Cardiovascular Toxicity

IR-Cardiovascular toxicities

There is a range of CV toxicities caused by ICI therapy, including IR-myocarditis, pericarditis, vasculitis, acute coronary syndrome (ACS), conduction disease (including complete heart block), atrial and ventricular arrhythmias, Takotsubo syndrome, non-inflammatory left ventricular dysfunction and heart failure.

IR-myocarditis, pericarditis, vasculitis and cardiacconduction disease usually present in the first four cycles of treatment, although a quarter of cases present after four cycles.

IR-non-inflammatory heart failure usually presents after 3 months of ICI treatment and most commonly after the first 6 months. IR-arrhythmias and ACSs can occur throughout treatment, and atrial tachycardias may be primary or secondary to acute thyrotoxicosis, acute systemic inflammatory syndromes or other irAEs associated with significant electrolyte imbalance. Severe IR-myocarditis occurs in <1% of cases, but with increased utilisation oftroponin measurement (including high sensitivity cardiac troponin assays) and cardiac imaging, CV complications can occur in 5% of patients receiving ICIs.

Diagnostic criteria for IR-myocarditis

Diagnosis requires one major or two minor criteria, (plus exclusion of ACS and acute infectious illnesses). Both major and minor diagnostic criteria have been proposed in a recent consensus paper from the InternationalCardio-Oncology Society.

Major Criterion:

CMR diagnostic for acute myocarditis (modified Lake Louise criteria). If CMR is not diagnostic or not available, consider endomyocardial biopsy or 68Ga-DOTATOC PET-CT if available.

Minor Criterion:

Clinical syndrome (including any one of the following: fatigue, myalgia, chest pain, diplopia, ptosis, shortness of breath, orthopnoea, lower extremity oedema, palpitations, light-headedness or dizziness, syncope, muscle weakness, cardiogenic shock)
Ventricular arrhythmia and/or new conduction system disease
Decline in cardiac function with or without regional wall motion abnormalities in a non-Takotsubo pattern
Other irAEs, particularly myositis, myopathy, myasthenia gravis

Management of IR-myocarditis

Purple: general categories or stratification; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.

FDG, [18F]2-fluoro-2-deoxy-D-glucose; Ga-DOTATOC, Gallium-68-DOTA(0)-Phe(1)-Tyr(3)-octreotide; ATG, anti-thymocyte globulin; CHB, complete heart block; CT,computed tomography; CV, cardiovascular; ECG, electrocardiogram; ECMO extracorporeal membrane oxygenation; EMB, endomyocardial biopsy; ICI, immune checkpoint inhibitor; IR, immune-related; i.v., intravenous; LVAD, left ventricular assist device; MDT, multidisciplinary team; MMF, mycophenolate mofetil; MRI, magneticresonance imaging; PET, positron emission tomography; T2STIR, T2-weighted short tau inversion recovery.

Recommendations

Suspected cases of IR-myocarditis should be admitted tolevel 2 or 3 care with electrocardiogram monitoring andresuscitation facilities [V, A].
Other causes of troponin elevation should be ruled out, including ACS if appropriate (patients with CV risk factors or established coronary artery disease) [V, A].
ICI therapy should be interrupted and, in most cases, if IRmyocarditis is confirmed, permanently discontinued [V, A].
A diagnostic CMR with inflammatory sequences (T2STIR,T1, LGE) and cardiac troponin are recommended in cases of suspected IR-myocarditis or pericarditis [IV, A].
If 68Ga-DOTATOCePETeCT is not available, endomyocardial biopsy should be considered to confirm or refute the diagnosis in suspected cases where CMR and troponin are not diagnostic before restarting ICI [V, A].
i.v. methylprednisone 500-1000 mg should be initiated daily for 3 days and then reviewed in confirmed cases of IR-myocarditis [V, A].
If troponin has fallen to <50% of peak level or to normal after 3 days of i.v. methylprednisolone and the patient is clinically stable (no heart failure, ventricular arrhythmias, complete heart block) then conversion to oral prednisolone 1 mg/kg/day (up to a maximum of 80 mg/day) is recommended, reducing by 10 mg/week with troponin monitoring providing CV stability continues [V, A].
Heart failure or cardiogenic shock should be treated according to the European Society of Cardiology heart failure guidelines [III, A].
An MDT discussion is recommended before restarting ICI treatment in patients with mild, clinically uncomplicated IR-myocarditis [V, A].
Treatment of uncomplicated IR-pericarditis with oral prednisolone and colchicine (500 mg twice daily) is recommended [IV, A].
Treatment of IR-pericarditis complicated by moderate or large pericardial effusion with i.v. methylprednisone 500-1000 mg and colchicine (500 mg twice daily) and temporary interruption of ICI are recommended. Large pericardial effusions with or without tamponade physiology require urgent percutaneous pericardiocentesis[V, A].

Treatment strategies for IR-cardiotoxicity

Cardiotoxicity	ICI strategy	Immunosuppression	Cardiac Treatment
Myocardities	Stop ICI	First-line: i.v. methylprednisolone 500-1000 mg daily for 3 days or until clinically stable, followed by oral prednisolone 1 mg/kg o.d. with tapering 10 mg/week with troponin monitoring Second line: MMF or tocilizumab 8 mg/kg Third line: ATG, alemtuzumab orabatacept	i.v. diuretics ± nitrates if pulmonaryoedemaACE inhibitor if LVEF <50%Beta blocker if sinus tachycardia, atrialtachycardias, VT or VF
New advanced conduction disease(second- or third degree heart block)	Stop ICI	Consider i.v. methylprednisolone if progressive PR prolongation or anyevidence of co-existing myocarditis e.g. elevated troponin, CMR evidence	Emergency pacing
Pericarditis complicated by cardiac tamponade	Interrupt ICI Consider ICI rechallenge when stable and no evidence of ongoing pericarditis	Colchicine 500 μg b.i.d. i.v. methylprednisolone 500-1000mg daily until clinically stable, followed by oral prednisolone 1mg/kg o.d. with tapering 10mg/week	Emergency pericardiocentesis Colchicine
Acute pericarditis (with or without effusion but without cardiac tamponade)	Interrupt ICI Consider ICI rechallenge when stable and no evidence of ongoing pericarditis	Colchicine 500 μg b.i.d. and oral prednisolone 0.5 mg/kg o.d. with tapering 10 mg/week
Acute MI	Stop ICI Carefully consider ICI rechallenge, but only when clinically stable and >30days post-MI with risk factors controlled and no alternative anticancer treatment	Consider i.v. methylprednisolone if evidence of coronary vasculitis on angiography	Follow ESC/ACC/AHA guidelines for STEMI or NSTEMI as appropriate Consider vasculitis if atherosclerosis absent at coronary angiography
New AF	Interrupt ICI Consider ICI rechallenge once stable and after myocarditis excluded		Follow ESC guideline for AF DCCV should be considered Anticoagulation unless CHA2DS2-VASc score 0, contraindication or limited life expectancy
VT or VF	Stop ICI	First-line: i.v. methylprednisolone 500-1000 mg daily if myocarditis evident until clinically stable andt roponin-negative followed by oral prednisolone 1 mg/kg o.d. with tapering 10 mg/week	Emergency defibrillation Beta blocker and/or amiodarone
Frequent VEs(>1% of heartbeats)	Interrupt ICI until myocarditis excluded Consider ICI rechallenge only after myocarditis excluded	Follow myocarditis protocol above if myocarditis confirmed	Beta blocker Consider EP opinion ECG and Holter surveillance if ICI continued
New LVSD without inflammation (functional LVSD)	Interrupt ICI if unstable Consider ICI rechallenge once LV function stabilised or recovered and after myocarditis excluded with surveillance		ACE inhibitor (or ARB if ACE inhibitor intolerant) Beta blocker Management as per ESC guideline for acute and chronic heart failure BNP, ECG and echocardiogram surveillance if ICI restarted
Takotsubo syndrome	Interrupt ICI Consider ICI rechallenge once LV function stabilised or recovered and after myocarditis excluded with surveillance		Follow HFA position statement management algorithm Avoid QT prolonging drugs
New early conduction abnormality on ECG	Continue ICI once Holter excludes advanced heart block		Arrange Holter to assess for advanced conducted disease If absent, increase surveillance with ECG before each cycle
New asymptomatic rise in BNP orNT-proBNP	Continue ICI unless myocarditis or new LVSD detected		Check troponin, ECG and echocardiogram CMR if myocarditis suspected
New asymptomatic rise in cardiac troponin(possible myocarditis)	Interrupt ICI Restart ICI rechallenge only after myocarditis and acute MI excluded		Check repeat troponin, CK, BNP, ECG, echocardiogram and CMR if myocarditis or MI Consider coronary angiography if ischaemic ECG changes and/or new regional LV wall motion abnormality

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