A 75-year-old woman with a newly discovered ovarian mass concerning for malignancy and recently diagnosed (1 month previously) bilateral pulmonary emboli (PE) presented to the emergency department with sudden-onset, heavy chest pain while having lunch with her friends. The pain radiated to her back, did not worsen with postural changes, and was associated with shortness of breath. Because of her recent diagnosis of PE, she sought further evaluation. She had been compliant with her medication regimen (twice daily apixaban, the only medication she was taking) for the past month. Her medical history was remarkable for hyperlipidemia and obstructive sleep apnea. She reported no history of coronary artery disease (CAD), diabetes, hypertension, or tobacco use. On presentation, vital signs revealed a body mass index of 36 kg/m2, heart rate of 80 beats/min, blood pressure of 205/89 mm Hg, temperature of 36.8°C, respiratory rate of 16 breaths/min, and normal oxygen saturation while breathing room air. Physical examination findings were notable for normal heart sounds, clear lung auscultation, and symmetric peripheral pulses. Initial electrocardiography (ECG) revealed normal sinus rhythm with no ST-segment changes. Laboratory evaluation revealed the following (reference ranges provided parenthetically): white blood cell count, 7.8 × 109/L (3.4 to 9.6 × 109/L); hemoglobin, 13.5 g/dL (11.6 to 15.0 g/dL); platelet count, 136 × 109/L (157 to 371 × 109/L); sodium, 143 mmol/L (135 to 145 mmol/L); potassium, 4.1 mmol/L (3.6 to 5.2 mmol/L); and creatinine, 0.88 mg/dL (0.59 to 1.04 mg/dL). Additionally, her N-terminal pro-B-type natriuretic peptide level was 84 pg/mL (10 to 227 pg/mL), and her initial high-sensitivity troponin concentration was 340 ng/L (≤10 ng/L). Chest radiography revealed no acute abnormalities.1.Based on the available clinical data, which one of the following is the most likely underlying etiology of this patient’s presenting symptoms?a.Pneumoniab.Acute pericarditisc.Aortic dissectiond.PEe.ST-elevation myocardial infarction (STEMI) Pneumonia is an unlikely diagnosis in the absence of fever, leukocytosis, cough, and infiltrates on chest radiography and would not typically present this acutely. Additionally, our patient did not have the typical pleuritic chest pain that improves with leaning forward and findings of diffuse ST-segment elevation on ECG to suggest acute pericarditis. Aortic dissection is a medical emergency classically presenting as severe, tearing chest pain. The triad of abrupt, stabbing thoracic or abdominal pain, unequal pulses, and evidence of aortic or mediastinal widening on chest radiography is suggestive of aortic dissection.1von Kodolitsch Y. Schwartz A.G. Nienaber C.A. Clinical prediction of acute aortic dissection.Arch Intern Med. 2000; 160: 2977-2982Crossref PubMed Scopus (280) Google Scholar With our patient’s symmetric peripheral pulses and unremarkable findings on chest radiography, her presenting symptoms are unlikely to be due to dissection. Although PE is classically associated with tachycardia, dyspnea, and pleuritic chest pain, many patients with PE present with little to no symptoms. In these cases, determining the pretest probability is important. Our patient’s chest pressure and dyspnea could certainly be due to another PE, given her Wells score2Wells P.S. Anderson D.R. Rodger M. et al.Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.Thromb Haemost. 2000; 83: 416-420Crossref PubMed Scopus (1319) Google Scholar of 2.5 for prior PE and likely presence of malignancy, placing her in the moderate risk category even without the 3 additional points for PE as most likely diagnosis. In addition, a large enough PE can result in right ventricular (RV) strain leading to troponinemia. Although our patient had reportedly been compliant with her apixaban, PE should still be considered in this moderate-risk patient with a PE just 1 month previously in the setting of likely undiagnosed ovarian malignancy. The diagnosis of STEMI in females requires elevation in cardiac biomarkers along with greater than 1-mm ST elevation in contiguous leads (or >1.5 mm in V2 and V3) on ECG. Our patient had normal ECG findings, but with her increasing troponin levels, a non-ST-elevation myocardial infarction (NSTEMI) remains a strong possibility, especially in the absence of right-sided heart failure and a normal N-terminal pro-B-type natriuretic peptide level, arguing against severe RV strain–associated troponinemia. Our patient was thus admitted to the hospital with a working diagnosis of PE vs acute coronary syndrome (ACS).2.Which one of the following is the most appropriate next step in management?a.Low-intensity heparin infusionb.Moderate-intensity heparin infusionc.Aspirin plus clopidogrel plus moderate-intensity heparin infusiond.High-intensity heparin infusione.Aspirin plus clopidogrel plus high-intensity heparin infusion Given the fairly high concern for PE, anticoagulation with heparin must be initiated immediately. Deciding on the intensity of the heparin infusion initially rests on the suspected etiology of the patient’s symptoms along with the consideration of adverse effects. Low-intensity heparin infusion is rarely used, typically in patients at high risk of bleeding. Treatment for ACS requires a moderate-intensity heparin infusion plus dual antiplatelet therapy (DAPT).3Amsterdam E.A. Wenger N.K. Brindis R.G. et al.2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2014;64(24):2713-2714].J Am Coll Cardiol. 2014; 64: e139-e228Crossref PubMed Scopus (2038) Google Scholar Early DAPT with aspirin and a P2Y12 receptor blocker (eg, clopidogrel) reduces platelet adhesion and aggregation, limiting progressive thrombotic occlusion. High-intensity heparin alone is preferred if PE is the only suspected diagnosis. Because of the suspicion of recurrent PE vs ACS, the patient was given a loading dose of aspirin, 324 mg, plus clopidogrel, 600 mg, and a high-intensity heparin infusion was initiated. Overnight, the patient’s troponin level increased to 580 ng/L at 2 hours and 1051 ng/L at 6 hours. A repeat ECG revealed new subtle ST elevations in the inferior leads, and the patient was taken to the cardiac catheterization laboratory for urgent evaluation for an evolving STEMI. Coronary angiography revealed a 100% obstruction by a discrete lesion with intracoronary thrombus present in the distal left anterior descending (LAD) artery with no collateral circulation or evidence of surrounding atherosclerotic disease. Percutaneous coronary intervention (PCI) was not performed given the distal nature of the lesion.3.Based on the clinical presentation and diagnostic findings thus far, which one of the following is the most likely diagnosis?a.PEb.Coronary artery embolismc.Distal rupture of atherosclerotic plaqued.Spontaneous coronary artery dissectione.Vasospastic angina Similar to an NSTEMI, a PE can also present with elevated troponin levels due to RV strain, which can be seen in 30% to 50% of patients with a moderate to large PE. Electrocardiography typically (70% of the time) will show sinus tachycardia and nonspecific ST-segment and T-wave changes,4Stein P.D. Saltzman H.A. Weg J.G. Clinical characteristics of patients with acute pulmonary embolism.Am J Cardiol. 1991; 68: 1723-1724Abstract Full Text PDF PubMed Scopus (124) Google Scholar while the development of a new right bundle branch block or the classic S1Q3T3 pattern is less common. Although a PE is still possible in this setting, we now have angiographic findings of a distinct coronary lesion as the probable cause of the patient’s clinical presentation. Coronary artery embolism can present with ACS, typically with elevated troponin levels and ischemic changes on ECG. It can be classified into 3 categories—direct, paradoxical, and iatrogenic.5Raphael C.E. Heit J.A. Reeder G.S. et al.Coronary embolus: an underappreciated cause of acute coronary syndromes.J Am Coll Cardiol Intv. 2018; 11: 172-180Crossref Scopus (73) Google Scholar The isolated occlusion of the distal LAD artery in the absence of background atherosclerotic disease strongly suggests an embolic phenomenon. A distal atherosclerotic plaque rupture would most commonly be seen in patients with conventional risk factors for CAD (eg, older age, male gender, hypertension, hyperlipidemia, diabetes, tobacco use). Such patients usually present with angiographic findings of a high-degree stenosis or occlusion in conjunction with multifocal atherosclerotic disease. Our patient had minimal CAD risk factors, and coronary angiography revealed an isolated 100% obstruction with no background atherosclerotic disease, favoring an embolic mechanism over an isolated plaque rupture. On coronary angiography, spontaneous coronary artery dissection can manifest as contrast dye in multiple planes of the arterial wall with slow clearance of dye or, more commonly, intramural hematoma with abrupt or tapered luminal stenosis.6Tweet M.S. Akhtar N.J. Hayes S.N. Best P.J. Gulati R. Araoz P.A. Spontaneous coronary artery dissection: acute findings on coronary computed tomography angiography.Eur Heart J Acute Cardiovasc Care. 2019; 8: 467-475Crossref PubMed Google Scholar Our patient’s angiogram did not show these findings and instead revealed an occlusion in the distal LAD artery. Vasospastic angina is characterized by intermittent episodes of chest pain at rest, thought to be due to sporadic coronary vasospasm. Electrocardiography may reveal transient ST-segment changes, and angiography may show spasm if caught in real time. Our patient’s angiogram did not show spasm. It was agreed that the patient had most likely suffered from a coronary embolism. Subsequent evaluation for the exact etiologic mechanism was initiated.4.Which one of the following diagnostic imaging modalities is most likely to determine the mechanism of this patient’s LAD occlusion?a.Computed tomographic angiography of the pulmonary arteriesb.Transthoracic echocardiography (TTE)c.Transesophageal echocardiography (TEE)d.Lower extremity venous ultrasonographye.Cardiac magnetic resonance imaging (MRI) Computed tomographic angiography effectively visualizes filling defects in the larger main, lobar, or segmental pulmonary arteries. It is not as effective in visualizing the smaller and peripheral subsegmental vessels supplying blood to the lungs, although newer scanners with increased resolution that can do so are now available. This modality of imaging is more than 90% sensitive and specific for a PE and would be the best option if PE was the most likely diagnosis. Transthoracic echocardiography is typically the initial cardiac imaging modality for assessing CAD. It allows for the evaluation of regional wall motion abnormalities, ejection fraction, and/or valvular disease. Additionally, it directly visualizes the 4 cardiac chambers, enabling the physician to look for intracardiac thrombi if there are concerns for an embolic event. Transthoracic echocardiography cannot visualize certain posterior structures such as the left atrial appendage or assess for a connection between the venous and arterial systems such as a patent foramen ovale (PFO), and therefore may miss potential etiologies of a coronary embolism.7Khandheria B.K. Seward J.B. Tajik A.J. Transesophageal echocardiography.Mayo Clin Proc. 1994; 69: 856-863Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar In contrast to TTE, TEE is performed with the ultrasound transducer visualizing the heart directly behind the esophagus. This view provides superior image quality of the posterior structures of the heart (ie, left atrium and left atrial appendage). It also allows for improved visualization of the interatrial septum to assess for the presence of an atrial septal defect (ASD) or PFO. Transesophageal echocardiography thus provides a more comprehensive assessment of potential etiologies of coronary embolism. Lower extremity venous ultrasonography assesses for noncompressible veins due to thrombi. Proximal deep venous thromboses (DVTs) are associated with twice the risk of embolization as distal DVTs. Nevertheless, a patient with an isolated distal DVT and risk factors such as active malignancy or prior DVT/PE has an increased risk for proximal extension.8Kearon C. Akl E.A. Comerota A.J. et al.Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [published correction appears in Chest. 2012;142(6):1698-1704].Chest. 2012; 141: e419S-e496SAbstract Full Text Full Text PDF PubMed Scopus (2922) Google Scholar Our patient should first undergo TEE to assess for a potential intracardiac thrombus, as well as a possible connection between the venous and arterial systems. If no right-to-left shunt is present, a lower extremity venous ultrasonography would not be helpful in understanding the embolic mechanism as there would be no pathway for a venous thrombus to travel into the arterial circulation. Cardiac MRI is an expensive and sophisticated imaging modality that allows for high spatial resolution assessment of ventricular volumes, ejection fraction, and wall thickness. Its use in detecting intraventricular thrombi is not well studied and thus not favored over echocardiography in the work-up of suspected coronary embolism. Transesophageal echocardiography revealed no intracardiac thrombus but did show new apical regional wall motion abnormalities and a PFO with a small bidirectional shunt at rest that increased with Valsalva maneuver. Subsequent lower extremity ultrasonography revealed a new acute thrombus in the right gastrocnemius vein. These findings suggested that the etiology of the patient’s symptoms was a myocardial infarction secondary to a paradoxical embolism (PDE) to the LAD artery in the setting of a preexisting right-to-left intracardiac shunt, despite therapeutic anticoagulation.5.Given the presumed recurrent venous thromboembolism (VTE) while the patient was taking apixaban, which one of the following long-term management strategies is most appropriate in preventing future VTE?a.Stop daily aspirin plus clopidogrel; resume apixabanb.Stop daily aspirin plus clopidogrel; switch from apixaban to warfarinc.Stop daily aspirin plus clopidogrel; switch from apixaban to enoxaparind.Continue daily aspirin plus clopidogrel; switch from apixaban to warfarine.Continue daily aspirin plus clopidogrel; switch from apixaban to enoxaparin In the absence of any angiographic evidence of atherosclerotic disease or planned PCI, there is no indication to continue DAPT.5Raphael C.E. Heit J.A. Reeder G.S. et al.Coronary embolus: an underappreciated cause of acute coronary syndromes.J Am Coll Cardiol Intv. 2018; 11: 172-180Crossref Scopus (73) Google Scholar It would not be wise to transition back to apixaban because our patient likely experienced breakthrough thrombus formation with subsequent embolism while taking this agent. Warfarin is a vitamin K antagonist that has long been used as an anticoagulant in the setting of atrial fibrillation or VTE. Vitamin K antagonists have been found to be inferior to low-molecular-weight heparin (LMWH) in preventing recurrent VTE in patients with acute VTE and cancer and are thus not the best option for this patient with a probable malignant ovarian mass.9Lee A.Y. Levine M.N. Baker R.I. et al.Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) InvestigatorsLow-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.N Engl J Med. 2003; 349: 146-153Crossref PubMed Scopus (2261) Google Scholar Enoxaparin is a LMWH and would be preferred to prevent future VTE in this patient with a PDE in the setting of potential malignancy. DAPT was administered empirically in this patient because of a possible NSTEMI, but now that the patient’s symptoms have been determined to be due to a PDE, only anticoagulation should be continued. Long-term DAPT would be required if she experienced an atherosclerotic plaque rupture with subsequent thrombus formation or underwent PCI with stent placement in order to stabilize the plaque or prevent stent thrombosis, respectively. As stated previously, enoxaparin is superior to warfarin in preventing/treating VTE in the setting of malignancy. However, DAPT should be discontinued because of the embolic mechanism of myocardial ischemia. Triple therapy would unnecessarily increase this patient’s risk for bleeding complications. Aspirin and clopidogrel were discontinued, and the patient was subsequently transitioned from apixaban to enoxaparin. Days later, she underwent an exploratory laparotomy and right salpingo-oophorectomy. Histopathologic examination revealed a high-grade carcinoma of the right ovary with mixed serous, clear cell, and mucinous differentiation and peritoneal involvement. A follow-up appointment with a medical oncologist was scheduled for further staging and management. Coronary artery embolism is categorized as direct, paradoxical, and iatrogenic. A direct coronary embolism originates from the arterial circulation such as the left atrial appendage or left ventricle. A paradoxical coronary embolism originates from the venous circulation and travels to the arterial circulation through a PFO, ASD, arteriovenous malformation, or other right-to-left shunt. An iatrogenic coronary embolism occurs as a complication in the perioperative or intraoperative (eg, PCI) setting.5Raphael C.E. Heit J.A. Reeder G.S. et al.Coronary embolus: an underappreciated cause of acute coronary syndromes.J Am Coll Cardiol Intv. 2018; 11: 172-180Crossref Scopus (73) Google Scholar Major and minor criteria have been formulated to aid in the diagnosis of coronary embolism.10Shibata T. Kawakami S. Noguchi T. et al.Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism.Circulation. 2015; 132: 241-250Crossref PubMed Scopus (176) Google Scholar Major criteria include angiographic evidence of coronary embolus (eg, filling defect, abrupt occlusion in an artery without severe atherosclerosis), concomitant coronary emboli in multiple vascular territories, concomitant systemic embolization without left ventricular thrombus attributable to acute myocardial infarction, histologic evidence of a venous origin of coronary embolic material, and evidence of an embolic source on imaging. Minor criteria include less than 25% stenosis on angiography in nonculprit vessels, atrial fibrillation, and presence of embolic risk factors (cardiomyopathy, rheumatic valve disease, prosthetic heart valve, PFO, ASD, history of cardiac surgery, infective endocarditis, or hypercoagulable state). Definite coronary embolism is considered to have ≥ 2 or more major criteria, 1 major and 2 minor criteria, or 3 minor criteria. Probable coronary embolism is considered to have 1 major and 1 minor criterion or 2 minor criteria.5Raphael C.E. Heit J.A. Reeder G.S. et al.Coronary embolus: an underappreciated cause of acute coronary syndromes.J Am Coll Cardiol Intv. 2018; 11: 172-180Crossref Scopus (73) Google Scholar Coronary embolism should be considered in patients presenting with ACS in the setting of a recent VTE and minimal CAD risk factors. If suspected on coronary angiography, TEE should be performed to look for intracardiac thrombi and/or a right-to-left shunt to investigate the etiologic mechanism of the embolism. Aspiration thrombectomy can be considered if a large thrombus burden exists because a recent meta-analysis reported that such an intervention was associated with reduced cardiovascular mortality.11Jolly S.S. James S. Džavik V. et al.Thrombus aspiration in ST-segment-elevation myocardial infarction: an individual patient meta-analysis; Thrombectomy Trialists Collaboration.Circulation. 2017; 135: 143-152Crossref PubMed Scopus (186) Google Scholar Medical management of coronary embolism without atherosclerotic disease or PCI involves long-term anticoagulation without antiplatelet agents. In the setting of malignancy, LMWH is preferred over vitamin K antagonists for VTE prevention/treatment. Direct oral anticoagulants are being investigated for VTE treatment/prevention12Phelps M.K. Wiczer T.E. Erdeljac H.P. et al.Comparison of direct oral anticoagulants versus low-molecular-weight-heparins for the treatment of cancer associated thrombosis.Blood. 2016; 128: 5013Crossref Google Scholar in cancer patients. A recurrent VTE in the setting of compliance with a direct oral anticoagulant thus warrants strong consideration for switching to a LMWH.
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Mar 12, 2024
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