Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography

Selected in JACC by N. Ryan , D. Milasinovic

EARLY ACS was a randomised control trial assessing early versus delayed use of eptifibatide in patients presenting with NSTE-ACS and high-risk features. In this subanalysis, the authors evaluate the association between morphine and ischaemic events in patients pre-treated with clopidogrel.

Reviewers

Nicola Ryan

@NicolaRyanI1

Interventional cardiologist / Cardiologist

Aberdeen Royal Infirmary - Aberdeen, United Kingdom

Dejan Milasinovic

@MilasinD18

Interventional cardiologist / Cardiologist

Clinical Centre of Serbia - Belgrade, Serbia

Our Comment

This joint review is part of the PCRonline GLOBAL Journal Club Initiative by selected members of the EAPCI/PCR Journal Club and PCR NextGen, and is based on the underlying idea of “Bringing peers together, exchanging ideas, towards a common standard of care”.

Why this study – the rationale/objective?

EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome) was a randomised control trial assessing early (at least 12 hours pre angiography) versus delayed (during or shortly after PCI) use of eptifibatide in patients presenting with NSTE-ACS and high risk features. In this post hoc subanalysis the authors evaluate the association between morphine and ischaemic events in patients pre-treated with clopidogrel.

How was it executed – the methodology?

EARLY-ACS enrolled 9,406 patients, with randomisation stratified according to upstream use of clopidogrel. Of these 506 patients were excluded from the current analysis due to no coronary angiography (240, 2.6%) or missing data with regard to morphine administration (266, 2.9%). The primary population was patients treated with clopidogrel within 24 hours pre randomisation with the control population those not treated with clopidogrel within 24 hours pre randomisation. In order to control for causality bias (i.e. sicker patients being more likely to receive morphine), inverse probability treatment weighting (IPTW) was used to balance the groups for baseline characteristics.

• The primary endpoint was a composite of death, non-fatal MI, recurrent ischaemia with the need for urgent revascularisation or thrombotic bailout at 96 hours.
• Secondary endpoint was death or MI at 30 days, TIMI major or minor bleeding was analysed at 120 hours.
• Exploratory endpoints were death or MI at 96 hours as well as TIMI bleeding at 96 hours.
• A landmark analysis set at 48 hours was performed.

What is the main result?

Pre-randomisation clopidogrel was administered in 5,438 patients, of whom 617 (11.3%) received pre-randomisation morphine. Patients receiving morphine were more likely to have previous MI, PCI, or heart failure with more patients presenting with > Killip I and more pre-treatment with nitrates. In the control arm, 3,462 patients, 11.8% (407) received pre-randomisation morphine. After IPTW the groups were balanced for baseline characteristics.

• In the primary population morphine use was associated with increased rates of death, non-fatal MI, recurrent ischaemia with the need for urgent revascularisation or thrombotic bailout at 96 hours (adjusted OR 1.4; 95%CI: 1.04-1.87; p = 0.026), stratification for early or delayed eptifibatide gave similar results (p interaction = 0.71).
• Morphine use was associated with a trend towards increased death or MI at 30 days in the primary population (adjusted OR 1.29; 95%CI 0.98-1.7; p=0.072), with no increase in TIMI minor or major bleeding at 120 hours (adjusted OR 0.96; 95%CI: 0.59-1.57; p = 0.89).
• Also, the exploratory endpoints showed a higher rate of death/MI at 96 hours (adjusted OR 1.46; 95%CI 1.06-2.01; p = 0.019) with no differences in bleeding (adjusted OR 0.91; 95%CI 0.55-1.52; p = 0.73). • In the control population, not receiving clopidogrel within 24 hours of randomization, morphine use was not associated with higher rates of death, non-fatal MI, recurrent ischaemia with the need for urgent revascularisation or thrombotic bailout at 96 hours (adjusted OR 1.05; 95%CI 0.74-1.49; p = 0.79).
• Landmark analysis showed the association between death/MI and morphine within the first 48 hours (adjusted HR 1.54; 95%CI 1.07-2.23; p = 0.021), whereas the use of morphine was not associated with later events, in clopidogrel pre-treated patients. In the control population, without clopidogrel pre-treatment, morphine use was not associated with death/MI neither within the first 48h nor afterwards.

Critical reading and the relevance for clinical practice

The results of this analysis show that concomitant administration of clopidogrel and morphine is associated with an increased short-term risk of ischaemic events in NSTE-ACS patients. As clopidogrel is dependent on intestinal absorption and morphine delays gastric emptying, a clinical interaction between these medications as shown in pharmacological studies is the most likely explanation for this association. The lack of association between morphine and ischaemic events in the control population not pre-treated with clopidogrel supports this.

A note of caution when interpreting the results, this was a post hoc analysis of a trial where all patients received GP IIb/IIIa inhibitors randomised by timing of administration, other strategies such as use of IV ADP receptor inhibitors or use of oral P2Y12 inhibitors alone may give differing results. Morphine is the most commonly used opiate in ACS, however, the PACIFY study showed that fentanyl reduced ticagrelor's effectiveness perhaps suggesting that this is a class effect, a hypothesis under investigation in the PERSEUS trial.

In summary, this analysis provides clinical data supporting the interaction between morphine and clopidogrel. Given that delayed administration of clopidogrel has no effect on ischaemic outcomes there may be an argument to support a further loading dose of clopidogrel once the effects of morphine have worn off. Other strategies to ensure adequate platelet inhibition such as administration of parenteral antiplatelets in conjunction with opiates have been investigated, however the optimal antiplatelet regimen in NSTE-ACS patients remains a topic of debate.

Clopidogrel and morphine in NSTE-ACS

Clopidogrel and morphine in NSTE-ACS