Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon

Disclosures

Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

Adenosine as a Treatment for Myocardial Preservation

Adenosine is released under conditions of ischemia or increased myocardial energy demand, and in animal models, preconditioning with adenosine significantly decreases ischemia–reperfusion-induced myocardial damage, but in humans, preconditioning is impractical.[98–100] The germane issue is whether adenosine administration to humans during or immediately after myocardial infarction can limit damage and extend life expectancy. Unfortunately, studies in humans have not been as promising as might be anticipated based on results in mammalian models, although there are some potentially encouraging findings.

An early human trial of adenosine, Asymptomatic Myocardial Ischemia in STroke and Atherosclerotic Disease (AMISTAD) 1, was designed to explore whether, during the time of thrombolysis, adenosine (70 μg/kg/min over 3 h) could significantly reduce the extent of a myocardial infarction if given within 6 h of infarction onset.[101] This prospective, open-label trial randomized 236 patients to adenosine or placebo with a primary endpoint of infarct size as determined by Tc-99 imaging. In AMISTAD 1, reduction in infarct size was observed only in cases of anterior infarction, while underpowering did not allow determination of whether overall clinical outcomes were improved. A second, larger trial, AMISTAD 2, randomized 2118 patients with electrocardiographic evidence of anterior ST-segment elevation myocardial infarction to 3 h of either 50 or 70 μg/kg/min adenosine along with fibrinolysis or percutaneous coronary intervention.[102] AMISTAD 2 confirmed that adenosine lowers infarct damage in patients suffering an acute anterior infarct undergoing reperfusion therapy. In a post hoc analysis, adenosine was found to have positive impact on clinical outcomes when reperfusion was initiated early (within 3.17 h of symptom onset) in the course of anterior myocardial infarction. Patients reperfused after the median 3.17 h received no clinical outcome benefit from adenosine, giving insight into the optimal timing and methods of this adjunct therapy. Adenosine added more value when administered along with thrombolytic therapy than when it was given with percutaneous coronary intervention.[103]

Marzilli et al.[104] used adenosine as an adjunct to a percutaneous coronary intervention in acute myocardial infarction. A total of 54 patients within 3 h of onset of acute myocardial infarction referred for percutaneous coronary intervention were randomized to receive intracoronary adenosine or placebo (saline). Those who received adenosine had a 6.4% reduction in residual diameter stenosis versus the saline group, and each patient receiving adenosine achieved TIMI 3 blood flow in the occluded artery. In contrast, 19 patients had TIMI 3 and eight patients had TIMI 2 flow in the saline group, revealing a decrease in blood-flow strength. The study also found improved left ventricular wall motion after 1 week in 64% of the initially dyssynergic segments in the adenosine group and in only 36% of segments in the saline group (P = 0.001). Regarding clinical outcomes, five patients died in the saline group, compared to none in the adenosine group (P < 0.02). There was an improvement in clinical outcomes in the adenosine group versus saline, although the study included a small sample size.

Quintana et al.[105] led the Attenuation by Adenosine of Cardiac Complications (ATTACC ) study to evaluate the possible beneficial effect on left ventricular function of adenosine adjuvant therapy in patients between age 18 and 80 years with chest pain of less than 12 h duration and acute myocardial infarction treated with thrombolysis. Patients received adenosine (10 μg/kg/min) or saline before or at the initiation of thrombolysis with either tissue plasminogen activator or streptokinase. The 10 μg/kg/min adenosine dosage was better tolerated in comparison to 40 μg/kg/min adenosine in an earlier pilot study. Enrollment consisted of 302 patients given adenosine and 306 given placebo. The primary endpoint for ATACC was indices of left ventricular systolic function by echocardiogram. Secondary endpoints reported during a 12-month follow-up period included all-cause and cardiovascular death, non-fatal myocardial infarction, and the composite endpoint which combined cardiac mortality and non-fatal acute myocardial infarction. Short-term side effects, including hypotension, bradycardia, AV block, recurrent chest pain, and congestive heart failure, were similar between adenosine and placebo groups. There were no significant differences in left ventricular function between the two groups, even when analyzed via infarct location (wall motion score indices and ejection fraction data showed similar trends when comparing adenosine and placebo groups). Non-fatal acute myocardial infarction and the composite endpoint were alike at the 12-month follow-up. Twelve-month follow-up data of cardiovascular death showed lower levels of mortality in the adenosine group versus placebo (risk reduced by greater than 3%). Furthermore, when the patients were sorted by specific infarct damage location, total and cardiovascular mortality improved in patients with anterior acute myocardial infarction after a 12-month follow-up and during the complete follow-up (absolute risk reduction exceeding 6%). Although these trends were non-significant in this sample size and study, the potential for therapeutic benefit may warrant a larger study.

In a double-blind study of 201 patients with ST-segment elevation myocardial infarction receiving percutaneous coronary intervention, subjects were randomized to receive either intracoronary adenosine (4.5 mg) or saline control prior to reperfusion.[106] The study failed to show an effect of adenosine on infarct size, but suggested possible myocardial preservation in those with short ischemia duration of less than 200 min.

Two randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase 2b clinical trials have been newly initiated to study the effect of a partial adenosine A1 receptor agonist, neladenoson bialanate, in patients with heart failure and a preserved ejection fraction (≥ 45%) or heart failure with a reduced ejection fraction (≤ 35%).[107,108] These two studies are designed to find the optimal dose of neladenoson bialanate for a potential phase 3 trial. Possible benefits of an A1 partial agonist in heart failure include better mitochondrial function, halting of ventricular remodeling with reduced fibrosis and protection against ischemic injury.

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