There have been a number of publications recently maligning the use of morphine for the treatment of acute coronary syndrome (ACS). The hypothesis proposed is that morphine slows the absorption of the oral p2y12 inhibitors, such as ticagrelor, delaying the dual- platelet inhibition desired by cardiologists worldwide.

The most recent data supporting this hypothesis was published in the European Heart Journal in 2016 (1). Appropriately entitled the IMPRESSION trial, its results propagated a concept, that while appearing valid on the surface, may not represent the underlying reality.

In this single center trial, Kubica et al randomized patients presenting with acute myocardial infarctions, destined for cardiac catheterization, to receive either 5 mg of IV morphine or placebo just prior to receiving a 180 mg loading dose of ticagrelor. Drug concentrations and platelet function were measured over the next 12-hours of each patient’s hospital course.

The authors found just what they set out to, the use of morphine inhibited the absorption of ticagrelor, and delayed its platelet inhibitory effects. The serum levels of ticagrelor were generally higher in the patients who were randomized to receive placebo when compared to morphine. Also noted, the time to reach peak serum drug levels was significantly delayed in the patients randomized to receive IV morphine. These pharmacokinetic shortcomings directly translated into delays in platelet inhibition measured using platelet function assays. In the placebo group the time to reach therapeutic platelet inhibition was 1-hour, compared to 2-hours in the patients who received IV morphine.

This reasonably robust evidence demonstrates the pharmacokinetic and pharmacodynamic influence morphine has on ticagrelor’s platelet inhibitory capabilities. At first glance, this seems to condemn yet another staple in the Emergency Department’s management of ACS. But as with so many questions involving the use of p2y12 inhibitors, the pharmaceutical companies, in this case Astrazeneca, have purposefully and cunningly changed the question, deflecting attention from the more important inquiry. What benefits if any do p2y12 inhibitors provide in the Emergency Department management of ACS?

If we are to believe that morphine is harmful when utilized in patients experiencing a myocardial infarction, then we first have to believe that early upstream use of p2y12 inhibitors provides some clinically important benefit, despite the preponderance of literature demonstrating the exact opposite. As far back as the CURE trial, the use of p2y12 inhibitors have failed to prove themselves capable of providing clinically important outcomes in patients presenting with ACS. The authors were able to demonstrate a statistically significant benefit through the use of statistical bullying tactics. The small benefits found were achieved through recruitment of large sample sizes and the use of questionable composite endpoints. The majority of difference resulted from the reduction of type 4a MIs of question clinical consequence (2).

Achieving these paltry benefits has never been shown to be dependent on the upstream administration of these medications in Emergency Department. In fact, multiple trials have demonstrated an identical level of mediocrity can be achieved once stent appropriate anatomy has been defined.

We have covered this topic in detail in a previous post, but in brief the CREDO trial examined the upstream use of clopidogrel prior to cardiac catheterization and found no clinical benefit to the early dual-antiplatelet effects this prompt administration provided (3).

In the 2013 ACCOAST trial, Montalescot et al examined early loading of prasugrel in patients requiring urgent catheterization after experiencing an NSTEMI (4). These authors randomized patients to receive prasugrel upstream in the Emergency Department or in the cath lab, only after anatomy appropriate for stenting was defined. Similar to the CREDO trial, these authors found no benefit to the upstream use of prasugrel, reporting no difference in cardiovascular death, myocardial infarction, stroke, urgent revascularization or glycoprotein IIb/IIIa bailout (10.8% vs 10.8%). Not surprisingly the pretreatment group was found to have approximately 1% increase in major bleeding, most due to an increase in CABG related bleeding (20.7% vs 13.7%).

Finally, the ATLANTIC trial which was published in the NEJM in 2014 by Montalescot et al, examined the use of prehospital ticagrelor in patients presenting with ST-elevation MI (5). The authors randomized 1,862 patients to receive a prehospital 180 mg loading dose of ticagrelor or a delayed dose in the cath lab prior to the start of the procedure. And just like the multitude of trials before it, these authors found no benefit in the rate of cardiovascular deaths, MIs, strokes, urgent revascularizations, or definitive stent thrombosis (4.5% vs 4.4%) between the groups. Nor did they find a difference in the rate of 70% or greater resolution of ST-segment elevation before PCI, or the proportion of patients who did not meet the criteria for TIMI flow grade 3 in the infarct-related artery at angiography before PCI. In an attempt to save face the authors noted the one subgroup that demonstrated a statistically significant finding in favor of the patients receiving prehospital ticagrelor. In patients who did not receive IV morphine, the rates of 70% or greater resolution of ST-segment elevation before PCI, were more frequently observed in patients randomized to upstream ticagrelor use. This observation did not translate into a difference in the rate of TIMI III flow in this subset of patients.

Despite the well known dangers of multiple outcomes and subset analyses, those in support of the hypothesis proposed by the IMPRESSION authors cling to this statistical life boat, suggesting the use of morphine was responsible for the failure of the ATLANTIC trial to find benefit in the upstream administration of p2y12 inhibition. And while this statistical anomaly, discovered while dredging a sea of insignificance, may in fact represent a true clinically important interaction, there is a far more likely explanation. The majority of trials examining the utility of p2y12 inhibition have found trivial improvements and no trial has ever demonstrated these marginal benefits are dependent on their timely administration. Despite claims of harms, the authors of the IMPRESSION trial reported no difference in the rates of patient oriented outcomes, death, MI, stent thrombosis, or stroke. And while statistically underpowered, these results are consistent with the remainder of the literature. As such, the negative results demonstrated in the ATLANTIC trial are likely because the upstream use of p2y12 inhibitors provide no clinically meaningful benefits. When the literature is examined in total this latter explanation seems far more plausible.

But plausibility and truth do not sell medications. For that purpose, all that is required is composite endpoints, stacked on surrogate outcomes, piled on top of methodologically manufactured p-values served to us under a physiologically palatable fiction such as dual-antiplatelet therapy.

Sources Cited:

Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016;37(3):245-52. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-20. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010. Montalescot G et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371(24):2338-9.