Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings

Abstract

Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials.

Co‐morbidities and co‐medications as confounders of cardioprotection—Does it matter in the clinical setting?

“…Statins protect the heart against ischaemia/reperfusion injury in preclinical studies, but statin treatment may interfere with the infarct size-limiting effect of preconditioning (Ferdinandy et al, 2014 (Birnbaum, Birnbaum, Ye, & Birnbaum, 2015). In clinical trials, statins have been added to a standard-of-care regimen, which includes sev-…”

Myocardial ischemic reperfusion injury – A review

“…Morphine could delay the onset of protection in patients with ST-elevation. Anti-platelet agents such as dipyridamole, cilostazol and ticagrelor may protect the myocardium from IRI due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels (Birnbaum et al, 2015). Non-ST elevation myocardial infarction (NSTEMI) patients are often managed with the blood thinner heparin (O'connor et al, 2010).…”

Ticagrelor – toward more efficient platelet inhibition and beyond

“…Both ticagrelor and rosuvastatin were shown to increase the concentration of adenosine in animal models, which may further contribute to the beneficial effect of their co-administration. 34 , 35 Nevertheless, a series of case studies have reported an increased risk of rhabdomyolysis when ticagrelor was co-administrated with high-dose statins in patients with CKD, suggesting that the ticagrelor–statins interaction may be clinically relevant in particular patient populations. 36 , 37 …”