Table 9.

Management of Cardiovascular irAEs in Patients Treated With ICPis

9.0 Cardiovascular Toxicities
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis
Definition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, progressive or acute dyspnea, pleural effusion, fatigue
Diagnostic work-up  At baseline   ECG   Consider troponin, especially in patient treated with combination immune therapies  Upon signs/symptoms (consider cardiology consult)   ECG   Troponin   BNP   Echocardiogram   CXR  Additional testing to be guided by cardiology and may include   Stress test   Cardiac catherization   Cardiac MRI
Grading	Management
G1: Abnormal cardiac biomarker testing, including abnormal ECG G2: Abnormal screening tests with mild symptoms G3: Moderately abnormal testing or symptoms with mild activity G4: Moderate to severe decompensation, IV medication or intervention required, life-threatening conditions	All grades warrant work-up and intervention given potential for cardiac compromise Consider the following: Hold ICPi and permanently discontinue after G1 High-dose corticosteroids (1–2 mg/kg of prednisone) initiated rapidly (oral or IV depending on symptoms)  Admit patient, cardiology consultation  Management of cardiac symptoms according to ACC/AHA guidelines and with guidance from cardiology  Immediate transfer to a coronary care unit for patients with elevated troponin or conduction abnormalities  In patients without an immediate response to high-dose corticosteroids, consider early institution of cardiac transplant rejection doses of corticosteroids (methylprednisolone 1 g every day) and the addition of either mycophenolate, infliximab, or antithymocyte globulin
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-threatening nature of cardiovascular complications. Holding checkpoint inhibitor therapy is recommended for all grades of complications. The appropriateness of rechallenging remains unknown. Note that infliximab has been associated with heart failure and is contraindicated at high doses in patients with moderate-severe heart failure.108
9.2 Venous thromboembolism
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream. Clinical signs and symptoms are variable and may include pain, swelling, increased skin vein visibility, erythema, and cyanosis accompanied by unexplained fever for DVT and dyspnea, pleuritic pain, cough, wheezing, or hemoptysis for PE
Diagnostic work-up  Evaluation of signs and symptoms of PE or DVT may include   Clinical prediction rule to stratify patients with suspected   venous thromboembolism Venous ultrasound for suspected DVT   CTPA for suspected PE  Can also consider D-dimer for low-risk patients based on risk stratification by clinical prediction rule for DVT/PE when CT or Doppler are not available or appropriate  Ventilation/perfusion scan is also an option when CTPA is not appropriate  Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas
Grading	Management
G1: Venous thrombosis (eg, superficial thrombosis)	Continue ICPi  Warm compress  Clinical surveillance
G2: Venous thrombosis (eg, uncomplicated DVT), medical intervention indicated G3: Thrombosis (eg, uncomplicated PE [venous], nonembolic cardiac mural [arterial] thrombus), medical intervention indicated	Continue ICPi  Management according to CHEST, ACC, and/or AHA guidelines and consider consult from cardiology or other relevant specialties  LMWH is suggested over VKA, dabigatran, rivaroxaban apixaban, or edoxaban for initial and long-term treatment  IVheparin is an acceptable alternative for initial use, and oral anticoagulants are acceptable for the long term
G4: Life-threatening (eg, PE, cerebrovascular event, arterial insufficiency), hemodynamic or neurologic instability, urgent intervention indicated	Permanently discontinue ICPi  Admit patient and management according to CHEST, ACC, and/or AHA guidelines and with guidance from cardiology  Respiratory and hemodynamic support  LMWH is suggested over VKA, dabigatran, rivaroxaban, apixaban, or edoxaban for initial and long-term treatment  IVheparin is an acceptable alternative for initial use, and oral anticoagulants are acceptable for the long term  Further clinical management as indicated based on symptoms
Additional considerations  While it may be impossible to determine the etiology of thromboembolic disease in patients with advanced cancer and the role, ifany, that ICPi treatment plays, it is reasonable to remove the potential inciting agents given the severity and life-threatening potential of G4 complications. Clinicians are to use clinical judgment and take into account the risks and benefits when deciding whether to discontinue ICPi treatment.  Anticoagulant therapy duration should continue for a minimum of 9–12 months to indefinitely in the setting of active cancer unless patient is asymptomatic, doing well, or in remission.109,110
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate.

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; BNP, brain natriuretic peptide; CT, computed tomography; CTPA, computed tomography pulmonary angiography; CXR, chest x-ray; DVT, deep vein thrombosis; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; LMWH, low-molecular-weight heparin; MRI, magnetic resonance imaging; PE, pulmonary embolism; VKA, vitamin K agonist.