Editorial

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American Journal of Emergency Medicine

journal homepage: www. elsevier.com/ locate/ajem

Upstream antiactivation antiplatelet therapy: first, do no harm. Then consider doing some good

In this issue of the journal, Diercks et al report from data abstracted from the NCDR ACTION Registry that emergency department (ED) administration of a thienopyridine (in this analysis, clopidogrel or prasugrel, most being the former, administered physically in the ED) to patients with non-ST-segment elevation myocardial infarction (NSTEMI) is not associated with in-hospital major bleeding or mortality [1]. Among those 9534 patients (only 24.2% of all those who received a thienopyridine within 24 hours of ED presentation), there were no efficacy signals, beneficial or otherwise [1]. Current American College of Cardiology Foundation/American Heart Associ- ation (ACCF/AHA) guidelines support upstream inhibition of the platelet P2Y12 (ADP) receptor in patients with NSTEMI, after taking into account the individual patient’s likely post-ED course (including the possibility of near-term Coronary artery bypass grafting [CABG] surgery), overall thrombotic risk, and concomitant bleeding risk [2]. Strong clinical trial data support this consideration.

Antiplatelet therapy for NSTEMI has evolved from the use of aspirin (ASA) alone to Dual antiplatelet therapy with ASA and clopidogrel, ticagrelor, or (post-percutaneous coronary intervention [PCI]) prasugrel. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the addition of clopidogrel to ASA within 48 hours of unstable angina/NSTEMI symptom onset signifi- cantly decreased the 30-day relative risk of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or stroke by 21% (P = .003) [3,4]. Importantly, when viewed from the perspective of the emergency care provider, the benefit of adding clopidogrel was apparent within 4 hours of treatment initiation, was significant by 24 hours, and was maintained through 12 months (20%; P b .001) [3,4].

Ticagrelor, which also inhibits the platelet P2Y12 receptor, has a faster onset and offset of action than clopidogrel and is a more potent inhibitor of platelet activation [5]. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, in which ticagrelor was compared with clopidogrel in 18624 patients with acute coronary syndrome (ACS) given ASA, ticagrelor significantly reduced the risk of CV death, MI, or stroke compared with clopidogrel (9.8% vs 11.7%; P b .001) [6]. Notably, the single outcome of CV mortality was also significantly reduced by ticagrelor (4.0% vs 5.1%; P = .001) [6]. These benefits were observed regardless of type of ACS (unstable angina/NSTEMI or ST- segment elevation myocardial infarction) or Management strategy (conservative or invasive) and were not associated with any significant increase in trial-defined major bleeding (11.6% vs 11.2%; P = .43) [6].

Although the ACCF/AHA guidelines do support early invasive management (ie, diagnostic angiography followed by medical therapy, PCI, or CABG as indicated) of NSTEMI, patients benefit from antiplatelet therapy regardless of downstream management,

offering reassurance to the upstream provider considering its initiation. Percutaneous coronary intervention is associated with significant reductions in both morbidity and mortality in NSTEMI [7], but the procedure itself can stimulate thrombosis. In the subset of subjects in CURE who underwent PCI (separately reported as “PCI-CURE” [8]), clopidogrel initiation before PCI reduced the relative risk of CV death and Ischemic events by 25% (8% vs 6%; P = .047). Among patients in the PLATO study who underwent invasive management, subjects in both the clopidogrel and tica- grelor arms were given study drug at a median of 8.9 hours (interquartile range, 4.0-18.0 hours) after the start of chest pain and

2.4 hours (0.8-11.4) after hospital admission [9], which is certainly an ED-pertinent timeframe. Although granular data on the potential time dependency of antiplatelet therapy initiation has not yet been published from PLATO, we do know that even in patients who were pretreated with clopidogrel, there was clinical benefit (without increased bleeding risk) associated with switching them to tica- grelor downstream [9], supporting the concept of a broader opportunity for action in the ED. There has been no upstream study of prasugrel in NSTEMI.

Despite the proven benefit of early dual antiplatelet therapy, emergency physicians and other upstream providers (hospitalists, noninterventional cardiologists) may be hesitant to initiate antiplate- let treatment before determination of the coronary anatomy due to concerns for risk of increased bleeding and near-term CABG. Factors associated with major bleeding include advanced age, female sex, diabetes mellitus, renal insufficiency, prior stroke, prior bleeding history, and low hemoglobin level on presentation. These factors can be used in an algorithm to approximate a quantitative bleeding risk [10], although the score is anecdotally not often familiar to emergency physicians. Quantitative risk modeling aside, the typical emergency physician is certainly capable of generally assessing bleeding risk in parallel fashion to the risk stratification ordinarily performed for adverse ischemic outcomes in the ACS patient.

Bleeding concerns may also delay CABG surgery if, at diagnostic angiography, triple-vessel or other disease not amenable to PCI is found. Bleeding is certainly more likely in patients going to CABG within 5 days of receiving a loading dose of antiactivation antiplatelet therapy, but in CURE, patients who underwent CABG more than 5 days after early clopidogrel plus aspirin treatment showed lower incidences of CV death, MI, stroke, or urgent revascularization without signifi- cantly increased Life-threatening bleeding [11]. An increased risk of major bleeding was seen in clopidogrel-loaded patients undergoing CABG within 5 days of clopidogrel discontinuation in CURE (9.6% vs 6.3%; P = .06), but there was no ischemic efficacy price to be paid [4]. It can certainly be argued that, in the CABG cohort of CURE, the benefits

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of starting clopidogrel before the anatomy was known outweighed the risks. Furthermore, in the Acute Catheterization and Urgent Interven- tion Triage Strategy trial, clopidogrel-loaded patients who went on to CABG had a lower 30-day rate of composite ischemia, compared with those who did not receive clopidogrel (12.7% vs 17.3%; P = .001), and experienced no increased risk of non-CABG-related major bleeding (3.4% vs 3.2%; P = .87) [12].

Data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines Registry, which did include a modicum of data specific to ED care, indicate that although bleeding is increased if clopidogrel is not stopped within 5 days of surgery, overall patient outcomes are not worse [13]. Adding to the “manageability” of the issue of concern for CABG is the fact that the number of patients with ACS who will require CABG is relatively low (7%-14% [14-16] and likewise well under 10% in the Diercks analysis [1]), emergency CABG following PCI is much rarer (0.3%-0.6%) [17,18], and significant bleeding occurs in only 3% to 5% of patients undergoing CABG [19,20]. The simple math, therefore, indicates that, if upstream antiplatelet pretreatment is routinely withheld because of concern for possible near-term CABG-related bleeding, then 86% to 93% of NSTEMI patients who are managed downstream with CABG are denied protection from ongoing thrombotic risk to benefit 7% to 14% who cannot be reliably identified upstream.

Therefore, findings both in clinical trials and “real-world” registries suggest that bleeding risk and likelihood of near-term CABG can be effectively evaluated in the upstream setting. A reasonable balance can be negotiated between ischemic protection and bleeding risk before knowing the coronary anatomy. This high- level, proactive decision making is not wholly the domain of the emergency physician but should be a collaborative decision with which downstream providers are in agreement. The option of evidence-based, prudently selected upstream antiplatelet therapy should be included in ED protocols for NSTEMI management and, in the presence of a favorable risk-benefit balance, should be used by emergency physicians to protect their patients while awaiting the results of diagnostic angiography.

Although it is recognized that we currently have insufficient data to assess fully the impact of upstream on primary ischemic outcomes in NSTEMI, it is clear that, in prudent emergency medicine practice that assesses both ischemic and hemorrhagic risk, upstream initiation of antiplatelet therapy can be beneficial in NSTEMI, regardless of the downstream management strategy. The current analysis of Diercks et al confirms the safety of this approach; further investigation will be required to determine its relative efficacy in comparison with therapy initiated post-ED.

Charles V. Pollack Jr. MD

Department of Emergency Medicine Pennsylvania Hospital, University of Pennsylvania

Philadelphia, PA E-mail address: [email protected]

References

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