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Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial

Robert A. Kloner, Mervyn B. Forman, Raymond J. Gibbons, Allan M. Ross, R. Wayne Alexander, Gregg W. Stone
DOI: http://dx.doi.org/10.1093/eurheartj/ehl094 2400-2405 First published online: 16 June 2006

Abstract

Aims The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II).

Methods and results Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 µg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. ≥ or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion <3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P=0.014), 6-month mortality (7.3 vs. 11.2%, P=0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P=0.022). Patients reperfused beyond 3 h did not benefit from adenosine.

Conclusion In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

  • Adenosine
  • Myocardial infarction
  • Thrombolysis
  • Fibrinolytic therapy
  • Percutaneous transluminal coronary angioplasty
  • Congestive heart failure
See page 2376 for the editorial comment on this article (doi:10.1093/eurheartj/ehl268)

Introduction

The second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II) trial demonstrated that high-dose intravenous adenosine as an adjunct to reperfusion therapy for acute anterior myocardial infarction (AMI) reduced myocardial infarct size (27% of the left ventricle in the placebo group vs. 11% in the high-dose adenosine group, P=0.023).1 The rate of occurrence, however, of the primary composite clinical endpoint of death, new onset congestive heart failure (CHF) beginning >24 h after randomization, or rehospitalization for CHF within 6 months were not statistically different between placebo (17.9%) and either the pooled-adenosine dose groups (16.3%), or separately the low-dose (50 µg/kg/min) or the high-dose (70 µg/kg/min) adenosine group (16.5 and 16.1%, respectively). Patients were enrolled in AMISTAD-II if reperfusion therapy [consisting of either thrombolysis or primary percutaneous coronary intervention (PCI)] was administered within 6 h of symptom onset. Given the well described impact of reperfusion delays on myocardial salvage and clinical outcomes2 and of the variability between PCI and thrombolytic therapy in achieving reperfusion success, the present post hoc subanalysis was performed to determine whether adenosine might have differential efficacy as a function of reperfusion time and modality.

Methods

The AMISTAD-II study was a double-blinded, placebo-controlled, randomized, multicentre, international study. Details of the methodology of the study have been described.1 Patients (n=2118), over 18 years or more, presenting with ongoing ischaemic pain for at least 30 min duration and with electrocardiographic evidence of an anterior ST-segment elevation MI [ST-elevation in at least two contiguous precordial leads or (presumed) new left bundle branch block], in whom reperfusion therapy was administered within 6 h of symptom onset, were randomized to receive either intravenous placebo, adenosine 50 µg/kg/min, or adenosine 70 µg/kg/min starting within 15 min of the start of fibrinolysis or prior to coronary intervention and continuing for 3 h thereafter.

Endpoints

The primary intention to treat composite clinical endpoint in AMISTAD-II was new onset in-hospital CHF occurring >24 h after initiation of reperfusion, rehospitalization for CHF, or death (from any cause) during the 6-month follow-up period. Six months was chosen to capture one long-term time point. CHF was found to be present if two of the following criteria were observed: new pulmonary oedema by chest X-ray in the absence of a non-cardiac cause, rales heard over one-third or more of the lung fields, pulmonary capillary wedge pressure >18 mmHg with a cardiac index <2.4 L/min/m2, dyspnea with PO2<80 mmHg or O2 saturation <90% without known pre-existing lung disease, and use of loop diuretics to treat pulmonary congestion. Secondary endpoints included death at 1-month, the individual components of the primary endpoint, and myocardial infarct size [measured by technetium-99 m sestamibi single-photon emission computed tomography (SPECT)] 120 to 216 hours after randomisation in a 266-patient substudy (243 of whom had suitable images for quantitative analysis).

For the present analysis, these endpoints were analysed according to: (i) time to initiating reperfusion therapy (less than or greater than or equal to the median of 3.17 h); and (ii) the type of reperfusion therapy used (thrombolysis vs. PCI). A total of 33 of 2118 patients (1.6%) received neither thrombolysis nor primary angioplasty, and were not included in the present analysis. As in the original study, outcomes were compared for patients in the placebo, pooled-adenosine, low-dose and high-dose adenosine groups.

Statistical analysis

Baseline features were compared with either the Fisher's exact test for categorical variables or t-test for continuous variables. For clinical outcomes, Kaplan–Meier estimates were generated and compared with the log rank test. Myocardial infarct size data were summarized as median (25th percentile, 75th percentile) and compared using the Kruskal–Wallis test. Formal interaction testing was performed to evaluate the impact of: (i) treatment assignment and reperfusion modality on mortality and infarct size; and (ii) treatment assignment and time to reperfusion (as a continuous variable) on the 6-month primary composite endpoint. Interaction testing was performed by creating multivariable models (Cox proportional hazards regression for time-to-event data, and linear regression for infarct size), with significant levels to enter and stay of 0.05 and 0.10, respectively. In addition to treatment assignment, time to reperfusion and reperfusion modality, the following variables were entered into the models: age, gender, prior MI, and Killip class 1 vs. 2–4. All analyses were intented for a treatment, and all P-values were two-sided. A P-value of <0.05 was considered statistically significant.

Results

Baseline features and outcomes of the study population stratified by the initiation of reperfusion time are shown in Table 1. Compared with patients receiving initiation of early reperfusion therapy (<3.17 h), those reperfused later (≥3.17 h) were slightly older, had more diabetes, and were less likely to have had a prior MI. Patients who were reperfused early were less likely to die and develop heart failure compared with patients reperfused late (Table 1). There were no statistically significant differences in the baseline features of the placebo- vs. adenosine-treated patients in either the early group (reperfusion <3.17 h) or the later group (reperfusion ≥3.17 h) (Table 2).

View this table:
Table 1

Baseline features and outcomes stratified by the initiation of early reperfusion therapy (<median of 3.17 h) vs. late reperfusion therapy (≥median)

Early (n=1066)Late (n=1018)P-value
Baseline features
 Age (years)59.2±12.661.7±12.8<0.0001
 Male76.9% (820/1066)70.2% (715/1018)0.0006
 Diabetes mellitus14.0% (149/1061)19.1% (192/1004)0.002
 Prior MI14.4% (152/1055)11.1% (112/1009)0.025
 Killip class 2–415.0% (160/1066)17.2% (175/1018)0.189
 Symptom onset to treatment (hours)2.15±0.664.48±0.92<0.0001
  Thrombolytic therapy (hours)2.11±0.704.55±0.86<0.0001
  Primary angioplasty (hours)2.41±0.674.55±0.94<0.0001
Outcomes
 Death at 1 month6.5%9.6%0.008
 Composite 6-month endpoint13.7%20.2%<0.0001
  Death8.6%13.1%0.0009
  In-hospital CHF3.5%4.8%0.15
  Rehospitalization for CHF3.1%5.8%0.005
 Infarct size (% of left ventricle)24.0 (2.0, 42.0) (n=133)19.0 (1.0, 39.0) (n=108)0.64
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Table 2

Baseline features in patients receiving reperfusion therapy in placebo vs. pooled-adenosine group

PlaceboPooled-adenosineP-value
Early (<median of 3.17 h)(n=350)(n=716)
 Age (years)59.1±13.0%59.2±12.4%0.841
 Male75.4% (264/350)77.7% (556/716)0.439
 Diabetes mellitus16.1% (56/348)13.0% (93/713)0.188
 Hypertension48.7% (169/347)45.7% (321/703)0.358
 Prior MI11.6% (40/345)15.8% (112/710)0.076
 Killip class 2–413.7% (48/350)15.6% (112/716)0.465
 Symptom onset to treatment (hours)2.18±0.642.13±0.660.249
Late (>median of 3.17 h)(n=341)(n=677)
 Age (years)61.1±13.2%62.0±12.7%0.265
 Male72.4% (247/341)69.1% (468/677)0.309
 Diabetes mellitus16.0% (54/338)20.7% (138/666)0.075
 Hypertension52.7% (177/336)55.4% (372/671)0.421
 Prior MI11.9% (40/337)10.7% (72/672)0.596
 Killip class 2–416.1% (55/341)17.7% (120/677)0.539
 Symptom onset to treatment (hours)4.52±0.954.46±0.910.367

Impact of reperfusion time

In patients who received initiation of reperfusion therapy early (<3.17 h), mortality at both 1 month and 6 months as well as the primary composite clinical endpoint at 6 months were significantly reduced in the pooled-adenosine group compared with placebo, with no clear distinction in efficacy between the low-dose and high-dose adenosine dose regimens (Table 3). A non-significant trend was present towards reduced infarct size in the high-dose adenosine group (n=49, P=0.143). In contrast to the beneficial effects of adenosine in the early reperfusion group, adenosine did not improve clinical outcomes in patients reperfused later (Table 3), though a trend was present for reduced infarct size in the pooled-adenosine group (P=0.082) and the high-dose adenosine group (n=34, P=0.081). The interaction between treatment and time to reperfusion as a continuous variable was significant at the P=0.045 level after adjusting for other covariates.

View this table:
Table 3

Impact of adenosine in patients receiving initiation of early reperfusion therapy (< median of 3.17 h) vs. late reperfusion therapy (≥median)

PlaceboPooled-adenosineP-value Pooled vs. placeboAdenosine 50 µg/kg/minAdenosine 70 µg/kg/min
Early reperfusion therapy
n350716350366
 Death at 1 month9.2%5.2%0.0145.1%*5.2%*
 Composite 6-month endpoint17.2%12.0%0.02210.9%**13.2%
  Death11.2%7.3%0.0337.2%***7.4%*****
  In-hospital CHF4.0%3.2%0.591.7%****4.6%
  Rehospitalization for CHF3.8%2.8%0.423.3%2.3%
 Infarct size (% of left ventricle)24.0 (4.0, 43.0) (n=41)21.5 (0.5, 42.0) (n=92)0.3527.0 (7.0, 42.0) (n=43)11.0 (0.0, 43.0) (n=49)
Late reperfusion therapy
n341677345332
 Death at 1 month9.1%9.9%0.6612.2%7.5%
 Composite 6-month endpoint19.1%20.7%0.4922.7%18.7%
  Death12.6%13.3%0.7413.9%12.7%
  In-hospital CHF4.1%5.2%0.546.4%3.9%
  Rehospitalization for CHF5.8%5.7%0.985.3%6.2%
 Infarct size (% of left ventricle)34.0 (0.0, 50.0) (n=35)14.0 (1.0, 36.0) (n=73)0.0816.0 (4.0, 38.0) (n=39)11.5***** (0.0, 31.0) (n=34)
  • *P=0.04 vs. placebo; **P=0.015 vs. placebo; ***P=0.065 vs. placebo; ****P=0.07 vs. placebo; *****P=0.08 vs. placebo.

Impact of reperfusion modality

As shown in Table 4, patients treated with primary PCI compared with thrombolytic therapy were slightly younger, had more diabetes, and were less likely to have had a prior MI. As expected, patients treated with primary PCI rather than thrombolytic therapy had lower rates of death at 1 month, composite clinical 6-month endpoint, less death at 6 months and less in-hospital CHF (Table 4).

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Table 4

Baseline features and outcomes stratified by treatment with thrombolytic therapy or primary angioplasty

Thrombolytic therapy (n=1234)Primary angioplasty (n=851)P-value
Baseline features
 Age (years)60.9±12.859.7±12.70.043
 Male70.5% (870/1234)78.1% (665/851)<0.0001
 Diabetes mellitus14.2% (173/1220)19.9% (168/846)0.0007
 Prior MI14.2% (174/1226)10.7% (90/839)0.022
 Killip class 2–417.3% (213/1234)14.3% (122/851)0.079
 Symptom onset to treatment (hours)3.27±1.443.33±1.370.338
Outcomes
 Death at 1 month10.6%4.4%<0.0001
 Composite 6-month endpoint20.5%11.7%<0.0001
  Death14.0%6.2%<0.0001
  In-hospital CHF4.9%2.9%0.025
  Rehospitalization for CHF4.6%4.1%0.592
 Infarct size (% of left ventricle)21.0 (6.0, 42.0) (n=77)19.0 (0.0, 41.0) (n=164)0.415

Randomization to adenosine rather than to placebo resulted in fewer deaths at 1 month and in strong trends towards less death at 6 months among patients treated with thrombolytic therapy early (Table 5). Adenosine (especially high-dose) also resulted in a reduction in infarct size in early lytic-treated patients. In contrast, patients treated with thrombolytic therapy later (Table 5) than the median time of 3.17 h had similar clinical outcomes with adenosine and placebo. Patients treated with early primary PCI had a non-significant trend towards lower death rates when they received adenosine (Table 6). There was no evidence that adenosine clinically benefited patients treated with late PCI (Table 6). By formal interaction testing, however, the impact of adenosine randomization was independent of reperfusion modality with regard to mortality (P=0.70) and infarct size (P=0.35).

View this table:
Table 5

Impact of adenosine in patients receiving thrombolytic therapy early (<median of 3.17 h) vs. late (≥median)

PlaceboPooled-adenosineP-value Pooled vs. placeboAdenosine 50 µg/kg/minAdenosine 70 µg/kg/min
Early reperfusion therapy
n213423212211
 Death at 1 month12.7%7.6%0.046.6%*8.5%
 Composite 6-month endpoint21.2%14.9%0.05512.8%**17.1%
  Death15.5%10.7%0.089.5%***11.9%
  In-hospital CHF4.2%3.5%0.661.9%5.2%
  Rehospitalization for CHF3.8%2.6%0.443.0%2.1%
 Infarct size (% of left ventricle)36.5 (13.5, 50.5) (n=16)17.0 (1.0, 42.0) (n=35)0.05432.0 (15.0, 46.0) (n=17)8.0**** (0.0, 26.0) (n=18)
Late reperfusion therapy
n198399195204
 Death at 1 month11.6%12.0%0.8615.9%8.3%
 Composite 6-month endpoint23.3%24.6%0.6628.7%20.6%
  Death15.7%15.5%1.0017.9%13.2%
  In-hospital CHF5.1%6.8%0.478.2%5.4%
  Rehospitalization for CHF6.8%6.3%0.845.5%6.9%
 Infarct size (% of left ventricle)34.0 (0.0, 48.0) (n=11)15.0 (9.0, 23.0) (n=15)0.3212.0 (9.0, 23.0) (n=7)19.0 (6.5, 30.0) (n=8)
  • *P=0.04 vs. placebo; **P=0.02 vs. placebo; ***P=0.06 vs. placebo; ****P=0.004 vs. placebo.

View this table:
Table 6

Impact of adenosine in patients receiving primary PCI early (<median of 3.17 h) vs. late (≥median)

PlaceboPooled-adenosineP-value Pooled vs. placeboAdenosine 50 µg/kg/minAdenosine 70 µg/kg/min
Early reperfusion therapy
n137293138155
 Death at 1 month3.7%1.7%0.212.9%0.6%*
 Composite 6-month endpoint11.0%7.9%0.278.0%7.8%
  Death4.4%2.4%0.253.6%1.3%
  In-hospital CHF3.6%2.7%0.561.4%3.9%
  Rehospitalization for CHF3.8%3.1%0.713.7%2.6%
 Infarct size (% of left ventricle)16.0 (3.0, 37.0) (n=25)24.0 (0.0, 43.0) (n=57)0.84724.5 (0.0, 39.0) (n=26)24.0 (0.0, 49.0) (n=31)
Late reperfusion therapy
n143278150128
 Death at 1 month5.6%6.9%0.617.4%6.3%
 Composite 6-month endpoint13.3%15.2%0.6014.8%15.6%
  Death8.4%10.1%0.578.7%11.7%
  In-hospital CHF2.8%2.9%1.004.0%1.6%
  Rehospitalization for CHF4.4%5.0%0.775.0%5.0%
 Infarct size (% of left ventricle)27.5 (3.5, 50.0) (n=24)13.5 (0.0, 37.0) (n=58)0.13622.5 (2.0, 38.5) (n=32)8.5 (0.0, 31.0) (n=26)
  • *P=0.07 vs. placebo.

Discussion

The major observations of the current analysis are as follows. (i) Consistent with prior reports, patients with anterior AMI who had initiation of reperfusion therapy early (less than the median of 3.17 h) were less likely to develop the composite endpoint of death, new in-hospital CHF, or first rehospitalization for CHF within 6 months compared with patients receiving reperfusion later than the median time. (ii) However, when a 3-h adenosine infusion was administered to patients as an adjunct to reperfusion within 3.17 h of symptom onset, mortality was significantly reduced at 1 and 6 months, and event-free survival was enhanced compared with placebo. (iii) In contrast, patients receiving later initiation of reperfusion therapy did not have a clinical benefit from adenosine. (iv) The benefits of early adenosine administration were observed primarily in patients receiving thrombolytic therapy and to a lesser extent in those with mechanical intervention.

Numerous prior studies of adjunctive therapy in patients with AMI undergoing reperfusion therapy have been performed to improve further clinical outcomes and reduce infarct size.3 Unfortunately, no pharmacologic adjunct has been clearly demonstrated to improve outcomes beyond that achieved by infarct artery recanalization alone, including adjunctive agents assessed for myocardial infarct size reduction by SPECT in the same laboratory (R.J.G) as in the current study. Prior to AMISTAD-II, several smaller studies had suggested that adenosine as an adjunct to reperfusion therapy might reduce infarct size and improve event-free survival.48 In the pivotal AMISTAD-II trial, high-dose (70 µg/kg/min) adenosine in patients with anterior AMI reduced the myocardial infarct size compared with placebo, consistent with the results of the earlier AMISTAD-I trial.1,6 Although there was a strong correlation between infarct size and adverse events in AMISTAD-II, the trial was underpowered to observe reduction in the primary clinical endpoint. Nevertheless, adenosine is one of the few pharmacologic agents that has provided a positive signal for reduction of infarct size in the clinical setting.

The ability of an adjunctive agent to impact positively the prognosis in AMI may depend on the duration of ongoing myocardial injury, as well as the type of reperfusion therapy employed. In this regard, AMISTAD-II enrolled patients with infarct duration up to 6 h before initiation of reperfusion therapy that was either thrombolysis or primary PCI. The results of the present analysis extend the findings of the original study by suggesting that adenosine significantly reduces mortality and improves event-free survival when administered to patients with anterior AMI early in the course of the infarct (within 3.17 h of symptom onset). Moreover, this benefit was observed primarily in patients receiving thrombolytic reperfusion therapy, with a non-significant trend towards a benefit in those undergoing mechanical intervention.

The mechanisms through which adenosine may further improve the prognosis of patients with anterior AMI treated early with thrombolysis is unknown. Potential mechanisms for adenosine's benefit include: an antiplatelet effect that may promote initial or sustained vessel patency;9 coronary vasodilatation, anti-inflammatory effects, and salutary impact on no-reflow;1012 and/or a possible antiarrhythmic effect during post-conditioning as described below. It is known that the thrombolytic therapy itself may activate platelets1316 and hence, an antiplatelet effect of adenosine would potentially be more prominent in the setting of a thrombolytic agent, but may have played some role in the trend towards a benefit in patients receiving angioplasty.

In experimental studies, adenosine can mimic ischaemic pre-conditioning.17 It is unlikely, however, that adenosine's benefit in the present study could have been related to ischaemic pre-conditioning, which necessitates the therapy be administered prior to the ischaemic event. In contrast, a recently described phenomenon called post-conditioning occurs when brief interruptions of reperfusion with short periods of coronary artery occlusion protect the myocardium.18 We have recently observed that post-conditioning has a powerful antiarrhythmic effect, significantly reducing the frequency and duration of ventricular tachycardia in an experimental model of ischaemia/reperfusion. 19 The effect of post-conditioning may be blocked by adenosine antagonists.20 Another recent preclinical study suggests that adenosine production protects the heart from ventricular arrhythmias induced by coronary occlusion.21 Hence, adenosine administered in the peri-reperfusion period, especially with thrombolytic therapy after which transient occlusion and recanalization are frequent22,23 may post-condition the myocardium and possibly reduce lethal ventricular arrhythmias.

The fact that the benefits of adenosine were observed in patients treated within 3 h of symptom onset with thrombolytic therapy suggests a myocardial salvage-dependent mechanism. In contrast, the fact that the low as well as the high dose of adenosine improved clinical outcomes in patients treated early, yet only the high dose reduced infarct size, suggests that the clinical benefits of adenosine may be in part independent of myocardial salvage. This discordance may be due to the small sizes of several of the subsets in the infarct size substudy. A larger confirmatory trial is required both to verify the present results and elucidate the mechanism of benefit of adenosine as an adjunct to thrombolytic therapy in patients presenting early within the course of evolving anterior AMI. Another possibility is that other factors, besides infarct size, contribute to cardiac death post-MIs. These may include post-MI left ventricular remodelling, arrhythmias, degree of inflammation within the infarct vessel or infarcted myocardium, re-occlusion of the infarct vessel, and other factors. Such factors could have played a role in the observation that mortality benefits were observed with both doses of adenosine when combined with early reperfusion but only high-dose appeared to affect infarct size.

There are several limitations of the present analysis. The current study was a post hoc analysis, and the outcomes from subset analyses should not be over interpreted. These results must therefore be considered hypothesis-generating only. Core laboratory angiographic analysis after reperfusion was not performed; and, thus, whether the differential efficacy of adenosine in thrombolytic-treated patients vs. those undergoing PCI might be explained in differences in coronary artery patency or microcirculatory perfusion between the two reperfusion modalities is unknown.

In conclusion, the results of the present analysis suggest that adenosine administered with reperfusion therapy within the first 3.17 h onset of anterior AMI may reduce mortality and enhance freedom from heart failure.

Acknowledgements

Full list of AMISTAD-2 investigators is found in ref. 1. The authors thank Dr King Jolly and Steve Jenkins of King Pharmaceuticals for support with data collection, and Martin Fahy and Yingbo Na of the Cardiovascular Research Foundation in New York, NY, USA, an affiliate of Columbia University Medical Center, for independent statistical analysis.

Conflict of interest: Dr Forman is a co-inventor along with Vanderbilt University of a use patent for adenosine in acute MI.

References

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