REOPEN-AMI Published: Adenosine Reduces ‘No-Reflow’ in STEMI Patients

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In patients undergoing primary percutaneous coronary intervention (PCI), intracoronary delivery of high-dose adenosine following thrombus aspiration improves microvascular perfusion and may reduce early clinical events, according to a randomized study published in the June 2013 issue of JACC: Cardiovascular Interventions. In contrast, intracoronary nitroprusside has no impact on perfusion or clinical outcomes.

Findings from the multicenter REOPEN-AMI (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction) trial were originally presented in October 2012 at the Transcatheter Cardiovascular Therapeutics scientific symposium in Miami Beach, FL.

For the trial, investigators led by Giampaolo Niccoli, MD, PhD, of the Catholic University of the Sacred Heart (Rome, Italy), enrolled 240 STEMI patients with TIMI flow grade 0/1 who were undergoing primary or rescue PCI. After administration of a glycoprotein IIb/IIIa antagonist and thrombus aspiration, patients were randomized to intracoronary adenosine (120 µg as fast bolus, then 2 mg in 33 mL of saline in 2 minutes as slow bolus; n = 80), nitroprusside (60 µg as fast bolus, then 100 µg in 33 mL of 5% glucose in 2 minutes as slow bolus; n = 80), or saline (n = 80) given distal to the occlusion.

ST-segment resolution greater than 70% on a surface ECG performed 90 minutes after PCI, the primary endpoint, was more frequent in the adenosine group than the saline group, while there was no difference between the nitroprusside and saline arms. Use of adenosine, but not nitroprusside, also showed a trend toward reduced angiographic microvascular obstruction (TIMI flow grade ≤ 2, or 3 with a myocardial blush grade < 2) and combined angiographic/ECG microvascular obstruction (concordance of lack of ST-segment resolution and angiographic microvascular obstruction). In addition, peak levels of CK-MB and troponin T, markers of infarct size, were markedly lower than placebo with adenosine but not nitroprusside (table 1).

Table 1. ECG, Angiographic, and Enzymatic Outcomes

 

Adenosine
(n = 80)

Nitroprusside
(n = 80)

Saline
(n = 80)

Pa Value,
Adenosine vs. Saline

Pa Value,
Nitroprusside vs. Saline

ST-Segment Resolution >70%

71%

54%

51%

0.009

0.75

Angiographic Microvascular Obstruction

18%

24%

30%

0.06

0.37

Angiographic/ECG
Microvascular Obstruction

8%

13%

18%

0.057

0.37

Peak CK-MB, ng/mL

78.7
(45.3-112.1)

123.1
(65.5-213.2)

116.6
(37.9-218.9)

0.002

0.99

Peak Troponin T, ng/mL

7.73
(3.01-9.97)

8.52
(1.94-21.05)

12.06
(2.42-16.54)

0.01

0.69

a For all data, statistical significance was defined as P <  0.025. 

The improvement in ST-segment resolution with adenosine vs. saline held firm after exclusion of patients (8 in the adenosine group, 9 in the nitroprusside group, and 7 in the saline group) in whom thrombus aspiration failed, requiring that therapy be infused through the guiding catheter.

The effect on ST-segment resolution was consistent across multiple prespecified subgroups including those based on age (threshold, 65 years), sex, diabetic status, ischemic time (threshold, 3 hours), and thrombus score 4/5. 

In terms of safety, there was a trend toward more transient AV block not requiring pacing with adenosine vs. saline (13% vs. 3%; P = 0.03). 

At 30 days, rates of MACE (composite of cardiac death, MI, TLR, and heart failure requiring hospitalization) were halved with adenosine compared with placebo, although the difference did not reach statistical significance. No difference was seen with nitroprusside for MACE, or for any of the individual endpoints for either agent.

Table 2. Clinical Outcomes at 30 Days

 

Adenosine
(n = 80)

Nitroprusside
(n = 80)

Saline
(n = 80)

P Value, Adenosine vs. Saline

P Value,
Nitroprusside vs. Saline

MACE

10%

14%

20%

0.08

0.29

Death

3%

3%

4%

0.98

0.98

TLR

5%

6%

8%

0.75

0.98

MI

1%

3%

4%

0.62

0.98

Heart Failure

1%

3%

5%

0.37

0.68


The authors stress that the study was underpowered to evaluate clinical outcomes.

Beyond Vasodilation

The fact that adenosine, an endogenous nucleoside with a short half-life, improved ST-segment resolution more than angiographic indices of reperfusion suggests that its benefit extends beyond brief vasodilation, Dr. Niccoli and colleagues observe, citing a range of other mechanisms by which adenosine may contribute to the protection of microcirculation.

Offering possible explanations for the failure of adenosine to show such an effect in some earlier trials, the authors conclude that “only high doses of adenosine reaching coronary microcirculation in the [infarct-related artery] territory immediately after flow restoration are able to improve [microvascular obstruction], as assessed by [ST-segment resolution].”

Robert A. Kloner, MD, PhD, of Good Samaritan Hospital (Los Angeles, CA), welcomed the current study, telling TCTMD in a telephone interview that in many respects it confirms the results of the AMISTAD I and II trials. Although thrombolysis was the primary therapy for all or most patients in those studies, both showed that IV infusion of adenosine reduced infarct size. Furthermore, a post hoc analysis of AMISTAD II patients reperfused within 3 hours of presentation found a clinical benefit in terms of reduced death and heart failure at 6 months (Kloner RA, et al. Eur Heart J. 2006;27:2400-2405), he noted.

Adenosine’s cardioprotective effect has been clearly shown in experimental models, Dr. Kloner noted. Although it is difficult to tease out which of its multiple properties are at work, he said he suspected that platelet inhibition may be important. Moreover, endogenous adenosine plays a role in ischemic preconditioning, which reduces infarct size, he reported.  

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said the fact that nitroprusside, which is a much stronger vasodilator than adenosine, did not reduce ‘no-reflow’ while adenosine did underlines the latter’s many ‘off-target’ effects. For example, adenosine has been linked to inhibition of apoptosis, he noted, and this  may have contributed to the reduction in infarct size implied by improved microvascular reperfusion.

Optimal Regimen Unclear

Dr. Kloner said the optimal protocol for adenosine administration is unknown, although in the positive AMISTAD trials it was delivered as a 3-hour infusion, while in some negative trials it was given as a single bolus.

The current study represents a kind of a hybrid approach, he commented. “When you give adenosine intravenously, you are more likely to get systemic effects,” he said. “And if adenosine is working through an antiplatelet mechanism, you want to have it onboard throughout the reperfusion phase. Giving adenosine by both intravenous and intracoronary routes would be very interesting.”

Dr. Brener, however, called the study protocol for adenosine administration “the way to go,” although he acknowledged that it is rarely given this way in practice. “If they use adenosine, most clinicians just give a little intracoronary bolus after reperfusion,” he reported.

One important issue the study did not address is whether adenosine should be used routinely in STEMI patients or only when there are signs of ‘no-reflow,’ Dr. Brener said, adding that in the absence of microvascular obstruction adenosine is unlikely to make a difference.

“There is definitely something to adenosine, and it should be explored in a larger, multicenter study,” Dr. Kloner concluded.

Dr. Brener advocated a more conservative approach, suggesting first a moderately sized study to determine whether adenosine significantly reduces infarct size as assessed by MRI. Only if that is confirmed would a larger trial powered for clinical endpoints be warranted, he said.

 


Source:
Niccoli G, Rigattieri S, De Vita MR, et al. Open-label, randomized, placebo-controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration during primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: The REOPEN-AMI study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction). J Am Coll Cardiol Intv. 2013;6:580-589.

 

 

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Disclosures
  • Drs. Niccoli, Kloner, and Brener report no relevant conflicts of interest.

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