Adenosine May Be the Tie That Binds Ticagrelor and Dyspnea

Patients with acute coronary syndromes (ACS) who take ticagrelor are known to be at higher risk for dyspnea than their counterparts who receive clopidogrel. New findings published online January 9, 2013, ahead of print in the Journal of the American College of Cardiology suggest that the side effect may stem from the drug’s ability to inhibit adenosine uptake.

Ticagrelor (Brilinta, AstraZeneca, Wilmington, DE) was approved by the US Food and Drug Administration in July 2011 based on results of the PLATO (PLATelet inhibition and patient Outcomes) trial. The study, published in the New England Journal of Medicine in September 2009, showed that the newer drug improved overall outcomes at 12 months compared with clopidogrel in over 18,000 ACS patients. But ticagrelor also was associated with more dyspnea than clopidogrel (13.8% vs. 7.8%; P < 0.001).

For the current study, Li-Ming Gan, MD, PhD, of Göteborg University (Göteborg, Sweden) and AstraZeneca (Mölndal, Sweden), and colleagues randomized 40 healthy male subjects to a single dose of ticagrelor (180 mg) or placebo in a double-blind crossover design. The men were given, in a stepwise fashion, 4 adenosine infusions ranging from 50 to 140 µg/kg/min followed by an infusion of the drug theophylline, known to block the action of adenosine.

Blood Flow, Dyspnea Both Affected

Adenosine-induced coronary blood flow velocity was assessed using transthoracic Doppler echocardiography. The area under the curve for this endpoint increased by 15% in subjects receiving ticagrelor and 4% in those receiving placebo (P = 0.008). In combination with ticagrelor, the effect on blood flow was significant at adenosine doses of 50 and 80 µg/kg/min. Theophylline infusion, meanwhile, reversed adenosine’s impact on coronary blood flow velocity for both the ticagrelor and placebo groups.

Moreover, in the absence of adenosine, coronary blood flow velocity remained stable before and after ticagrelor and placebo infusion, and after theophylline infusion.

Self-reported symptoms of dyspnea were more common with ticagrelor than placebo at adenosine doses of 80, 110, and 140 µg/kg/min (P < 0.01). Again, theophylline administration weakened adenosine’s effects.

A ‘Plausible’ Mechanism

“Taken together, this adenosine-mediated secondary mode of action of ticagrelor may provide a plausible mechanistic explanation for the cardioprotective effects, as well as the increased occurrence of dyspnea, observed in patients taking ticagrelor versus clopidogrel in the PLATO study,” Dr. Gan and colleagues conclude.

Ticagrelor’s ability to limit adenosine uptake, “may be important in vessel damage or hypoxia, where increased adenosine levels may contribute to vasodilation,” the investigators note, mentioning “ischemic preconditioning, inhibition of inflammatory response, and inhibition of platelet activation” as other possible benefits.

They caution, however, that the results may not extend to real-world ticagrelor use in ACS patients, because the study involved healthy male volunteers and exogenous rather than endogenous adenosine.

Long-term Effects Uncertain

In a telephone interview, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), told TCTMD that the findings are in line with what has been shown by preclinical research. “It’s a pretty cool study,” he said, adding, “It makes sense and is very nicely done. I’m sure adenosine is part of this.”

One question, Dr. Bates noted, is how the relationship between ticagrelor and adenosine holds up over the long term. In PLATO, dyspnea cases were temporary and lasted only a few days despite patients remaining on ticagrelor maintenance doses, he reported. “But the clinical benefit in the trial was [late not early]. You’re given this drug constantly and the dyspnea goes away, then the mortality benefit comes on later.”

All-cause death rates were 4.5% with ticagrelor and 5.9% with clopidogrel in PLATO (P < 0.001). The reasons for that disparity are unclear, Dr. Bates commented, but may involve adenosine. “People are struggling with why this drug reduces mortality when no other drug has done so.”

Dr. Bates pointed out that some studies have explored the idea of giving adenosine infusions to acute STEMI patients. “It hasn’t caught on as a therapeutic option, because it might just [help] a small subset of patients who are treated early and have big infarcts, but that theory is still out there,” he said.

 

 


 

Sources:1. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013;Epub ahead of print.

 

2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-1057.

 

 

 

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Disclosures
  • The study was supported by AstraZeneca, and 6 of 7 coauthors are employees of the company.
  • Dr. Bates reports serving on the advisory boards of AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, and Daiichi-Sankyo/Eli Lilly.

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