Risk of Stent Thrombosis in Patients With AMI and Cardiac Arrest Treated With Hypothermia
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 dysfunction35,36 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 analyses44,45 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.
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.
- Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016;133:e38-e360.
- Dumas F, Cariou A, Manzo-Silberman S, et al. Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry. Circ Cardiovasc Interv 2010;3:200-7.
- Knafelj R, Radsel P, Ploj T, Noc M. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation 2007;74:227-34.
- Kern KB, Lotun K, Patel N, et al. Outcomes of Comatose Cardiac Arrest Survivors With and Without ST-Segment Elevation Myocardial Infarction: Importance of Coronary Angiography. JACC Cardiovasc Interv 2015;8:1031-40.
- Stær-Jensen H, Nakstad ER, Fossum E, et al. Post-Resuscitation ECG for Selection of Patients for Immediate Coronary Angiography in Out-of-Hospital Cardiac Arrest. Circ Cardiovasc Interv 2015;8:e002784.
- Vyas A, Chan PS, Cram P, Nallamothu BK, McNally B, Girotra S. Early Coronary Angiography and Survival After Out-of-Hospital Cardiac Arrest. Circ Cardiovasc Interv 2015;8:e002321.
- Callaway CW, Schmicker RH, Brown SP, et al. Early coronary angiography and induced hypothermia are associated with survival and functional recovery after out-of-hospital cardiac arrest. Resuscitation 2014;85:657-63.
- Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015;132:S465-82.
- The Hypothermia after Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med 2002;346:549-56.
- Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63.
- Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768-86.
- Ornato JP. The Need for Both Therapeutic Hypothermia and Early Coronary Angiography After Out-of-Hospital Cardiac Arrest. JACC Cardiovasc Interv 2016;9:2413-15.
- Kern KB, Hanna JM, Young HN, et al. Importance of Both Early Reperfusion and Therapeutic Hypothermia in Limiting Myocardial Infarct Size Post-Cardiac Arrest in a Porcine Model. JACC Cardiovasc Interv 2016;9:2403-12.
- Straub A, Krajewski S, Hohmann JD, et al. Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target. Arterioscler Thromb Vasc Biol 2011;31:1607-16.
- Součková L, Opatřilová R, Suk P, et al. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol 2013;69:309-17.
- Ibrahim K, Christoph M, Schmeinck S, et al. High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2014;85:649-56.
- Bjelland TW, Hjertner Ø, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2010;81:1627-31.
- Ibrahim K. Increased rate of stent thrombosis due to clopidogrel resistance in patients in therapeutic hypothermia after sudden cardiac death. Eur Heart J 2011;32:252.
- Penela D, Magaldi M, Fontanals J, et al. Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J Am Coll Cardiol 2013;61:686-7.
- Kozinski M, Pstragowski K, Kubica JM, et al. ACS network-based implementation of therapeutic hypothermia for the treatment of comatose out-of-hospital cardiac arrest survivors improves clinical outcomes: the first European experience. Scand J Trauma Resusc Emerg Med 2013;21:22.
- Rosillo SO, Lopez-de-Sa E, Iniesta AM, et al. Is therapeutic hypothermia a risk factor for stent thrombosis? J Am Coll Cardiol 2014;63:939-40.
- Joffre J, Varenne O, Bougouin W, Rosencher J, Mira JP, Cariou A. Stent thrombosis: an increased adverse event after angioplasty following resuscitated cardiac arrest. Resuscitation 2014;85:769-73.
- Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009;30:2714-21.
- Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J 2015;36:3320-31.
- Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.
- Kukreja N, Onuma Y, Garcia-Garcia HM, et al. The risk of stent thrombosis in patients with acute coronary syndromes treated with bare-metal and drug-eluting stents. JACC Cardiovasc Interv 2009;2:534-41.
- Brodie B, Pokharel Y, Garg A, et al. Predictors of early, late, and very late stent thrombosis after primary percutaneous coronary intervention with bare-metal and drug-eluting stents for ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2012;5:1043-51.
- Shah N, Chaudhary R, Mehta K, et al. Therapeutic Hypothermia and Stent Thrombosis: A Nationwide Analysis. JACC Cardiovasc Interv 2016;9:1801-11.
- van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009;53:1399-409.
- Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. Circulation 2007;115:1440-55.
- Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667-78.
- Attizzani GF, Capodanno D, Ohno Y, Tamburino C. Mechanisms, pathophysiology, and clinical aspects of incomplete stent apposition. J Am Coll Cardiol 2014;63:1355-67.
- Rosencher J, Gouffran G, Bougouin W, Varenne O. Optimal antiplatelet therapy in out-hospital cardiac arrest patients treated by primary percutaneous coronary intervention. Resuscitation 2015;90:e7-8.
- Adrie C, Monchi M, Laurent I, et al. Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am Coll Cardiol 2005;46:21-8.
- Kern KB, Sasaoka T, Higashi H, Hilwig RW, Berg RA, Zuercher M. Post-resuscitation myocardial microcirculatory dysfunction is ameliorated with eptifibatide. Resuscitation 2011;82:85-9.
- Brenoche CSM, Timerman S, Kopel L, Kern KB, Lage S. Therapeutic hypothermia after sudden cardiac arrest: Is endothelial function compromised during treatment? Resuscitation 2014;85:S99.
- Straub A, Breuer M, Wendel HP, Peter K, Dietz K, Ziemer G. Critical temperature ranges of hypothermia-induced platelet activation: possible implications for cooling patients in cardiac surgery. Thromb Haemost 2007;97:608-16.
- Kounis NG, Kounis GN, Soufras GD, Tsigkas G, Hahalis G. Therapeutic hypothermia, stent thrombosis and the Kounis mast cell activation-associated syndrome. Int J Cardiol 2015;179:504-6.
- Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614-23.
- Orban M, Mayer K, Morath T, et al. The impact of therapeutic hypothermia on on-treatment platelet reactivity and clinical outcome in cardiogenic shock patients undergoing primary PCI for acute myocardial infarction: Results from the ISAR-SHOCK registry. Thromb Res 2015;136:87-93.
- Casella G, Carinci V, Cavallo P, et al. Combining therapeutic hypothermia and emergent coronary angiography in out-of-hospital cardiac arrest survivors: Optimal post-arrest care for the best patient. Eur Heart J Acute Cardiovasc Care 2015;4:579-88.
- Gouffran G, Rosencher J, Bougouin W, et al. Stent thrombosis after primary percutaneous coronary intervention in comatose survivors of out-of-hospital cardiac arrest: Are the new P2Y12 inhibitors really more effective than clopidogrel? Resuscitation 2016;98:73-8.
- Patel N, Nair S, Mooney M, et al. Risk of Stent Thrombosis in Cardiac Arrest Patients with ST- Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention and Therapeutic Hypothermia: International Cardiac Arrest Registry. Poster presented at: ACC 2015 Scientific Meeting, San Diego, CA.
- Erlinge D, Götberg M, Noc M, et al. Therapeutic hypothermia for the treatment of acute myocardial infarction-combined analysis of the RAPID MI-ICE and the CHILL-MI trials. Ther Hypothermia Temp Manag 2015;5:77-84.
- Villablanca PA, Rao G, Briceno DF, et al. Therapeutic hypothermia in ST elevation myocardial infarction: a systematic review and meta-analysis of randomised control trials. Heart 2016;102:712-9.
Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, SCD/Ventricular Arrhythmias, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging
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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