Introduction

There are approximately 347,000-362,000 cases of out-of-hospital cardiac arrest (OHCA) in the United States every year.¹ A small percentage of these patients have return of spontaneous circulation (ROSC), and of these only a fraction survives to hospital discharge. In 2014, the percentage of adult OHCA patients who were treated by emergency medical service who survived to hospital discharge was only 12%.¹ Notably, 30-40% of patients presenting with OHCA have an unstable coronary lesion, even in the absence of any significant electrocardiographic (ECG) abnormalities.^2-4 Acute coronary occlusion in the setting of OHCA is poorly predicted by initial clinical and ECG characteristics.⁵ Therefore, urgent coronary angiography with or without percutaneous coronary intervention (PCI) is indicated in all OHCA patients, irrespective of their ECG findings. Several studies have shown the importance of early coronary angiography and reperfusion in resuscitated OHCA patients.^4,6,7 In fact, a 2015 American College of Cardiology (ACC) and American Heart Association (AHA) guideline update recommends immediate coronary angiography in all resuscitated cardiac arrest patients with a suspected cardiac etiology of arrest, regardless of the presence or absence of ST elevations on initial ECG.⁸ Therapeutic hypothermia has been shown to improve survival and neurologic outcomes in OHCA patients who remain comatose after ROSC.^9,10 In 2010, the ACC/AHA guidelines strongly recommended therapeutic hypothermia (32°C to 34°C) in OHCA patients with initial shockable rhythm viz. pulseless ventricular tachycardia or ventricular fibrillation as a Class I recommendation.¹¹ In the 2015 guideline update, therapeutic hypothermia was recommended for all comatose patients with ROSC after cardiac arrest, even for those with an initial nonshockable rhythm, as a Class I recommendation.⁸ Thus, a combination of therapeutic hypothermia and early coronary angiography in resuscitated cardiac arrest patients without a clear-cut non-cardiac cause of the arrest is an optimal strategy associated with the most favorable outcomes.^7,12 In fact, a recent study published by Kern et al. showed that a combination of early reperfusion and hypothermia had a synergistic effect in reducing infarct size in a porcine model of cardiac arrest secondary to acute coronary occlusion.¹³

Despite the established benefits of therapeutic hypothermia and early invasive strategy with PCI in resuscitated cardiac arrest patients, there has been significant controversy about the effect of hypothermia on blood coagulability, with studies suggesting enhanced thrombogenicity and platelet reactivity¹⁴ and reduced efficacy of antiplatelet medications with hypothermia.^15-17 Hence, some experts argue that any potential benefit of therapeutic hypothermia in resuscitated cardiac arrest patients who undergo PCI may be offset by a higher incidence of stent thrombosis. There is a lack of consensus opinion about the relationship between hypothermia and stent thrombosis in currently published studies in the literature.^18-22 In this review, we will summarize the current evidence on the risk of stent thrombosis in cardiac arrest patients undergoing PCI who are treated with therapeutic hypothermia.

Stent Thrombosis: Incidence, Mechanisms, and Risk Factors

Stent thrombosis is a serious clinical event presenting as ST-segment elevation myocardial infarction in most cases and is associated with high mortality rates.²³ Prior data have demonstrated that stent thrombosis is a rare occurrence with routine coronary intervention, with an incidence of <1% following PCI.²⁴ However, the incidence of stent thrombosis is higher in the setting of acute myocardial infarction (AMI), with data from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial reporting a 0.8% incidence of acute (within 24 hours) and 1.2% incidence of subacute (24 hours to 30 days) stent thrombosis in patients undergoing primary PCI for AMI.²⁵ Other studies have also demonstrated an acute and subacute stent thrombosis rate of around 2.5% in patients with AMI.^21,26,27 The incidence of early stent thrombosis (within 30 days) may be even higher in patients with cardiac arrest and AMI, with some studies showing an incidence of around 5%.^18,28

The risk factors for stent thrombosis can be divided into patient-, procedure-, or device-related factors.²⁴ Patient-related factors include diabetes, low left-ventricular function, non-compliance or discontinuation of antiplatelet therapy, coexisting malignancies, genetic traits, and high platelet reactivity.²⁹ Procedure-related factors include primary PCI for AMI, complex lesions, stent undersizing, stent edge dissection, residual stenosis, and decreased Thrombolysis in Myocardial Infarction flow post-stent.²⁹ Device-related factors include use of early generation drug-eluting stents such as sirolimus- or paclitaxel-eluting stents compared with bare-metal stents or newer generation drug-eluting stents.^30,31 Early stent thrombosis occurs due to the procedure-related factors listed above.²⁴ Late (after 30 days) stent thrombosis occurs when stent malapposition (e.g., due to undersizing or underexpansion) remains after discontinuation of antiplatelet therapy.³² Patient- and device-related factors also play in important role in late stent thrombosis.

Stent Thrombosis in Cardiac Arrest Patients: A Special Subgroup?

As discussed, the incidence of stent thrombosis is higher in the setting of AMI, low left-ventricular function, and post-cardiac arrest state. Several mechanisms have been proposed to explain the higher incidence of stent thrombosis in cardiac arrest patients. The comatose state of patients after resuscitation makes it difficult to administer oral medications, resulting in an inability to administer full dose dual antiplatelet therapy prior to cardiac catheterization.^22,28 There is unreliable gastrointestinal absorption of antiplatelet medications administered via orogastric or nasogastric tubes. Post-cardiac arrest shock and multi-organ failure result in reduced metabolism of clopidogrel and prasugrel, which are pro-drugs and need hepatic metabolism to be converted to an active metabolite.³³ Additionally, the critical illness associated with post-cardiac arrest status results in a hypercoagulable and prothrombotic state.³⁴ The residual effect of high doses of vasoconstrictor medications administered during cardiopulmonary resuscitation and a high level of circulating catecholamines and inflammatory cytokines in the immediate post-resuscitation period may also contribute to the risk of stent thrombosis.²⁸ Other mechanisms such as no-flow followed by restoration of flow associated with successful resuscitation and associated myocardial microcirculatory and endothelial dysfunction^35,36 have also been proposed.

In line with the aforementioned theories, a recent study from our group including 49,109 AMI patients presenting with cardiac arrest showed a 4.7% incidence of stent thrombosis during the index hospitalization,²⁸ which is almost twice the incidence of early stent thrombosis in AMI patients without cardiac arrest.^25-27 Moreover, we observed an even higher incidence of stent thrombosis in the presence of heart failure, cardiogenic shock, or use of hemodynamic support,²⁸ further affirming the contribution of critical illness and circulatory collapse to the risk of stent thrombosis. Thus, critically ill AMI patients presenting with cardiac arrest certainly form a special subgroup of AMI patients who are at a significantly higher risk of early stent thrombosis.

Stent Thrombosis and Therapeutic Hypothermia: Is There a Real Relationship?

The proposed mechanisms behind increased risk of stent thrombosis with hypothermia include impaired metabolism and bioavailability of antiplatelet drugs, reduced or ineffective platelet inhibition in the presence of therapeutic hypothermia,^15-17 and enhanced thrombogenicity due to increased platelet activation, reduced adenosine diphosphate clearance, increased shedding of platelet microparticles, and hypothermia-induced mast cell degranulation.^14,37,38 Platelet reactivity index has been proposed as a metric to evaluate platelet function in the setting of therapeutic hypothermia;³⁹ however, studies looking at the relationship between therapeutic hypothermia and platelet reactivity index in AMI patients undergoing PCI show conflicting results.^16,40

Whether the theoretical risk of stent thrombosis with therapeutic hypothermia translates into clinically significant events remains controversial. The current literature on stent thrombosis in AMI patients undergoing therapeutic hypothermia is limited by few studies with small sample sizes showing no consistent relationship between therapeutic hypothermia and stent thrombosis. Most of these studies lack robust comparison groups. In 2007, Knafelj et al. in a study of 72 patients with AMI and cardiac arrest undergoing PCI showed 1 stent thrombosis event (3.1%) in the therapeutic hypothermia group (n = 32) and no stent thrombosis events (0%) in the group not receiving therapeutic hypothermia (n = 40).³ In 2011, Ibrahim et al. reported a 14.8% incidence of stent thrombosis in 27 cardiac arrest patients undergoing therapeutic hypothermia and PCI, compared with no stent thrombosis events in 30 cardiac arrest patients undergoing PCI without therapeutic hypothermia.¹⁸ In 2013, Penela et al.¹⁹ observed 5 stent thrombosis events in 11 cardiac arrest patients treated with therapeutic hypothermia; however, there was no comparison group. Kozinski et al.²⁰ showed no stent thrombosis events in 37 OHCA patients with AMI undergoing therapeutic hypothermia and PCI. Similarly, Casella et al.⁴¹ showed no stent thrombosis events in 45 cardiac arrest patients undergoing PCI and therapeutic hypothermia treatment. In 2014, Rosillo et al. reported a 2.7% stent thrombosis incidence in 77 patients undergoing therapeutic hypothermia and primary PCI, which was not significantly different from the incidence in non-cardiac arrest AMI patients undergoing primary PCI.²¹ Joffre et al. in 2014²² and Gouffran et al. in 2015⁴² observed a 10.9% incidence of stent thrombosis in their populations of 55 and 101 patients, respectively, undergoing therapeutic hypothermia after primary PCI. Both studies lacked a comparison group. In 2015, a report from the International Cardiac Arrest Registry showed 2 definite early stent thrombosis events (1.4%) in 141 cardiac arrest patients undergoing PCI and therapeutic hypothermia.⁴³ In 2015, Erlinge et al., in a combined analyses of 2 prospective randomized controlled trials of therapeutic hypothermia in AMI with a total of 140 patients (70 in each group), reported only 1 patient in the therapeutic hypothermia group to have a reinfarction without specifically mentioning stent thrombosis.⁴⁴ Finally, a meta-analysis by Villablanca et al. including data from 6 randomized controlled trials with a total of 819 patients showed no difference in all-cause mortality, major adverse cardiovascular events, or recurrent infarction in AMI patients receiving therapeutic hypothermia compared with those not receiving therapeutic hypothermia.⁴⁵

Thus, although some small single-center studies show higher incidence of stent thrombosis with therapeutic hypothermia, contemporary pooled analyses^44,45 do not show a higher incidence of adverse cardiovascular events with therapeutic hypothermia. Moreover, it is important to remember that the post-cardiac arrest state itself is associated with a higher risk of stent thrombosis. Therefore, in order to find out the true contribution of therapeutic hypothermia to stent thrombosis, AMI patients with cardiac arrest undergoing PCI and therapeutic hypothermia must be compared with AMI patients with cardiac arrest undergoing PCI but no therapeutic hypothermia. In a recent study published by our group,²⁸ we analyzed a large US nationwide database including 49,109 AMI patients with cardiac arrest undergoing PCI. The incidence of stent thrombosis during the index hospitalization in 1,193 patients undergoing therapeutic hypothermia in our study was 3.9% compared with 4.7% incidence of stent thrombosis in those not undergoing therapeutic hypothermia (p = 0.61). Similar results were seen after propensity matching to account for baseline differences in the therapeutic hypothermia and no therapeutic hypothermia groups (3.5% in therapeutic hypothermia group vs. 6.1% in no therapeutic hypothermia group, p = 0.17). These findings support the hypothesis that the high incidence of stent thrombosis in AMI patients with cardiac arrest is due to the cardiac arrest state itself and that therapeutic hypothermia does not appear to increase this risk any further.

Conclusions

AMI patients presenting with cardiac arrest who remain comatose after ROSC represent a high-risk subgroup of patients who often require a combination of PCI and therapeutic hypothermia to achieve the most favorable outcomes. Following PCI, these patients have a high risk of early stent thrombosis, largely due to their critical illness and cardiac arrest state rather than the use of therapeutic hypothermia. In AMI patients with cardiac arrest undergoing PCI, the morbidity and mortality benefits of therapeutic hypothermia far outweigh any potential risks or concerns of stent thrombosis. Thus, therapeutic hypothermia can be safely combined with primary PCI in the appropriate clinical setting, and it would not be justified to withhold therapeutic hypothermia because of the fear of stent thrombosis.

References

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Keywords: Out-of-Hospital Cardiac Arrest, Drug-Eluting Stents, Coronary Occlusion, Coronary Angiography, Angiography, Ventricular Fibrillation, Risk Factors, Blood Platelets, Hypothermia, Constriction, Pathologic, Ventricular Function, Left, Myocardial Infarction, Percutaneous Coronary Intervention, Thrombosis, Hypothermia, Induced, Diabetes Mellitus, Electrocardiography, Tachycardia, Ventricular, Acute Coronary Syndrome

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