nearest community hospital without a catheter laboratory (located <120 km from the next PCI centre) were randomised to either thrombolysis administered at the initial receiving hospital (thrombolysis group, n=421) or immediate transport (within 30 min of randomisation) for primary PCI (PCI group, n=429).

The primary endpoint was mortality at 30 days (death from any cause within 30 days after randomisation).

Secondary endpoints included the presence of any serious clinical event (death/non-fatal re-infarction/non-fatal stroke) at 30 days, and mortality at 30 days among subgroups of patients treated within 0–3 h and 3–12 h after symptom onset.

Results

A non-significant reduction in mortality for the PCI group compared with the thrombolysis group (6.8% versus 10.0%; p=0.12) was observed at 30-days.

Prague-2: 30-day mortality (n=850)

Prague-2  30  day  mortality Non significant reduction in mortality for the PCI group was observed in comparison with thrombolysis

While mortality was similar between groups for the 551 patients that were randomised within 3 h (mean: 1 h 41 min), mortality for the 299 patients that were randomised after 3 h (mean: 5 h 6 min) was significantly higher in the thrombolysis group (15.3% versus 6.0%; p>0.02). This difference led the ethical committee to stop the trial prematurely.

Prague-2: Time delay: PCI versus thrombolysis (n=850)

Prague-2  Time  delay  PCI  versus  thrombolysis High mortality rate with thrombolysis was observed with patients randomised after 3 hrs.

At long-term follow up (5 years), the benefit of primary PCI persisted. There was a reduction in the cumulative incidence of primary endpoint (death, re-infarction, stroke or revascularisation) for the PCI group (40% versus 53%; p<0.001). This benefit was almost exclusively derived from differences in event rate during the first 30 days.

Conclusion

  • Thrombolysis is less effective than primary PCI in “late presenters” (i.e. those patients presenting >3 h) and therefore these patients should be routinely transferred for primary PCI.
  • The results of this study are limited since streptokinase was used rather than a more potent thrombolytic; however, results were in good agreement with those from DANAMI-2, in which alteplase, a tissue plasminogen activator, was used.

References:

  1. Widimsky P, et al. Long-term outcomes of patients with acute myocardial infarction presenting to hospitals without catheterization laboratory and randomized to immediate thrombolysis or interhospital transport for primary percutaneous coronary intervention. Five years' follow-up of the PRAGUE-2 trial. Eur Heart J 2007;28:679-684.
  2. Widimský P, 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. Eur Heart J 2003;24:94-104.
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