Tenecteplase in STEMI

Assessment of the clinical pharmacology of tenecteplase in humans with AMI

Evaluation of pharmacokinetics and gross safety and efficacy of TNK in 113 patients with AMI:

  • prolonged half-life allows for single-bolus administration,
  • TNK is highly fibrin specific with encouraging patency and safety profiles.

A prospective angiographic comparison of single-bolus tenecteplase with accelerated alteplase in 886 patients:

  • rate of TIMI grade 3 flow at 90 minutes with tenecteplase 40 mg was comparable to that of accelerated alteplase

Pharmacokinetics

Tenecteplase exhibits a biphasic disposition in the plasma. The initial disposition phase is predominant with a mean half-life of 17-24 minutes and a mean terminal half-life of 65-132 minutes. Over the clinically relevant dose range 30-50 mg investigated in TIMI 10B:

  • mean clearance (CL) was 105 mL/min,
  • mean initial volume of distribution (V1) was 4.2-6.3 L, and is weight related,
  • approximating plasma volume, and volume of distribution at steady state was 6.1-9.9 L, suggesting limited extravascular distribution or binding.

The graphic illustrates the time-dependent plasma concentrations of alteplase and tenecteplase. The plasma concentration after a single bolus of tenecteplase was higher than that of alteplase given as bolus plus 90-minute infusion, but the area under the curve was similar to that of alteplase.

TIMI 10B: Pharmacokinetics of TNK-t-PA

TIMI  10B  Pharmacokinetics  of  TNK  t  PA The graph showing time-dependent plasma concentrations of TNK and TPA

TIMI 10B: Fibrin specificity of TNK

TIMI  10B  Fibrin  specificity  of  TNK The graph showing specificity of TNK and TPA for fibrin and plasminogen

High Fibrin specifity, low plasminogen specificity

Tenecteplase has a far less effect on systemic coagulation factors than alteplase, because it is more fibrin specific. There was a 5-10% drop in fibrinogen over the first six hours after administration of tenecteplase, compared with a 40% drop after alteplase. The fall of plasminogen was only 10-15% after tenecteplase, compared to a 50% drop after alteplase.

Efficacy of clots lysis with TNK

Patency (TIMI grade 2/3 flow) at 90 min was 76.8-88.2% for tenecteplase and 81.7% for alteplase, the lower rate with 30 mg tenecteplase was the only significant difference. The rate of TIMI grade 3 flow was 62% for doses of 0.5 mg/kg and higher, but was 51-54% at doses lower than this (p=0.028 across quintiles of weight-corrected dose of TNK).

TIMI 10B: Efficacy of clot lysis with TNK

TIMI  10B  Efficacy  of  clot  lysis  with  TNK  Bar graph showing efficacy of clot lysis with TNK  and TPA treatment groups

TIMI 10B: Efficacy of clot lysis with TNK

TIMI  10B  Efficacy  of  clot  lysis  with  TNK  Line graph showing patency (TIMI grade 3 flow) at 90 min for TNK and TPA treatment groups

References:

  1. Cannon et al. Circulation 1998; 98 (25): 2805–2814.

ASSENT-1 (Assessment of the Safety and Efficacy of a New Thrombolytic) was a phase II randomised, open label, multicentre trial of TNK in AMI. A large cohort of 3235 AMI patients who presented within 12 hours of symptom onset in order to identify an appropriate dose of tenecteplase received a single bolus over 10 seconds for testing in a large mortality trial. 1705 patients received 30 mg, 1457 received 40 mg. Only 73 patients received 50 mg, because this dose was replaced by 40 mg along with reduced-dose heparin protocol when an increased incidence of stroke was observed in the concurrently running TIMI 10B study. It is conceivable that the increased stroke incidence with 50 mg in TIMI 10B was due to chance, as no ASSENT-1 patient receiving 50 mg experienced a stroke and the stroke pattern in ASSENT-1 didn’t display a dose-event relationship.

The graphic shows the major clinical outcomes recorded at 30 days for the total study population. In general, survival rates and net clinical benefit (survival without stroke) were high, especially in patients treated within 6 hours. No striking differences were found between the 30 mg and 40 mg tenecteplase groups with the exception of a higher incidence of reinfarction in the 30 mg group.

The total stroke rate (1.5%) at 30 days was similar to that observed in other trials of thrombolytic therapy, as was the overall safety profile.

There was a non significant trend towards lower rates of intracranial haemorrhage among those patients treated within 6 hours after symptom onset and among those treated after heparin doses were lowered and titration of heparin was started at 6 hours.

ASSENT-1 protocol design

ASSENT  1  protocol  design  Flowchart showing ASSENT 1 study design in which STEMI < 12 hours patients are randomised into treatment groups of different doses of TNK-tPA

ASSENT-1: Major clinical outcomes at 30 days

ASSENT  1  Major  clinical  outcomes  at  30  days  Graphic showing incidence of death, reinfarction, non-fatal stroke occuring in different doses of tenecteplase in 30 days

Incidence of stroke at 30 days

Incidence  of  stroke  at  30  days  Graphic showing incidence of stroke, ICH, ischaemic stroke occuring in different doses of tenecteplase in 30 days

Subgroup analysis of ICH

Subgroup  analysis  of  ICH Graphic showing incidence of ICH in TNK treatment subgroups treated at different time durations and with varied doses of heparin

 

References:

  1. Van de Werf et al. Am Heart J 1999; 137 (5): 786–791.

 

Design

This study was a double-blind, randomised equivalency trial with 16,949 STEMI patients in 29 countries to receive either

  • 100 mg alteplase infused over 90 minutes or
  • 30-50 mg tenecteplase administered as a single bolus over 5-10 seconds, dosed according to body weight (0.50-0.55 mg/kg ), which is identical to the recommendation in the current licence for Metalyse®.

The efficacy results from TIMI 10B and the safety data from ASSENT-1 suggested that a tenecteplase dose of 0.53 mg/kg represented the inflection point between continuous reperfusion benefit with increasing dose and the plateau of no further benefit with further increasing doses. Therefore, this dose was selected for testing against front-loaded alteplase in the ASSENT-2 phase III mortality trial.

Additionally all patients received:

  • aspirin, 150-325 mg as soon as possible, followed by 15-325 mg daily, and
  • heparin, bolus of 4000 U and infusion of 800 U/h for patients who weighted 67 kg or less or 5000 U bolus and infusion of 1000 U/h for patients who weighted more, adjusted to maintain an activated partial thromboplastin time of 50-75 seconds for 48-72 hours.

The primary endpoint of the study was all-cause mortality at 30 days, secondary endpoints included net clinical benefit (absence of death or non-fatal stroke at 30 days), major non-fatal cardiac events in hospital, and stroke.

ASSENT-2: Study design

ASSENT  2  Study  design  ASSENT 2 randomised STEMI patients <= 6 h into either tenecteplase or alteplase treatment arm and observed all-cause mortality at 30 days as primary endpoint.

30-day mortality

Overall, 30-day mortalities for treated patients were almost identical:

  • 6.18% in the tenecteplase group and
  • 6.15% in the alteplase group.

The one-sided 95% CI of the absolute and relative differences in 30-day mortality fulfilled the pre-specified criteria of equivalence. There was no subgroup of patients with significant differences between tenecteplase and alteplase, with the exception of patients treated after 4-6 hours from symptom onset. This group benefits from a statistically significant absolute difference of 2.2% in 30-day mortality (7.0% for tenecteplase versus 9.2% for alteplase, p=0.018). The higher fibrin specificity of tenecteplase compared to alteplase probably leads to better dissolution of older thrombi.

ASSENT-2: 30-day mortality confirms equivalence of tenecteplase and alteplase

ASSENT 2  30  day  mortality  confirms  equivalence  of   tenecteplase  and  alteplase  30 day mortalities for patients treated in TNK-t-PA and rt-PA groups were almost identical

ASSENT-2: 30-day mortality in patient subgroups

ASSENT 2  30  day  mortality  in  patient  subgroups  Table showing no significant differences in 30 day mortality in patient subgroups treated either with TNK or rt-PA

Frequency of non-intracranial bleeding

In the tenecteplase group significantly fewer major bleeding complications occurred, resulting in a significantly lower need for blood transfusions, probably because of the higher fibrin specificity of tenecteplase.

Frequency of strokes

Rates of total stroke were comparable in both treatment groups:

  • 1.78% for tenecteplase and
  • 1.66% for alteplase.

Rates of intracranial haemorrhage (ICH) were similar, too. Overall, the stroke rates seen in ASSENT-2 were similar to those seen in earlier trials such as GUSTO-III.

ASSENT-2: Frequency of non-intracranial bleeding complications

ASSENT  2  Frequency  of  non  intracranial  bleeding  complications  Table showing frequency of non-intracranial bleeding complications on treatment either with TNK-t-PA or rt-PA

ASSENT-2: Frequency of strokes

ASSENT  2  Frequency  of  strokes  Table showing comparable rates of stroke and intracranial haemorrhage on treatment either with TNK-t-PA or rt-PA

Risk factors for intracranial haemorrhage

Increasing age, low body weight, history of hypertension and systolic blood pressure >140 mm/Hg on admission were independent risk factors identified by multivariate analysis, similar to those reported in other trials. Patients that are generally considered to be at high risk of ICH did not have particularly high rates of ICH when treated with tenecteplase. In fact, patients with the composite risk profile of being female, age >75 years and weight <67 kg tended to have lower rates of ICH when treated with tenecteplase (3/264, 1.14%) than with alteplase (8/265, 3.02%). Such observations confirm the safety of tenecteplase in high-risk patients.

ASSENT-2: Risk factors for intracranial haemorrhage

ASSENT  2  Risk  factors  for  intracranial  haemorrhage  Table showing effect of TNK or rt-PA treatment and various other risk factors on intracranial haemorrhage

One year follow-up

The total mortality rate of 9.2% with single-bolus tenecteplase and 9.1% of front-loaded alteplase remain equivalent after one year. The lower 30-day mortality rate in patients treated 4-6 hours after onset of symptoms persisted at one year follow-up, but was no longer statistically significant.

The results of ASSENT-2 confirm that tenecteplase is equivalent to alteplase in treatment of AMI with respect to the 30-day and one year outcomes for mortality and the combined outcomes for mortality and non-fatal stroke.

ASSENT-2: One year follow-up

ASSENT  2  One  year  follow  up  Kaplan-Meier curve showing survival rate on treatment either with Alteplase or Tenecteplase after one year

References:

  1. ASSENT-2 Investigators. Lancet 1999; 354 (9180): 716-722.
  2. Van de Werf Eur Heart J 2001; 22 (24): 2253-2261. (link is external)
  3. Sinnaeve et al. Am Heart J 2003; 146 (1): 27-32. (link is external)

As current fibrinolytic therapies fail to achieve optimum reperfusion in many patients and low-molecular-weight heparins and platelet glycoprotein IIb/IIIa inhibitors have shown the potential to improve pharmacological reperfusion therapy in the HART II trial, the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 study, compared the efficacy and safety of tenecteplase plus enoxaparin or abciximab, with that of tenecteplase plus weight-adjusted unfractionated heparin in patients with acute myocardial infarction.

The ASSENT-3 Plus trial was a trial of pre-hospital fibrinolysis with tenecteplase randomly assigned to enoxaparin or unfractionated heparin, that involved 106 sites in 12 countries incorporating a wide variation in population density, emergency medical services resources, and physician's interpretation of ECG and administering pre-hospital fibrinolysis. Understanding this diversity will help in evaluating the general applicability and feasibility of pre-hospital fibrinolysis in various health systems, as well as the pre-hospital care of ST elevation myocardial infarction patients regardless of reperfusion strategies.

Study design

The ASSENT-3 trial was a randomised, open-label trial designed to compare the efficacy and safety of tenecteplase plus enoxaparin or abciximab, with that of tenecteplase plus weight-adjusted unfractionated heparin. A total of 6095 patients with acute myocardial infarction were randomised to one of three open-label regimens:

  • Full-dose tenecteplase and enoxaparin (a low molecular weight heparin) for a maximum of 7 days (n=2040).
  • Half-dose tenecteplase with weight-adjusted low-dose unfractionated heparin and a 12-hour infusion of abciximab (n=2017).
  • Full-dose tenecteplase with weight-adjusted unfractionated heparin for 48 hours (n=2038). The chart shows the overall trial profile.

ASSENT-3: Study design

ASSENT 3  Study  design ASSENT 3 randomised STEMI patients into three open label treatment arms: Tenecteplase plus enoxaparin or tenecteplase plus heparin plus abciximab or tenecteplase plus heparin

The primary efficacy endpoint

At 48 hours, the end of the unfractionated heparin infusion, differences in the primary endpoints among the three groups were already present.

For the primary efficacy endpoint, event rates were:

  • 6.1% for full-dose tenecteplase plus enoxaparin,
  • 5.2% for half-dose tenecteplase plus abciximab, and
  • 8.8% for full-dose tenecteplase plus unfractionated heparin (P<0.0001).

At 30 days, when compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and halfdose tenecteplase with abciximab were associated with significant reductions in the primary end points: 15.4% vs 11.4% vs 11.1%, respectively for the efficacy composite endpoint (3 way P<0.0001). The Kaplan-Meier curves for the enoxaparin and abciximab arms start to separate early from that of unfractionated heparin.

The results of the primary efficacy endpoint are shown here in a bar graph after correcting for multiple testing (Bonferroni). Conventional significance was reached for the primary efficacy endpoint when the enoxaparin group was compared to the unfractionated heparin group (p=0.0009) and when the abciximab group was compared to the unfractionated heparin group (p=0.0002).

ASSENT-3: Efficacy endpoints

ASSENT 3  Efficacy  endpoints  Bar graph showing significant reduction in the risk of death, reinfarction or refractory ischaemia when treated with TNK + enoxaparin and TNK + abciximab in comparison with TNK + heparin treatment>

Efficacy plus safety endpoints

Kaplan-Meier curves for the primary efficacy and safety composite endpoint show that differences were already apparent between the three groups at 48 hours, the end of the unfractionated heparin infusion. For the primary efficacy and safety endpoint, event rates were 8.1% for full dose tenecteplase plus enoxaparin, 8.2% for half dose tenecteplase plus abciximab, and 10.3% for full-dose tenecteplase plus unfractionated heparin.

At 30 days, when compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and half-dose tenecteplase with abciximab were associated with significant reductions in the efficacy plus safety composite end point. Again, the curves for the enoxaparin and abciximab arms start to separate early from that of unfractionated heparin. There does not appear to be any early hazard associated with the therapy. Most of the benefit appeared to accure during the first week of therapy. There did not appear to be any rebound after discontinuation of the enoxaparin after the first week.

ASSENT-3: Efficacy plus safety endpoints

ASSENT 3  Efficacy  plus  safety  endpoints At 30 days, TNK + enoxaparin and TNK + abciximab were associated with significant reduction in efficay and safety  endpoints in comparison with TNK + heparin.

Thrombocytopenia and bleeding rates

However, just as in GUSTO-V, the benefit of increased patency is achieved at a price in terms of higher rates of thrombocytopenia, major bleeding complications and blood transfusions. It is particularly noteworthy that no benefit and perhaps even harm was observed in patients above 75 years and in diabetics, suggesting a need for caution in both groups.

ASSENT-3: Rates of in-hospital thrombocytopenia and bleeding episodes

ASSENT 3  Rates  of  in  hospital  thrombocytopenia  and  bleeding  episodes  Higher rates of thrombocytopenia, major bleeding complications and blood transfusions were observed with TNK + enoxaprin, TNK + abciximab in comparison with TNK + heparin treatment

30-day mortality

The results of the primary efficacy and safety composite endpoint are presented in a graphic format. When compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and half-dose tenecteplase with abciximab were associated with significant reductions in the efficacy plus safety composite endpoint (3 way p=0.0062).

For the comparison of full-dose tenecteplase plus enoxaparin vs fulldose tenecteplase plus unfractionated heparin the P value was 0.0037 for the primary efficacy and safety endpoint. For the comparison of half-dose tenecteplase plus abciximab vs full-dose tenecteplase plus unfractionated heparin the P-value was 0.0142 for the primary efficacy and safety endpoint. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy and safety endpoint at 30 days in the enoxaparin group (p=0.0146) but not in the abciximab group (p=0.057). A 3 way P value showed no statistically significant difference across the 3 arms in 30-day mortality.

ASSENT-3: 30-day mortality

ASSENT 3  30  day  mortality  Bar graph showing no significant difference between TNK + enoxaparin, TNK + abciximab and TNK + heparin treatment groups in 30-day mortality

ASSENT-3 PLUS

The ASSENT-3 PLUS satellite study was the first large randomised study to evaluate the feasibility and efficacy of pre-hospital thrombolysis in a multinational environment. It compared tenecteplase administered prior to hospital arrival against the full-dose tenecteplase cohort in the ASSENT-3 trial treated in hospital. A total of 1639 patients with ST elevation myocardial infarction and chest pain of less than 6 hours duration were evaluated at home or in ambulance by an emergency medical team. In each case, a 12-lead ECG was transmitted to the Emergency Department from the ambulance, and patients were randomised to one of two treatment groups, with treatment started during transport:

  • tenecteplase plus IV bolus of 30 mg enoxaparin followed by 1 mg/kg subcutaneously BID for up to 7 days (n=818).
  • tenecteplase plus weight-adjusted unfractionated heparin for 48 hours (n=821).

ASSENT-3 PLUS: Trial profile

ASSENT  3  PLUS  Trial  profile  ASSENT 3 PLUS randomised STEMI patients into either TNK plus enoxaprin or TNK plus heparin treatment arm

Pre-hospital use of tenecteplase

ASSENT-3 PLUS clearly supports the concept that early treatment is beneficial as “Time is Muscle”:

Symptom onset to treatment times were reduced by 47 minutes. 53% of patients were treated within 2 hours, which represents a significant improvement over ASSENT-3, in which only 29% of the 4,000 patients receiving the same regimens in the hospital setting were treated within the same time period.

Earlier treatment was associated with improved 30-day mortality:

  • 4.4% among those treated at 0-2 hours,
  • 6.2% among those treated at 2-4 hours, and
  • 10.4% among those treated at 4-6 hours.

In subgroup analysis, intracranial haemorrhage was found to be greater in the enoxaparin group in patients more than 75 years old (6.7 versus 0.8% p=0.04). Such patients represent a higher-risk population, which may explain the non-statistically significant trend toward increased major bleeding in the enoxaparin group (4.04% vs. 2.80%, p=0.168). Therefore, reduced or weight-adjusted dosing of enoxaparin may be warranted in these patients.

References:

  1. Ross et al. Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II). ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358 (9282): 605–613.
  2. Wallentin et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003; 108 (2): 135–142.

The Assessment of the Safety and Efficacy of a New Treatment Strategy with percutaneous coronary intervention (ASSENT-4 PCI) study was intended to be a large randomised trial in patients facing delays to intervention in the range of 1 to 3 hours. PCI is more effective than thrombolytic therapy in patients with ST-elevation acute myocardial infarction (STEMI) when the time to treatment is short. The aim of ASSENT-4 PCI was to investigate whether full-dose tenecteplase administered prior to a delayed percutaneous coronary intervention (facilitated PCI) could mitigate the negative effect of the delay to PCI.

The study was stopped prematurely on the recommendation of the Data and Safety Monitoring Board due to higher mortality in the facilitated PCI group compared to the standard PCI group.

Study design

The ASSENT-4 PCI study randomly assigned 1,667 (of a planned 4,000) patients with ST-elevation myocardial infarction (STEMI) of ≤6 h duration (scheduled to undergo PCI with an anticipated delay of 1 to 3 h) to standard PCI (n=838) or PCI preceded by full-dose tenecteplase (n=829). All patients received aspirin and a bolus, without an infusion, of unfractionated heparin. Patients were enrolled from 24 countries at tertiary care hospitals, community hospitals without PCI centres, and ambulances in which pre-hospital thrombolysis was available.

The primary endpoint was a composite of 90-day mortality or cardiogenic shock* or congestive heart failure*.

*adjudicated by the Clinical Event Committee

ASSENT-4 PCI: STUDY DESIGN

ASSENT 4  PCI  STUDY  DESIGN   ASSENT 4 randomised STEMI patients of <=6 h to Full-dose TNK+PCI or primary PCI

Trials summary

The ASSENT trials: ASSENT-2, ASSENT-3/ ASSENT 3-PLUS, ASSENT-4 PCI have provided a deep insight into the effects of tenecteplase. The table below gives a brief summary of these studies.

Trials summary Table

Results

The time between onset of symptoms and randomisation and catheterisation was similar between groups. The median time to administration of tenecteplase was 10 min. The time delay to PCI was 107 min in the PCI only group and 115 min in the facilitated PCI group.

The primary endpoint was significantly higher in the facilitated PCI group than in the standard PCI group (19% versus 13%; relative risk 1.39; 95% confidence interval [CI] 1.11 to 1.74; p=0.0045). However, there was no significant difference in any of the individual components of this composite endpoint (death, CHF, cardiogenic shock).

The facilitated PCI group had higher rates of stroke (1.8% versus 0%; p<0.0001), re-infarction (6% versus 4%; p=0.0279), repeat target revascularisation (7% versus 3%; p=0.0041) than the standard PCI group within 90 days. However, there was no significant difference in the rate of major non-cerebral bleeding complications (6% versus 4%; p=0.3118).

ASSENT-4 PCI: Kaplan-Meier curve for primary endpoint

ASSENT 4  PCI  Kaplan  Meier  curve  for  primary  endpoint  The primary endpoint was significantly higher in the TNK+PCI group than the PCI alone

Conclusion

Facilitated PCI, using full-dose tenecteplase 1-3 hours prior to PCI was associated with more major adverse events than PCI alone in STEMI and cannot be recommended.

References:

  1. ASSENT-2 Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-722.
  2. Sinnaeve P, et al. One-year follow-up of the ASSENT-2 trial: a double-blind, randomized comparison of a single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction. Am Heart J 2003;146:27-32.
  3. ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-613.
  4. Wallentin L, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting. The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS Randomized Trial in Acute Myocardial Infarction. Circulation 2003;108:135-142.
  5. ASSENT-4 PCI Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet 2006;367:569-578.

The STrategic Reperfusion Early After Myocardial Infarction (STREAM) study investigated whether thrombolysis at first medical contact, followed by timely angiography or rescue percutaneous coronary intervention (PCI) if indicated in patients with acute ST-segment elevation myocardial infarction (STEMI) presenting within 3 h not able to undergo primary PCI within 60 min, is an appropriate and effective alternative reperfusion strategy (pharmaco-invasive) to PPCI.

The objective was to evaluate the outcome of patients presenting with STEMI within 3 h of symptom onset treated by the early administration of tenecteplase followed by angiography within 6-24 hours unless rescue intervention is indicated. The comparator arm consisted of the treatment with routine primary PCI alone according to local standards.

Study design

STREAM was an open-label, prospective, parallel, randomised, multinational trial to evaluate the outcome of acute STEMI patients presenting within 3 h of symptom onset, with approximately 1,000 patients in each arm. Patients who cannot undergo PCI within an hour are randomised to thrombolysis with tenecteplase within a pharmaco-invasive strategy or PPCI.1 It is important to note that STREAM was not a trial of lytic-facilitated PCI trial, in which all patients undergo immediate PCI.1 In STREAM, only lytic-treated patients with ECG or clinical evidence of failed reperfusion undergo immediate rescue intervention; the others undergo cardiac catheterisation (and any required follow-up procedures) between 6 and 24 h.1

Figure 1. STREAM: Study design

STREAM Study design  Figure showing STREAM study design describing therapy in two different groups and endpoints of the study

The primary endpoint at 30 days was a composite of death from any cause, shock, congestive heart failure (CHF), or re-infarction.1

Results

1,915 patients from 15 countries were enrolled between March 2008 and July 2012. Of these, 1892 patients were randomised and provided informed consent to receive pharmaco-invasive therapy (n=944) or primary PCI (n=948).1

The primary endpoint occurred in 116 of 939 patients (12.4%) in the thrombolysis group and in 135 of 943 patients (14.3%) in the PPCI group (relative risk in the thrombolysis group, 0.86; 95% confidence interval [CI], 0.68 to 1.09; p=0.21).1

Figure 2. STREAM: primary endpoint at 30 days

STREAM  Primary  endpoint  at  30  days  Graph showing the STREAM primary endpoints such as death, shock,CHF,ReMI at 30 days

Figure 2 shows the STREAM primary endpoint at 30 days.2 This result was consistent across the pre-specified subgroups, namely age, gender, Killip class, time to randomisation, place of randomisation, infarct location, systolic blood pressure, weight, history of diabetes or hypertension, TIMI risk score, and randomisation before or after the protocol amendment.2

When looking at the individual components of the primary endpoint, cardiogenic shock and congestive heart failure tended to occur more frequently in the primary PCI group than in the thrombolysis group (Figure 3).2

Figure 3. STREAM: Individual divponents of the primary endpoint at 30 days

STREAM  Individual  components  of  the  primary  endpoint  at  30  days  Bar graph comparing the incidence of individual components of the STREAM primary endpoints at 30 days in the primary PCI group with the thrombolysis group.

The incidence of intracranial bleeding was higher in the pharmaco-invasive group compared to the PPCI group (1.0% vs. 0.2%, p=0.04), but this was reduced when the protocol was altered so that patients older than 75 years of age received half-dose tenecteplase instead of full-dose (intracranial bleeding: 0.5% for pharmaco-invasive group vs. 0.3% for PPCI, p=0.45).2

Conclusion

  • A strategy of thrombolysis with bolus tenecteplase and contemporary antithrombotic therapy given before transfer to a PCI-capable hospital coupled with timely coronary angiography:1,2
    • Circumvents the need for an urgent procedure in about two thirds of thrombolytic-treated STEMI patients.
    • Is associated with a slightly increased risk of intracranial bleeding.
    • Is as effective as PPCI in STEMI patients presenting within 3 hours of symptom onset who cannot undergo PPCI within one hour of first medical contact.
  • STREAM has demonstrated how established fibrinolytic therapy has evolved to a new fibrinolytic strategy and how it can be safely and efficiently delivered. For patients with STEMI around the world who do not have timely access to PPCI, pharmaco-invasive treatment strategy should be implemented unless contraindicated, with fibrinolytic therapy followed by timely coronary angiography, if logistically and economically possible.3

STREAM: time delay

This pre-specified analysis addresses the issues of increasing time delay of therapy on patient outcomes.4

Key results

Composite of death/congestive heart failure/cardiogenic shock/myocardial infarction in the pharmaco-invasive (PI) strategy and PPCI arms occurred in 10.6% vs 10.3% (≤55 min, p=0.910); 13.9% vs 17.9% (>55–97 min, p=0.148) and 13.5% vs 16.2% (>97 min, p=0.470), respectively.4

STREAM: composite* endpoint according to time delay

STREAM: time delay

Outcomes of patients in the PI arms were consistent across different time groups, whereas outcomes worsened for patients in the PPCI arm as PCI-related delay increased (p(trend)=0.038). A PCI-related delay of 55 minutes or less was associated with fewer rates of adverse events in the PPCI arm. However, the PI strategy showed better outcomes when the time delay exceeded 55 minutes, suggesting beneficial effects of the PI strategy as PCI-related delay increases (p(interaction)=0.094).4

Figure 4. Relative association of continuous PCI-related delay (min) and pharmaco-invasive treatment with 30-day composite outcome (CHF, shock, MI)

Relative association of continuous PCI related delay  Figure showing relative association of continuous PCI-related delay and pharmaco-invasive treatment with 30 day composite outcome.

[Gerschlick et al., 2015].4

The analysis demonstrated an increasing trend towards improved outcomes for PI patients with every 10-minute increment in delay (p(interaction)=0.073).4

Conclusion

The pharmaco-invasive strategy demonstrated a trend towards favourable outcomes compared to PPCI as PCI-related delay increased beyond guideline-mandated timelines. A pharmaco-invasive approach may therefore provide an alternative treatment option in cases of prolonged delays.4

STREAM: aborted MI

Evaluated the pre-specified STREAM endpoint, aborted MI (AbMI), to compare a pharmaco-invasive strategy with PPCI.5

Key results

Rates of aborted MI (AbMI) were significantly higher in PI patients (11.1%) compared to in patients treated with PPCI (6.9%) (p<0.01). The likelihood of experiencing an AbMI was associated with fewer Q waves at baseline, less summed ST-deviation and shorter total ischaemic times.5

PI patients with AbMI had a significantly shorter time to fibrinolysis (90 vs. 100 min, p=0.015), while the total ischaemic time was 100 min longer in PPCI patients with AbMI. No ischaemic time difference was observed in PPCI patients with or without AbMI.5

No significant interaction was observed between rates of AbMI and treatment regarding the composite endpoint including death, shock, congestive heart failure and recurrent MI (p=0.292), but among PI patients, the incidence of this endpoint was significantly lower in patients experiencing an AbMI (5.1% vs. 12.0%; p=0.038). No such difference emerged in patients treated with PPCI.

A total of 45 patients (2.5%) balanced across treatment arms did not show ST-elevation but rather had infarct masquerade.

Results of the 30-day outcomes across the AbMI and non-AbMI groups irrespective of the treatment is presented in Figure 4.5

Table 1. Relative risk plot of the primary composite outcome and its components. AbMI vs non-AbMI

STREAM  Aborted  MI  Relative  risk  plot  Table showing relative risk plot of the primary composite outcome and its components

AbMI, aborted myocardial infarction; CHF, congestive heart failure; reMI, recurrent myocardial infarction
*Adjusted for Thrombolysis In Myocardial Infarction (TIMI) risk score
Continuous variables presented as median (25th-75th percentile)
*5.1 vs 12.0%, p=0.038
#The composite primary endpoint was death, cardiogenic shock, congestive heart failure, and recurrent myocardial infarction
Data from Maleki et al. 2014.5

Conclusion

A pharmaco-invasive strategy of early fibrinolysis coupled with anti-thrombotic and antiplatelet therapy more frequently aborts MI than PPCI. Such patients showed more favourable outcomes compared to non-AbMIs.

ECG insights into strategic reperfusion

Comparison of ECG metrics and clinical outcomes in three groups; i.e. fibrinolysis requiring 37 rescue angiography (n=348), fibrinolysis with scheduled angiography (n=516), and 38 PPCI (n=927).6

Key results

Compared to those pharmaco-invasive patients undergoing scheduled angiography, rescue-fibrinolytic patients were more likely male, diabetic and have anterior MI. They also had more baseline sum ST-segment deviation and Q-waves.6

Thirty minutes post angiography, residual ST-segment elevation ≥2mm occurred in 27.9%, 7.9%, and 24.8% of rescue, scheduled and PPCI patients, respectively.6

Thirty-day composite event rates in these groups were: rescue 18.7%, scheduled 5.5%, and PPCI 13.9%; all-cause death: 6.1%, 2.1%, and 3.9%; shock: 7.5%, 2.0%, and 5.4%; heart failure: 11.8%, 2.3%, and 7.6% and recurrent MI: 1.5%, 1.4%, and 2.2%, respectively (Figure 5).6

Figure 5. Reperfusion strategy and 30-day composite endpoint and individual clinical events.

Reperfusion  strategy  and  30  day  composite  endpoint  Figure showing reperfusion strategy and 30 day composite endpoint and individual clinical events

[Welsh et al., 2014].6

Compared to patients undergoing scheduled angiography post TNK, the adjusted relative risk (RR) of the primary outcome was 2.92 (95% confidence interval (CI) (1.92–4.45)) in patients undergoing rescue, and 2.32 (RR; 95% CI (1.57–3.44)) in patients treated with PPCI.6

Conclusion

Whereas early STEMI patients randomised to a pharmaco-invasive strategy had overall similar outcomes to PPCI, fibrinolytic-treated patients not requiring rescue had ECG evidence of superior reperfusion and lower clinical event rates than PPCI. By contrast those patients requiring rescue angiography had higher risk with more baseline co-morbidities and worse 30-day outcomes.6

STREAM: elderly patients

Baseline characteristics, clinical outcomes, and the relationship of the TNK dose reduction to the efficacy, safety, and electrocardiographic indicators of reperfusion efficacy were evaluated in STEMI patients ≥75 years.7

Key results

Before TNK dose reduction, 3/42 of the elderly (≥75 years) patients (7.1%) suffered an intracranial haemorrhage (ICH), of which two cases were fatal.

No ICH occurred after dose amendment (half dose for patients ≥75 years) in 93 elderly patients receiving half-dose TNK.7

The numbers of elderly patients showing either a median extent of ST-segment resolution (≥50%) or those with ≥2 mm in the electrocardiogram lead with greatest ST-segment elevation were similar before and after TNK dose amendment (63.2% vs. 56% and 43.6% vs. 40.0%, respectively).7

Likewise, the proportion of patients requiring a rescue coronary intervention after fibrinolysis were also comparable pre- and post-amendment (42.9% vs 44.1%). Rates of the primary composite endpoint (30-day all-cause death, cardiogenic shock, congestive heart failure, and reinfarction) were 31.0% before amendment and 24.7% after amendment (Figure 6).7

Figure 6. Relative association of amendment and study treatment with 30-day primary composite end point in elderly patients.

30 day primary composite endpoint  Bar graph showing relative association of amendments and study treatment with 30 day primary composite end point in elderly patients

Adjusted for TIMI risk score for STEMI. [adapted from Armstrong et al., 2015].7

Conclusion

In elderly STEMI patients, a half-dose of TNK reduces the likelihood of ICH without compromising efficacy of reperfusion. These observations are hypothesis generating and warrant further confirmation in randomised clinical trials in larger populations.7

The STREAM-2 study will compare outcomes in elderly patients (≥70 years) with acute STEMI randomised within 3 hours of onset of symptoms to a pharmaco-invasive strategy using half-dose tenecteplase followed by catheterisation within 6-24 h or rescue coronary intervention as necessary, or standard primary PCI.

For more details, click here

STREAM: 1-year mortality follow-up

To determine the effect of the STREAM treatment strategies on 1-year mortality.8

Key results

Information on vital status at one year was available for 99.2% (936/944) of PI treated patients and 99.3% (941/948) of patients treated with PPCI.

Rates of all-cause mortality at one year were comparable for patients in both treatment categories (PI: 6.7% vs PPCI: 5.9%; p=0.49; risk ratio, 1.13; 95% confidence interval, 0.79-1.62) (Figure 7).8

Likewise, 1-year cardiac mortality was also similar in both treatment groups (PI: 4.0% vs PPCI: 4.1%; p=0.93; risk ratio, 1.13; 95% confidence interval, 0.62-1.54) (Figure 7).8

Figure 7. All-cause mortality / cardiac mortality after 1-year

All cause mortality Bar graph showing all cause mortality or cardiac mortality for STREAM study after 1 year

Between day 30 and 1 year, a total of 34 patients died (20 PI patients, 14 PPCI patients), 20 of 34 deaths were non-cardiac related (13 PI patients, 7 PPCI patients).

Overall, there was no significant difference in 1-year all-cause mortality between the 2 treatment groups among the pre-specified subgroups.

Conclusion

At 1 year, mortality rates in the PI strategy and PPCI arms were similar in STEMI patients presenting within 3 hours after symptom onset and unable to undergo PPCI within 1 hour.8

STREAM: infarct size impact on outcome

A pharmaco-invasive strategy for early presenting ST-segment elevation myocardial infarction nominally reduced 30-day cardiogenic shock and congestive heart failure compared with PPCI. This study evaluated whether infarct size (IS) was related to this finding. IS was divided into 3 groups: small (≤2 times the upper limit normal [ULN]), medium (>2 to ≤5 times the ULN) and large (>5 times the ULN).9

Key results

Patients of both treatment groups were stratified by IS. Overall, a higher proportion of patients treated with PPCI vs. PI showed large IS, despite similar ischaemic times between groups for each treatment strategy (PI vs. PPCI: small IS - 49.8% vs 50.2%; medium IS - 56.9% vs 43.1%; large IS - 48.4% vs 51.6%; p=0.035).9

Figure 8. Distribution of infarct size for different patient distribution across three groups (p=0.035)

STREAM: cardiac results

An accumulation of shock and congestive heart failure was observed with increasing IS in both treatment arms with exception of the small IS group.

Within the small IS group, the difference in shock and congestive heart failure in favour of the PI strategy (4.4% vs 11.6%, p=0.026) was most likely linked to higher rates of aborted myocardial infarctions (72.7% vs 54.3%, p=0.005).

A trend for a beneficial effect favouring the PI strategy remained after adjustment (relative risk 0.40, 95% CI 0.15 to 1.06, p=0.064). In the medium and large IS groups, no treatment-relates differences were observed (Figure 9).9

Figure 9. Relative risk plot of the 30-day composite endpoint of shock/CHF. Infarct size groups and 30-day shock/CHF by treatment strategy.

Relative risk plot of the 30 day composite endpoint  Figure showing relative risk plot of the 30 day composite endpoint of shock or CHF by treatment strategy

*Adjusted for thrombolysis in myocardial infarction risk score. CHF indicates congestive heart failure; PI, pharmaco-invasive; PPCI, primary percutaneous coronary intervention; ULN, upper limit normal. [adapted from Shavadia et al., 2015].9

Conclusion

A PI strategy may potentially alter the pattern of IS after STEMI, resulting in higher rates of medium IS and lower rates of large IS compared with PPCI. Despite similar numbers of small infarcts, PI patients in this small IS group had higher rates of aborted myocardial infarctions and less 30-day shock and congestive heart failure.9

References:

  1. Armstrong PW, et al. The Strategic Reperfusion Early After Myocardial Infarction (STREAM) study. Am Heart J 2010;160:30-35(e31).
  2. Armstrong PW, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013;368:1379-1387.
  3. Bates ER. Evolution from fibrinolytic therapy to a fibrinolytic strategy for patients with ST-segment-elevation myocardial infarction. Circulation. 2014;130(14):1133-1135.
  4. Gershlick A, et al. Impact of a pharmacoinvasive strategy when delays to primary PCI are prolonged. Heart 2015;101:692-698.
  5. Maleki ND, et al. Aborted myocardial infarction in ST-elevation myocardial infarction: insights from the STrategic Reperfusion Early After Myocardial infarction trial. Heart. 2014;100(19):1543-1549.
  6. Welsh RC, et al. Outcomes of a pharmacoinvasive strategy for successful versus failed fibrinolysis and primary percutaneous intervention in acute myocardial infarction (from the STrategic Reperfusion Early After Myocardial Infarction [STREAM] study). Am J Cardiol 2014;114(6):811-819.
  7. Armstrong PW, et al. Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the Strategic Reperfusion Early After Myocardial infarction trial. Am Heart J. 2015;169(6):890-898.
  8. Sinnaeve PR, et al. STEMI patients randomized to a pharmaco-invasive strategy or primary PCI: The STREAM 1-Year mortality follow-up. Circulation 2014;130(14):1139-1145.
  9. Shavadia J, et al. Infarct size, shock, and heart failure: does reperfusion strategy matter in early presenting patients with ST-segment elevation myocardial infarction? J Am Heart Assoc. 2015;4(8):e002049.

The NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction (NORDISTEMI) compared immediate transfer for percutaneous coronary intervention (PCI) with an ischaemia-guided approach after thrombolysis for patients in rural areas that had very long transfer distances to PCI centres.

Study design

In a remote area of Norway, a total of 266 patients with ST-elevation myocardial infarction (STEMI) of less than 6 h duration and more than 90 min expected time delay to PCI received thrombolysis (full-dose tenecteplase), aspirin, enoxaparin and clopidogrel, and were then randomised to either an early invasive strategy or a conservative strategy:

  • Early invasive strategy: Immediate coronary angiography/PCI of the infarct-related artery if indicated (≥50% diameter stenosis).
  • Conservative strategy: Admitted to hospital for continued care, with urgent transfer only for a rescue indication or with clinical deterioration.

The primary endpoint was a 12-month composite of death, re-infarction, stroke, or new myocardial ischaemia.

Secondary endpoints included a 12-month composite of death, re-infarction or stroke, transport-related complications, bleeding at 30 days, and infarct size (by SPECT and troponin T levels).

NORDISTEMI: Study design

NORDISTEMI  Study  design STEMI patients with less than 6 hours duration and more than 90 min delay to PCI were given thrombolytic therapy and randomised to either an early invasive strategy or a conservative strategy.

Results

The results support an early invasive strategy after thrombolysis, even for patients with long transfer distances.

At 30 days, the early invasive strategy was associated with a significant reduction in the primary endpoint (relative risk 0.49; 95% CI 0.27 to 0.89; p=0.03) and a non-significant reduction in the secondary composite endpoint (relative risk 0.45; 95% CI 0.18 to 1.16; p=0.14).

At 12 months, the early invasive strategy was associated with a non-significant reduction in the primary endpoint (HR 0.72; 95% CI 0.44 to 1.18; p=0.19) and a significant reduction in the secondary composite endpoint of death, re-infarction or stroke (HR 0.36; 95% CI 0.16 to 0.81; p=0.01).

NORDISTEMI: Primary endpoint (n=266)

NORDISTEMI  Primary  endpoint            Early invasive strategy reduced the primary endpoint incidence in patients even with long transfer distances.

NORDISTEMI: Death, reinfarction or stroke

NORDISTEMI  Death  reinfarction  or  stroke Early invasive strategy reduced the secondary composite endpoint of death, re-infarction or stroke in patients.

It is important to note that angiography was performed in the majority of patients in both the early invasive (99%) and conservative groups (95%), at an average time of 130 min and 5.5 days post-lysis respectively. PCI was also performed in the majority of patients in both groups, at an average time of 163 min and 3 days post-lysis respectively.

NORDISTEMI: Invasive procedures in the 2 randomisation groups

NORDISTEMI  Invasive  procedures  in  the  2  randomisation  groups          Angiography and PCI was performed in majority of the patients in both the early invasive and conservative groups.

Conclusion

  • The significant reduction in the composite of death, re-infarction or stroke suggests that an early invasive strategy after thrombolytic therapy may be preferable, even for patients in areas with long transfer distances.

References:

  1. Bøhmer E, et al. The NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction (NORDISTEMI). Scand Cardiovasc J 2007;41:32-38.
  2. Bøhmer E et al. Efficacy and safety of immediate angioplasty versus ischaemia-guided management after thrombolysis in acute myocardial infarction in areas with very long transfer distances: Results of the NORDISTEMI (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction). J Am Coll Cardiol 2010;55:102-110.

The Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) compared the outcome of a pharmacoinvasive strategy (transfer to a PCI centre for routine early PCI within 6 h) and a standard treatment (early transfer only for failed reperfusion, otherwise catheterisation >24 h) for high-risk STEMI patients receiving thrombolysis at non-PCI centres.

Study design

A total of 1,059 patients with high-risk ST-segment elevation myocardial infarction (STEMI), presenting at non-PCI centres within 12 h of onset of symptoms, were randomised to a pharmacoinvasive strategy (transfer for routine PCI within 6 h of fibrinolysis; n=537) or to standard treatment after fibrinolysis (n=522). All patients received aspirin, tenecteplase, and heparin or enoxaparin; concomitant clopidogrel was recommended.

Pharmacoinvasive strategy:

Patients were transferred urgently by land or air ambulance to a participating PCI centre as soon as possible and underwent coronary angiography and PCI of the infarct-related artery within 6 h of fibrinolysis, regardless of chest pain, ST-elevation, or coronary flow.

Standard treatment:

Patients had a repeat electrocardiogram 60 to 90 min after randomisation and were transferred for rescue PCI only if they had persistent chest pain and <50% ST-segment resolution, or if they became haemodynamically unstable. Otherwise, patients remained at the enrolling hospital and did not undergo cardiac catheterisation within the first 24 h. Elective cardiac catheterisation within the first 2 weeks was encouraged but not mandated.

TRANSFER-AMI: Study design

TRANSFER  AMI  Study  design Patients with high risk STEMI were randomised to a pharmaco-invasive strategy or to a standard treatment. Stable patients within 24 hrs of PCI were repatriated.

The 30-day primary endpoint was a composite of death, re-infarction, recurrent ischaemia, new or worsening congestive heart failure (CGF), and cardiogenic shock.

The secondary endpoints included death or re-infarction at 6 months.

Results

The 30-day clinical outcomes support the "pharmacoinvasive" strategy over the standard "wait-and-see" strategy for high-risk STEMI patients receiving thrombolysis at non-PCI centres.

The early routine PCI group was associated with a significant reduction in the primary endpoint (11.0% versus 17.2% for standard treatment; relative risk 0.64; 95% confidence interval [CI] 0.47 to 0.87; p=0.004). There were reductions in re-infarction, recurrent ischaemia and new or worsening congestive heart failure (CHF) in the early routine PCI group; however the study was not powered to detect these differences.

There were more mild bleeding events (according to GUSTO criteria) in the early PCI group (13.0% versus 9.0%, p=0.04) but no differences in moderate or severe bleeding. There were no differences in major or minor bleeding events as assessed by the TIMI criteria.

At 6 months, the rates of re-infarction and death did not differ significantly between the two groups.

TRANSFER-AMI: Primary endpoint at 30 days

TRANSFER  AMI  Primary  endpoint  at  30  days                The 30 day clinical outcomes supported superiority of pharmaco-invasive strategy  over standard strategy with significant reduction in primary endpoint.

TRANSFER-AMI: secondary outcomes at 30 days

TRANSFER  AMI  secondary  outcome  at  30  days Reductions in re-infarction, recurrent ischaemia, new or worsening congestive heart failure were observed in early routine PCI in comparison with standard treatment.

Conclusion

  • For high-risk STEMI patients receiving thrombolysis at non-PCI centres, routine transfer and PCI within 6 h was associated with a reduction in the primary endpoint, a 30-day composite of death, re-infarction, recurrent ischaemia, new or worsening congestive heart failure (CHF), and cardiogenic shock.
  • Transfer to PCI centres should be initiated immediately after thrombolysis without waiting to see whether reperfusion is successful.
  • Regional systems should be developed to ensure timely transfers of STEMI patients to PCI centres.

References:

  1. Cantor, WJ, Fitchett, D, Borgundvaag, B, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009;360:2705-2718.
  2. Cantor, WJ, Fitchett, D, Borgundvaag, B, et al. Rationale and design of the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008;155:19-25.

In patients with ST-segment elevation acute myocardial infarction (STEMI), primary percutaneous coronary intervention (PCI) is often not available or is subject to delays. The GRupo de Análisis de la Cardiopata Isquémica Aguda (GRACIA-2) study evaluated whether lytic-based early routine PCI was a reasonable option for STEMI patients.

Study design

The GRACIA-2 study randomly assigned 212 STEMI patients within 12 h of symptom onset to treatment with full tenecteplase followed by stenting within 3 to 12 h of randomisation (n=104) or to undergo primary stenting with abciximab within 3 h of randomisation (n=108).

The primary endpoint was post-PCI epicardial and myocardial reperfusion, and the extent of left ventricular myocardial damage (infarct size and left ventricular function at 6 weeks).

Secondary endpoints included acute bleeding, and the composite at 6 months of death, re-infarction, stroke, and repeat ischaemia-driven coronary revascularisation.

GRACIA-2: Study design

GRACIA  2  Study  design GRACIA 2 randomised STEMI patients into facilitated intervention or optimal primary PCI group to primarily observe adequate revascularisation and extent of myocardial damage.

Results

Thrombolysis followed by early routine PCI resulted in a higher incidence of complete epicardial and myocardial reperfusion (21% vs 6%, p=0.03) compared to primary PCI.

Both groups were similar in terms of the 6-month cumulative incidence of death, non-fatal re-infarction, disabling stroke, and ischaemia-driven revascularisation (9.6% versus 12%; p=0.57; relative risk 0.80; 95% confidence interval [CI] 0.37 to 1.74).

GRACIA-2: Study outcomes

GRACIA  2  Study  outcomes Facilitated thrombolysis resulted in higher adequate revascularisation

Conclusion

  • Thrombolysis plus early routine PCI is as safe as primary PCI and equivalent in terms of preserving myocardial function.
  • Thrombolysis plus early routine PCI results in better and earlier myocardial reperfusion.
  • If these findings are confirmed by larger-scale trials, the proportion of patients with STEMI who can benefit from PCI could increase dramatically.

References:

  1. Fernandez-Aviles F, et al. Primary angioplasty vs. early routine post-fibrinolysis angioplasty for acute myocardial infarction with ST-segment elevation: the GRACIA-2 non-inferiority, randomized, controlled trial. Eur Heart J 2007;28:949-960.

The Which Early ST-elevation myocardial infarction Therapy (WEST) trial assessed whether optimal pharmacological therapy at the earliest point of care (ideally pre-hospital) was non-inferior to primary percutaneous coronary intervention (PCI) among ST-elevation myocardial infarction (STEMI) patients.

Study design

The WEST trial randomised 304 STEMI patients with symptoms lasting ≥20 min accompanied by ECG evidence of high risk to 1 of 3 groups:

(A) Tenecteplase plus usual care

(B) Tenecteplase followed by routine or rescue PCI within 24 h

(C) Primary PCI with 300 mg loading dose of clopidogrel

The 90-day primary endpoint was a composite of death, re-infarction, refractory ischaemia, congestive heart failure, cardiogenic shock and major ventricular arrhythmia.

Secondary endpoints included 90- and 180-min ST-resolution, and infarct size.

Results

There was no significant difference in the primary endpoint between the three groups (25% versus 24% versus 23%). However, patients in the tenecteplase plus usual care group were more likely to experience a combination of death and re-infarction than patients in the primary PCI group (primary PCI versus tenecteplase plus usual care; unadjusted hazard ratio 0.29; 90% confidence interval [CI] 0.11 to 0.74; p-logrank=0.021). There was no difference between patients in the tenecteplase followed by routine or rescue PCI group and patients in the primary PCI group (p=0.378).

WEST: Outcomes at 30 days

WEST  Outcomes  at  30  days  Primary endpoint shows no significant difference between pharmacologic therapy, pharmacologic therapy coupled with PCI and primary PCI

Conclusion

  • Strategies of thrombolysis coupled to early routine or rescue PCI are non-inferior to primary PCI.

References:

  1. Armstrong, PW. A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J 2006;27:1530-1538

Aim

STEPP-AMI compared the efficacy and safety of a pharmaco-invasive strategy versus PCI in Indian STEMI patients <75 years of age, presenting within 12 h of symptom onset

Study design

A prospective, observational, multi-centre pilot study with 1-year follow-up. Patients could choose between:

  • Group A (n=45): TNK + immediate rescue PPI upon failed thrombolysis
  • Group B (n=155): PPCI

Primary endpoint

Composite of death, cardiogenic shock, re-infarction, repeat revascularisation of culprit artery and congestive heart failure at 30 days

STEPP-AMI: primary endpoint*

Kaplan-Meier curves for the primary endpoint

Conclusions

  • There was a trend towards benefit for PPCI, especially during the early phase of follow-up, but significance was not reached.
  • Even though PPCI remains the preferred treatment option, a pharmaco-invasive strategy can be implemented safely in patients <75 years who do not undergo PPCI in India.
  • In a developing country like India, pharmaco-invasive strategy may successfully alleviate the logistic or geographical barriers of PPCI in the treatment of AMI.
  • Given the limited sample size, these findings require additional investigation.

References:

  1. Victor SM, et al. A prospective, observational, multicentre study comparing tenecteplase facilitated PCI versus primary PCI in Indian patients with STEMI (STEP-AMI). Open Heart 2014;1(1):e000133.

 

 

 

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