Cardiotoxicity of Targeted Oncology Therapies

Updated: 26 Feb 2026

BTK inhibitors

Example: Ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib

Common indications: CML, mantle cell lymphoma

Cardiotoxicity: Hypertension, AF, CTRCD, ventricular arrhythmia

Management: For atrial fibrillation, avoid DTI and CCBs (drug-drug interaction)

Does therapy need to be modified?: If severe AF, consider switching to acalabrutinib, zanubrutinib, or pirtobrutinib

First-Generation: Ibrutinib

Second-Generation: Acalabrutinib, Zanubrutinib are designed to be more specific to BTK and have lower rates of cardiovascular complications.

Third-Generation/Next-Generation (Reversible): Pirtobrutinib (LOXO-305) binds non-covalently, making it highly effective against the C481S mutation that causes resistance to previous generations. It is active even when previous inhibitors fail.

Drug-drug interaction with cardiovascular drugs

Ibrutinib inhibits the P-glycoprotein (P-gp) efflux pump, reducing intestinal elimination of dabigatran and increasing its plasma concentrations, thereby increasing bleeding risk.
For rate control, beta-blockers (eg, metoprolol) are preferred over non-dihydropyridine calcium channel blockers (eg, diltiazem). Diltiazem inhibits CYP450 enzymes (CYP3A4 and CYP2J2), leading to increased ibrutinib plasma levels.
Dihydropyridine calcium channel blockers (eg, amlodipine, felodipine, nifedipine) are primarily CYP3A4 substrates and do not significantly affect ibrutinib metabolism.

Monitoring

Baseline assessment:
- ECG and echocardiography are recommended before starting ibrutinib in patients at higher cardiovascular risk, such as those with:
  - Multiple risk factors
  - Male sex
  - Age ≥ 65 years
  - History of hypertension or diabetes
  - QTc ≥ 480 ms
  - Atrial fibrillation (AF)
  - Heart failure (HF)
  - Cardiomyopathy
  - Severe valvular heart disease
Ongoing monitoring:
- During treatment, a repeat ECG is recommended every 3–6 months (every 3 months during the first year), and thereafter based on clinical symptoms and risk profile.

- During treatment, repeat ECG has been recommendedevery 3 to 6 months (every 3 months for the first year of treatment) and after that based on clinical symptoms.

Interactions between Ibrutinib and cardiovascular drugs

Drug	Level	Effect	Mechanism of interaction
Diltiazem/ verapamil	Major	Increases plasma level of ibrutinib (6 - 9 fold)	CYP450 3A4 inhibition of ibrutinib
Digoxin	Moderate	Increases plasma level of digoxin	P-glycoprotein inhibition of ibrutinib
Amiodarone/ dronedarone	Major	Increases plasma level of ibrutinib (6 - 9 fold)	CYP450 3A4 inhibition of amiodarone/ dronedarone
Factor Xa inhibitors	Moderate	Increases plasma level of FXa inhibitors	CYP450 3A4 and P-glycoprotein inhibition of ibrutinib
Direct thrombin inhibitor	Major	Increases plasma level of dabigatran	P-glycoprotein inhibition of ibrutinib

Antiplatelets

Dual antiplatelet therapy (DAPT) is contraindicated in patients receiving ibrutinib.
If antiplatelet therapy is required and ibrutinib must be continued, use a single antiplatelet agent—typically a P2Y12 inhibitor—with close clinical monitoring.
Second-generation BTK inhibitors (eg, acalabrutinib, zanubrutinib) also increase bleeding risk.

Preoperative

For procedures with a significant bleeding risk, ibrutinib should be withheld—usually for 3 days before and after minor procedures and 7 days before and after major procedures—to reduce bleeding risk.

New-Onset Ventricular Arrhythmia

After myocardial ischemia or infarction has been excluded, management should follow standard clinical guidelines. Beta-blockers with antiarrhythmic properties, such as sotalol, are considered safe options for ibrutinib-associated ventricular arrhythmias because they have a lower potential for drug–drug interactions.

Immune checkpoint inhibitors

Example: Ipilimumab, nivolumab, atezolizumab, pembrolizumab, durvalumab

Common indications: Metastatic melanoma, genitourinary cancers, non-small cell lung cancer, head and neck cancer

Cardiotoxicity: Myocarditis, pericarditis, arrhythmia, ASCVD, vasculitis

Management: For myocarditis, first line high-dose i.v. steroids, second-line immunosuppressants (see therapy for specific myocarditis)

Does therapy need to be modified?: Discontinue ICI agent if clinically significant myocarditis, consider rechallenge in select cases with a different ICI agent with close monitoring.

Myocarditis is a major and life-threatening toxicityassociated with ICIs.

Incidence of myocarditis reportedly ranges from 0.04% to 1.14%.

Approximately 20%-50% of cases of ICI-associated myocarditis are potentially fatal.

FDA-approved ICIs

Drugs

1. CTLA-4 antibodies: ipilimumab, tremelimumab

2. PD-1 antibodies: nivolumab, pembrolizumab,cemiplimab, retifanlimab, dostarlimab, toripalimab, tislelizumab

3. PD-L1 antibodies: avelumab, atezolizumab,durvalumab

4. LAG3 antibodies: relatlimab

Drug target

Immune checkpoint inhibitors (ICIs) bind to inhibitory receptors expressed mainly on T cells and, to a lesser extent, on tumor cells and other immune cells, thereby enabling T-cell activation and an effective antitumor immune response.

Drug type and administration route

Immunotherapeutic drugs are administered through IV or subcutaneous injection

Baseline risk assessment and monitoring

There is currently no validated risk stratification tool to estimate an individual patient’s pretreatment risk of developing ICI-associated cardiovascular toxicity.

Consider ECG, Cardiac troponin, Natriuretic peptides, Baseline echocardiography, and global longitudinal strain.

CytotoxicT-lymphocyte–associated protein 4 inhibitor (ipilimumab or tremelimumab) has a significantly higher risk compared with monotherapy with programmed death-1 or programmed death-ligand 1 inhibitor.

ICI-associated myocarditis can present similarly to, and may overlap with, acute coronary syndrome. Importantly, the presence of obstructive coronary artery disease on angiography does not rule out concomitant ICI-associated myocarditis.

Symptom

Patients may present with one of the classic clinical syndromes—chest pain, heart failure or cardiogenic shock, or arrhythmias—or with atypical symptoms such as isolated fatigue.

The concomitant presence of other immune-related adverse events (eg, rash/dermatitis, pneumonitis, myositis, colitis, hepatitis, thyroiditis) should further raise suspicion for ICI-associated myocarditis.

Cardiac biomarkers

cTnT is elevated in ~94%–100% of cases, whereas cTnI is elevated in ~82%–83%.
cTnT expression in skeletal muscle (diaphragmatic muscleweakness) makes it a marker of broader “myotoxicity” and may indicate concomitant myositis.
An additional advantage of cTnT is its ability to detect the “triple M” syndrome—myocarditis, myositis, and myasthenia gravis—which has been reported in approximately one-third of patients with ICI-associated myocarditis.
cTnI has been recognized as a more specific marker for isolated myocarditis.
A failure of cardiac biomarkers to downtrend after percutaneous coronary intervention should raise suspicion for concurrent myocarditis and prompt further evaluation with multimodality imaging—including echocardiography, cardiac MRI, or nuclear perfusion imaging.

Other biomarkers

Elevations in creatine phosphokinase (CPK), aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase occur in the vast majority of ICI-associated myocarditis cases, with at least three of these biomarkers elevated in approximately 95% of patients.
Concurrent elevation of cardiac and skeletal muscle biomarkers reflects the widespread systemic immune activation that characterizes ICI-related toxicity.

Prognosis

Modest elevations in high-sensitivity cTn (less than 2× the upper limit of normal; ie, <28 ng/L) are common in patients treated with ICIs and are usually benign and self-limiting.
A rise in high-sensitivity cTnT to more than twice the upper limit of normal (ie, >28 ng/L) has been associated with the development of ICI-associated myocarditis.

Endomyocardial biopsy

Endomyocardial biopsy is an invasive test with a procedure-related major complication (cardiac tamponade or complete atrioventricular block) rate of around 0.8% and a minor complication rate of nearly 3.3%, which, however, varies depending on institutional expertise.

Myocarditis with myositis/myasthenia gravis overlap syndrome

This overlap syndrome is associated with more severe clinical presentations and higher mortality, with respiratory failure from respiratory muscle myositis being a common cause of death and compounding the cardiovascular complications.

Cardiac imaging

Cardiac magnetic resonance (CMR) with tissue characterization is considered a gold-standard imaging modality for diagnosing acute myocarditis of various etiologies.

CMR diagnosis is based on the modified Lake Louise criteria, which require evidence of both:

(1) myocardial edema, assessed by T2‑weighted sequences; and

(2) inflammatory myocardial injury, evaluated with T1‑based techniques such as late gadolinium enhancement, increased native T1 signal, or increased extracellular volume (ECV).

Echocardiography

Echocardiographic strain parameters—global longitudinal, radial, and circumferential strain—may offer additional diagnostic value, particularly in patients with known baseline values for these measures.

Lower global longitudinal strainvalues were observed in patients with ICI-associatedmyocarditis, regardless of left ventricular ejection fraction

International Cardio-Oncology Society Consensus-Based Diagnostic Criteria for ICI-Associated Myocarditis

Pathohistologicaldiagnosis (EMB)

Multifocal inflammatory cell infiltrates with overtcardiomyocyte loss by light microscopy

Clinical diagnosis

Cardiac troponin elevation* (a new or significantchange from baseline) with 1 major criterion or 2 minor criteria (after exclusion of ACS and acuteinfectious myocarditis based on clinical suspicion)

Major criterion: CMR diagnostic for acute myocarditis (modifiedLake Louise criteria)

Minor criteria:

Clinical syndrome (including any 1 of thefollowing: fatigue, myalgias, chest pain, diplopia, ptosis, shortness of breath, orthopnea, lower-extremity edema, palpitations, light-headedness/dizziness, syncope, muscleweakness, cardiogenic shock)
Ventricular arrhythmia (including cardiacarrest) and/or new conduction system disease
Decline in left ventricular systolic function, with or without regional wall motion abnormalities in a non-Takotsubo pattern
Other immune-related adverse events, particularly myositis, myopathy, myastheniagravis
Suggestive CMR

Severity of myocarditis

Fulminant: hemodynamic instability, HF requiring noninvasive or invasive ventilation, complete or high-grade heart block, and/orsignificant ventricular arrhythmia

Nonfulminant: including symptomatic but hemodynamically and electrically stable patients and incidental cases diagnosed at the same timeas other immunity-related adverse events. Patients may have reduced LVEF but no features of severe disease

Steroid refractory: nonresolving or worsening myocarditis (clinical worsening or persistent troponin elevation after exclusion of other etiologies) despite high-dose methylprednisolone

Common Terminology Criteria for Adverse Events Version 5.0 Criteria for Adverse Event Reporting

Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnosticobservations only; intervention not indicated
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living
Grade 4 Life-threatening consequences; urgent intervention indicated
Grade 5 Death related to adverse events

Treatment

Discontinue ICI

Consideration of temporary pacemaker(AV block) and mechanical circulatorysupport in hemodynamically unstablepatients

High-dose steroids
- A pulse dose of steroids consisting of intravenous methylprednisolone 1,000 mg daily for a minimum of 3 days, followed by a slow taper over approximately 5 weeks (Wean oﬀ IV methylprednisoloneat the rate of 10 mg/week).
- Switch to oral prednisone(1 mg/kg/day)
- Weekly troponin monitoring
- Monitor adverse effect

Consider additional immunosuppressive agents (eg, mycophenolate mofetil, tacrolimus, plasmapheresis, ruxolitinib, abatacept) in patients whose cTn fails to decrease, who lack clinical response, or who deteriorate with steroid taper.

• Abatacept

• Ruxolitnib

• Alemtuzumab

• Mycophenolate mofetil

• Tacrolimus

• Antithymocyte globulin

• Immunoglobulin

• Plasma exchange

Multidisciplinary discussion with subspecialists, including transplant cardiologists, rheumatologists, neurologists, and specialty pharmacists

Consider prophylaxis against opportunistic infections (eg, Pneumocystis jirovecii pneumonia) during prolonged steroid tapers or when additional immunosuppressive agents are used, although evidence is lacking.

VEGF inhibitors

Example: Bevacizumab, cabozantinib, Lenvatinib, pazopanib, axitinib, sorafenib, sunitinib, sotorasib

Common indications: Renal cell carcinoma, hepatocellular cancer, thyroid cancers

Cardiotoxicity: Hypertension, CTRCD, arterial and venous thromboembolism

Management: Hypertension Antihypertensive therapies (ACEI/ARB and/or CCB)

Does therapy need to be modified?: Continuing treatment with VEGF inhibitors while concomitantly managing hypertension.

VEGF/VEGF receptor interaction

Drugs: aflibercept, bevacizumab, brolucizumab,conbercept, faricimab, pegaptanib, ramucirumab, ranibizumab

VEGF receptor tyrosine kinase

Drugs: anlotinib, apatinib, axitinib, cabozantinib,fruquintinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, tivozanib, vandetanib

VEGF receptor downstream signaling pathways

KRAS: Kirsten rat sarcoma viral oncogene homolog

○ Drug: sotorasib

BRAF: V-Raf murine sarcoma viral oncogene homolog B

○ Drugs: dabrafenib, encorafenib, vemurafenib

MEK1 or MEK2: Mitogen-activated protein kinasekinase 1 or 2

○ Drugs: binimetinib, cobimetinib, selumetinib,trametinib

PI3K: Phosphoinositide-3-kinase

○ Drugs: alpelisib, copanlisib, duvelisib, idelalisib

Adverse effects reported of VEGF inhibitors

Drug	HT	HF	SSE/ VTE	QTc > 500 ms
axitinib	✓
bevacizumab	✓
cabozantinib	✓
lenvatinib	✓
pazopanib	✓	✓
ponatinib		✓	✓
ramucirumab	✓
regorafenib	✓
selpercatinib	✓
sorafenib	✓
sunitinib	✓	✓
vandetanib	✓			✓
zivaftibercept	✓

HT: Hypertension, HF: Hear failure & LV dysfunction SSE: Stroke & Systemic embolism, VTE: venous thromboembolism, QTc: Corrected QT

Baseline and ongoing monitoring

Preexisting Cardiovascular Risk Factors:

The presence of ≥ 2 of the following risk factors, or disease states, has been associated with an increase in the likelihood of cardiovascular toxicity and is classified as high risk:

Age >60 years
Hypertension
Diabetes
Arterial or venous thromboembolism (prior MI, CVA, DVT, PE)
Heart failure
Coronary artery disease
BMI ≥25 kg/㎡
Cigarette smoking

Treatment-Related Risk Factors:

Combination therapy with anthracyclines, platinum, or taxanes
History of anthracycline therapy
Dose of VEGF-targeted antibody

Contraindications for Initiating Anti-VEGF Therapy:

Uncontrolled arrhythmias
Uncontrolled hypertension (≥180 mm Hg systolic blood pressure and/or ≥110 mm Hg diastolic blood pressure) before initiation of therapy
Baseline clinically significant QTc prolongation
Poorly controlled angina
Recent ACS or MI

Baseline Cardiovascular Diagnostic Testing

Before Initiating Therapy

All patients, regardless of their cardiovascular risk, should undergo a baseline cardiovascular assessment that includes:

a lipid panel
Glycated hemoglobin (HbA1c)
blood pressure measurement
ECG.

Patients at high risk ≥ 2

additional cardiacimaging with echocardiography or CMR

Monitoring

HMBP during the 1st cycle, then every 2-3 weeks
In patients on anti-VEGF agents, known to beassociated with a high risk of QTc prolongation.
Perform transthoracic echocardiography and natriuretic peptide testing if the patient develops clinical signs or symptoms of heart failure.

Management of cardiovascular complication induced by anti-VEGF agents

Management of hypertension

Temporarily withhold anti-VEGF therapy when severe hypertension occurs (systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg) and resume after blood pressure has been controlled to <160 mm Hg systolic and <100 mm Hg diastolic.
Hypertension managed with an antihypertensive agent, aiming to achieve atarget blood pressure of >130/80 mm Hg regardless of the presence of cardiovascular risk factors
- prefer ACEIs or ARBs (theoretical possibility of limiting progression to HF).
- Dihydropyridine CCBs (vascular dysfunction in the development of hypertension with anti-VEGF agents)

Nondihydropyridine CCBs such as verapamiland diltiazem should generally be avoided because oftheir potential for cytochrome P450 3A4 drug-drug interactions with anti-VEGF agents

Blood pressureshould be closely observed even after discontinuation of anti-VEGF therapy, particularly in patients who requireantihypertensive treatment during therapy.

Management of Cancer Therapy–Related CardiacDysfunction/HF

Guideline-directed medical therapy—including angiotensin receptor–neprilysin inhibitors, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers; beta-blockers; mineralocorticoid receptor antagonists; and sodium-glucose cotransporter 2 inhibitors

Management of venous thromboembolism

The efficacy ofdifferent direct oral anticoagulants is similar. However, direct oral anticoagulants tend to interact with other drugs.

LMWH is preferred in GI/GU malignancy

Consideration

Thromboembolic risk assessment(patient-, cancer-, or treatment-related factors)
Bleeding risk assessment (thrombocytopenia, GI involvement, Unoperated GI/GU cancer,intracranial lesions, major bleeding, renal impairment)
Drug-dug interactions(CYP3A4, P-glycoprotein)
patient preference

Management of Arterial Thromboembolic Events

Manage myocardial infarction, stroke, and peripheral arterial disease according to the relevant clinical guidelines.

The decision on whether to withhold the VEGF inhibitor that caused the event must be based on multidisciplinary discussion with the cardiologists and oncologists managing the patient’s care.

Ponatinib carries an FDA Boxed Warning for arterial occlusive events, including fatal myocardial infarction, stroke, cerebral arterial stenosis, severe peripheral arterial disease, and urgent revascularization.

Routinely assess for peripheral arterial occlusive disease, including symptoms review and, when indicated, ankle–brachial index or arterial Doppler studies.
Cardiovascular risk reduction measures such as antiplatelet therapy, statin use, and strict blood pressure control.

References

1) Ganatra S, Barac A, Armenian S, Cambareri C, Denlinger CS, Dent SF, Hayek S, Ky B, Leja M, Lucas CH, Makwana B, Palaskas NL, Vo JB. Diagnosis and Management of Cardiovascular Adverse Effects of Targeted Oncology Therapies: Bruton's Tyrosine Kinase, Immune Checkpoint, and Vascular Endothelial Growth Factor Inhibitors: 2025 ACC Concise Clinical Guidance: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2026 Feb 10;87(5):654-682. doi: 10.1016/j.jacc.2025.10.018. Epub 2025 Dec 10. PMID: 41369617.

2) Ivy, S. P., Wick, J. Y., & Kaufman, B. M. (2009). An overview of small-molecule inhibitors of VEGFR signaling. Nature Reviews Clinical Oncology, 6(10), 569-579. https://doi.org/10.1038/nrclinonc.2009.130