Invasive and antiplatelet treatment of patients with non‐ST‐segment elevation myocardial infarction: Understanding and addressing the global risk‐treatment paradox

Abstract Clinical guidelines for the treatment of patients with non‐ST‐segment elevation myocardial infarction (NSTEMI) recommend an invasive strategy with cardiac catheterization, revascularization when clinically appropriate, and initiation of dual antiplatelet therapy regardless of whether the patient receives revascularization. However, although patients with NSTEMI have a higher long‐term mortality risk than patients with ST‐segment elevation myocardial infarction (STEMI), they are often treated less aggressively; with those who have the highest ischemic risk often receiving the least aggressive treatment (the “treatment‐risk paradox”). Here, using evidence gathered from across the world, we examine some reasons behind the suboptimal treatment of patients with NSTEMI, and recommend approaches to address this issue in order to improve the standard of healthcare for this group of patients. The challenges for the treatment of patients with NSTEMI can be categorized into four “P” factors that contribute to poor clinical outcomes: patient characteristics being heterogeneous; physicians underestimating the high ischemic risk compared with bleeding risk; procedure availability; and policy within the healthcare system. To address these challenges, potential approaches include: developing guidelines and protocols that incorporate rigorous definitions of NSTEMI; risk assessment and integrated quality assessment measures; providing education to physicians on the management of long‐term cardiovascular risk in patients with NSTEMI; and making stents and antiplatelet therapies more accessible to patients.


| Disease burden of non-ST-segment elevation myocardial infarction
Non-ST-segment elevation myocardial infarction (NSTEMI) is the leading cause of emergency hospitalization for acute coronary syndrome (ACS) in Europe and North America. [1][2][3][4] Although both patients with NSTEMI and ST-segment elevation myocardial infarction (STEMI) are at a high risk of recurrent cardiovascular events, patients with NSTEMI have higher long-term mortality and cardiovascular risk than those with STEMI. [5][6][7][8] Furthermore, the proportion of patients with acute myocardial infarction (MI) who have NSTEMI is increasing relative to those with STEMI. [9][10][11] Results from the French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI) and the Swedish Websystem for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry showed that the 6-month and 1-year mortality of patients with STEMI or NSTEMI have generally decreased since 1995. 11,12 However, since 2010, there has been no improvement in the 6-month mortality of patients with NSTEMI, regardless of whether or not they received percutaneous coronary intervention (PCI); in striking contrast, mortality has continued to decline in patients with STEMI during this time. 11

| Guideline recommendations for invasive and antiplatelet treatment of patients with NSTEMI
The standard of care for patients with NSTEMI at high ischemic risk is an early invasive strategy with cardiac catheterization within 24 hours of the onset of symptoms, with prompt revascularization using PCI or coronary artery bypass graft (CABG) surgery as clinically indicated. [13][14][15] Major international guidelines also recommend initiation of at least 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor (ticagrelor, prasugrel, or clopidogrel) in patients with NSTEMI who are managed with medical therapy and/or who are treated with revascularization (ie, irrespective of initial treatment strategy), unless there are previous or ongoing contraindications. [13][14][15][16][17][18] Ticagrelor is recommended over clopidogrel for patients with NSTEMI, including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). Ticagrelor is contraindicated in patients with previous intracranial hemorrhage or ongoing bleeds. [13][14][15][16][17][18] Prasugrel is recommended for patients with NSTEMI who have received angiography and are undergoing PCI. However, prasugrel is not recommended for patients in whom coronary anatomy is unknown and an indication for PCI is not clearly established; patients who are 75 years of age or older; or patients with a body weight of less than 60 kg. Prasugrel is contraindicated in patients with previous intracranial hemorrhage, previous ischemic stroke or transient ischemic attack, or ongoing bleeds. [13][14][15][16][17][18] Clopidogrel is a less potent P2Y 12 inhibitor than ticagrelor and prasugrel; it is recommended for patients who cannot receive ticagrelor or prasugrel, or who require oral anticoagulation. [13][14][15][16][17][18] Clinical risk scores, such as the DAPT score, can help guide decisions around whether to continue antiplatelet therapy beyond 1 year, by providing a risk-benefit ratio based on age, smoking status, comorbidity, and medical history. 19 For patients with NSTEMI who are elderly and have a high comorbidity burden, conservative treatment could be a reasonable approach. 16,19 1.3 | Invasive strategy and P2Y 12 inhibitor treatment evidence for NSTEMI An early invasive strategy of cardiac catheterization has a central role in the management of patients with NSTEMI because it facilitates: confirmation of the diagnosis of ACS related to obstructive epicardial coronary artery disease; identification of the culprit lesion(s); the establishment of the indication for revascularization using PCI or CABG; the stratification of the patient's short-and long-term ischemic risk. 15 Compared with a more conservative strategy, an early invasive strategy has been shown to improve clinical outcomes and reduce recurrent ACS episodes, subsequent rehospitalization, and revascularization. 15  superiority of ticagrelor to clopidogrel for the prevention of cardiovascular events in patients with NSTEMI. 27

| Suboptimal treatment of patients with NSTEMI
Despite the above recommendations and findings, patients with NSTEMI often receive less aggressive secondary prevention treatment than patients with STEMI. 8,28 Moreover, patients who have the highest ischemic risk often receive the least aggressive treatment, including both invasive and medical management; a phenomenon that has been termed the "treatment-risk paradox." [29][30][31][32] Suboptimal treatment of patients with multiple ischemic risk factors was highlighted in the Pattern of Repeat Cardiovascular Events During Follow-up After First Diagnosis Event-MI-2 (PRECLUDE-2) registry study. 33 Ischemic risk factors consisted of multivessel disease, diabetes mellitus, chronic kidney disease, prior MI, and age of at least 65 years. 33 Results from the PRECLUDE-2 study, which included invasively managed patients with MI, showed a higher ischemic risk compared with bleeding risk during a median follow-up of 3.6 years; having five ischemic risk factors, compared with only one risk factor, was associated with a 5 to 9 times increased incidence of ischemic events and a 2 to 4 times increased incidence of major bleeding. 33 The incidence of ischemic events increased with increasing number of ischemic risk factors, highlighting an unmet need for additional preventive measures in these high-risk patients. 33 The challenges for the treatment of patients with NSTEMI can be categorized into four "P" factors that contribute to poor clinical outcomes in these patients: patient characteristics, physician guideline implementation, procedure availability, and policy within the healthcare system. Here, we will consider each in turn and suggest some solutions to address these challenges in order to improve the standard of healthcare for this group of patients. There is also heterogeneity in the demographics of NSTEMI patient populations across the world, as indicated by the variety of patient demographic data across different countries. [37][38][39] This heterogeneity could partly explain the variation in mortality of patients with cardiovascular disease between countries. 37,38,40 Furthermore, patients with NSTEMI are more likely to be older in age and have a higher rate of comorbidities, such as diabetes, impaired renal function, and lung disease, than patients with STEMI. 41,42 These comorbidities contribute to a greater burden of coronary artery disease and an increased risk of cardiovascular events for patients with NSTEMI, and therefore lead to increased long-term mortality. 5,15 The wide variation in risk in patients with NSTEMI affects treatment decisions. Some patients are considered at too low risk of recurrent cardiovascular events to warrant an invasive strategy, whereas others are regarded as "too sick" to undergo coronary angiography and/or subsequent revascularization because of advanced age or severe comorbidities. 43 Figure 1 shows the benefit of invasive management vs. medical management on the survival of patients with NSTEMI.
Diagnosis of NSTEMI is also less straightforward than that of STEMI, which can be identified rapidly based on an electrocardiogram (ECG) measurement. The identification of patients with NSTEMI is often delayed owing to the frequent lack of definitive ECG changes and uncertainty about the definition of NSTEMI with regard to elevated cardiac troponin levels. 42 Implementation of high-sensitivity cardiac troponin assays will lead to an increase in the diagnosis of NSTEMI. 44 Age, sex, comorbidities, and in-hospital management strategies (eg, PCI or medical management) may also influence decisions in patients with NSTEMI regarding prescription at discharge. 28 43 Abbreviation: CAG, coronary angiography in these patients, which contributes to the suboptimal use of treatments and is suggestive of barriers to guideline implementation. 31,41 In the ACS II Canadian registry, the most common reason for not choosing an invasive treatment strategy in patients with NSTEMI was an underestimation of ischemic risk by physicians, even though a large proportion of these patients were at intermediate to high risk according to their Thrombolysis in Myocardial Infarction (TIMI) risk score. 46,47 Results from the registry also showed weak correlations between risk assessment by physicians and TIMI and Global Registry of Acute Coronary Events (GRACE) risk scores, 48 which are recommended for guiding treatment decisions for patients with NSTEMI in international guidelines. 13,15 Objective risk assessment using the GRACE risk score provided superior risk discrimination to physician-perceived risk for 6-month mortality in patients with ACS in the Perceived Risk of Ischemic and Bleeding Events in Acute Coronary Syndrome Patients (PREDICT) study. 49 Here, physicians were shown to overestimate the risk of 6-month mortality among patients with a low GRACE score and underestimate risk among those with a high GRACE score, consistent with the treatment-risk paradox. 49 Patients with NSTEMI at high ischemic risk were also not treated There is also evidence to suggest that patients with NSTEMI may be less likely to be treated in academic medical centers than patients with STEMI, and therefore less likely to be directed to larger hospitals with catheterization laboratories; indicating some degree of referral bias toward patients with STEMI. 42 The risk may be underestimated by physicians based on the intensity of treatment the patients are receiving and the advanced age of the patient, despite evidence that an early intensive strategy in the eldest patients with NSTEMI is associated with the greatest reduction in 1-year mortality. 47 In China, a nationwide database study that included 1055 tertiary hospitals showed an in-hospital mortality of 3.6% and a PCI utilization rate of 37.2% in patients with NSTEMI (corresponding rates in patients with STEMI were 5.1% and 47.8%, respectively). 55 The study identified wide variations in the rates of in-hospital mortality across geographical regions, and the rates were significantly lower in patients who received PCI than in those who did not. 55  P < .001). 67 There was a significantly lower rate of cardiac catheterization in the patients with a high GRACE risk score (P < .001), which was especially apparent in patients who presented by EMS. 67 Catheterization rates in community hospitals (84.4%) were higher than those in PCI centers (71.9%; P = .014) even though patients admitted to PCI centers had an overall higher GRACE risk score. 67 Aside from differences in the availability of specialist services, variation in healthcare for patients with NSTEMI across hospitals could also be due to differences in: the number of hospital admis-

| ADDRESSING THE CHALLENGES FOR THE TREATMENT OF PATIENTS WITH NSTEMI
The treatment-risk paradox in patients with NSTEMI is a global problem that is influenced by the four "P" factors discussed in this paper:

Domain of care Quality indicator Support from ESC guidelines
Main QI: The center should be part of a Network Organization with written protocols for rapid and efficient management covering the following points • Single emergency phone number for the patient to be connected to a medical system for triage • Pre-hospital interpretation of ECG for diagnosis and decision for immediate transfer to a center with catheterization laboratory facilities, bypassing the Emergency Department • Pre-hospital activation of the catheterization laboratory Secondary QI (1): routine assessment of relevant times for the reperfusion process in STEMI patients (ie, times from "call to first medical contact," "first medical contact to door," "door to arterial access" and "door-in door-out" for centers without a catheterization laboratory on site) Secondary QI (2) indicators had a significant inverse association with 30-day mortality (all P < .001), suggesting that quality indicators have the potential to improve patient healthcare and reduce varied mortality from acute MI ( Figure 2).
Guidelines and hospital protocols should emphasize the importance of documenting patient history, which could affect NSTEMI diagnosis, and of regularly assessing the risks and benefits of therapies to suit the patient's clinical status, which may change over time. 54 Furthermore, guidelines and protocols should include guidance on how to manage patients with dyspnea because some physicians are concerned about dyspnea related to ticagrelor use in their patients, given that dyspnea is more frequently reported in patients with ACS prescribed ticagrelor compared with clopidogrel. 73,74 The incidence of dyspnea in a realworld setting has been shown to be greater than that reported in clinical trials and may lead to higher rates of ticagrelor discontinuation. 74 However, given that there is evidence to suggest that dyspnea can resolve during inhibitor use, only in the case of persistent ticagrelor-related dyspnea should drug discontinuation be considered. 73 There is potential for reducing the impact of geographical variation  72 The composite opportunity QI was divided into the following categories: zero, received no interventions out of those eligible for; low, received <40% of interventions eligible for; intermediate, received ≥40% to <80% of interventions eligible for; and high, received ≥80% of interventions eligible for. Abbreviations: ACEI; angiotensin-converting enzyme inhibitor; ARB; angiotensin receptor blocker; BB, β-blocker; CI, confidence interval; DAPT, dual antiplatelet therapy; EF, ejection fraction; HF, heart failure; LV, left ventricular; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; QI, quality indicator; STEMI, ST-segment elevation myocardial infarction could be a reasonable approach to improve treatment outcomes for patients with NSTEMI, which could be facilitated by existing regional platforms for the management of patients with STEMI. 67

| CONCLUSIONS
Patients with NSTEMI have a higher long-term mortality risk than patients with STEMI but are often treated less aggressively, with those who have the highest ischemic risk often receiving the least aggressive treatment (the "treatment-risk paradox"). The suboptimal treatment of patients with NSTEMI can be explained by the heterogeneity of patient characteristics, an underestimation of the high ischemic risk compared with bleeding risk by physicians, procedure availability, and policy. To address these challenges, potential approaches include: developing guidelines and protocols that include rigorous definitions of NSTEMI, risk assessment, and integrated quality assessment measures; providing education to physicians on the management of long-term cardiovascular risk in patients with NSTEMI; and making stents and antiplatelet therapies more accessible to patients.

ACKNOWLEDGMENTS
Medical writing support for this review was provided by Tim Ellison, PhD, and Anja Becher, PhD, of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca.