2025 ACC Concise Clinical Guidance: CV Adverse Effects of Targeted Oncology Therapies (BTK, ICI, VEGF Inhibitors)

Authors, Journal, Affiliations, Type, DOI

• Authors: Ganatra S (Chair), Barac A (Vice Chair), Armenian S, Cambareri C, Denlinger CS, Dent SF, Hayek S, Ky B, Leja M, Lucas CH, Makwana B, Palaskas NL, Vo JB
• Journal: Journal of the American College of Cardiology, 2026;87(5):654–682
• Report of: ACC Solution Set Oversight Committee; approved November 2025
• Type: Concise Clinical Guidance (CCG) — point-of-care guidance, not a full guideline
• DOI: https://doi.org/10.1016/j.jacc.2025.10.018

Overview

This 2025 ACC Concise Clinical Guidance provides practical, algorithm-driven cardiovascular toxicity management for three classes of targeted anticancer therapies — BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), immune checkpoint inhibitors (ICIs), and VEGF inhibitors — using clinical case vignettes as anchor points. The document introduces the concept of "permissive cardiovascular toxicity," acknowledging that CV adverse effects may need to be managed while continuing life-extending cancer therapy rather than reflexively stopping treatment. Key new data includes: the landmark Salem et al. finding of 3.4% vs. 60% mortality with upfront abatacept+ruxolitinib vs. steroids alone in ICI myocarditis; CPK rising ~20 days before clinical ICI myocarditis presentation; ibrutinib-non-DHP CCB/amiodarone interactions increasing ibrutinib levels 6–9-fold; and VEGF inhibitor-induced hypertension targets and dual antihypertensive thresholds. The document is published in JACC 2026 and was approved in November 2025.

Keywords

BTK inhibitors; ibrutinib; acalabrutinib; zanubrutinib; pirtobrutinib; immune checkpoint inhibitors; myocarditis; VEGF inhibitors; cardiotoxicity; hypertension; atrial fibrillation; cardio-oncology; permissive cardiovascular toxicity

Key Takeaways

1. Introduction and Context

• Cancer survivors expected to rise from 18.6 million to >22 million by 2035; FDA approvals have made 44% of US adults with cancer eligible for ICI therapy
• Cardiovascular assessment with risk factor optimisation before cancer treatment is recommended for all patients
• "Permissive cardiovascular toxicity" — concept acknowledging that CV toxicity may need to be tolerated/managed (not solely used to stop therapy) to preserve oncological outcomes

2. BTK Inhibitors

2.1 Drug Profile (Table 1)

• Ibrutinib: First-generation; CLL/SLL, Waldenström macroglobulinaemia, graft-versus-host disease
• Acalabrutinib: Second-generation irreversible; MCL, CLL/SLL — greater BTK selectivity
• Zanubrutinib: Second-generation irreversible; MCL, Waldenström, MZL, CLL/SLL, follicular lymphoma
• Pirtobrutinib: Third-generation reversible; MCL and CLL/SLL after ≥2 prior lines including a BTKi

2.2 Cardiovascular Toxicity Profile (Table 2)

• Atrial fibrillation: Ibrutinib 3–16%; acalabrutinib 5–9%; zanubrutinib 3–6%; pirtobrutinib 3.2%
• Hypertension: Ibrutinib — new HTN in 71.6% of normotensive patients; worsening HTN in 82.4%; high-grade HTN (>160/100) in up to 18%; acalabrutinib 59%; zanubrutinib 5–11%
• HF: Ibrutinib — VigiBase pharmacovigilance ROR 3.5 (95% CI 3.1–3.8; P<0.0001) for HF
• Ventricular arrhythmia: Ibrutinib — 12× higher risk vs. idiopathic VA in non-ibrutinib-treated subjects; weighted average 394/100,000 person-years vs. 48.1 in similar-aged non-BTKi-treated subjects
• Bleeding: Ibrutinib — 2.22× overall bleeding, 1.80× major bleeding vs. controls; acalabrutinib — 3.45× overall bleeding

2.3 Risk Factors for CV Toxicity With Ibrutinib (Table 3)

Older age, male sex, valvular heart disease, hypertension, pre-existing CVD (CAD/HF/VA/pacemaker), left atrial abnormality on ECG

2.4 Baseline Assessment and Monitoring

• BP at every clinic visit (mandatory for all BTK inhibitor patients)
• Home BP monitoring recommended to distinguish white coat hypertension and track trends
• Higher-risk patients (male, ≥65 years, HTN, DM, QTc ≥480 ms, prior AF/HF/cardiomyopathy/severe VHD): ECG + echocardiogram before treatment
• During treatment: ECG every 3 months for year 1, then every 3–6 months
• Opportunistic AF screening: pulse palpation, ECG rhythm strip, wearable devices, Holter

2.5 Drug Interactions — Ibrutinib (Table 4)

• Dihydropyridine CCBs (amlodipine, felodipine, nifedipine): CYP3A4 substrates but do NOT inhibit ibrutinib metabolism — safe to use
• Direct thrombin inhibitors (dabigatran): do NOT co-administer

2.6 Management of Preexisting CV Conditions Before Ibrutinib (Table 5)

• Pre-existing AF: CHA₂DS₂-VASc risk assessment; rate control with beta-blockers (preferred) over non-DHP CCBs; avoid digoxin (P-gp interaction); avoid dabigatran; Factor Xa inhibitors preferred; consider LAA closure if anticoagulation contraindicated
• Pre-existing HTN: Beta-blockers and RAS inhibitors safe; DHP CCBs relatively safe; consider switch to 2nd/3rd-gen BTKi
• Pre-existing VA: Periodic ECG + Holter + echo; choose appropriate 2nd-gen BTKi to avoid ibrutinib interactions

2.7 Management of New CV Events During Ibrutinib

• New-onset or worsening AF: Hemodynamic stability determines strategy
  • Unstable → rhythm control (cardioversion)
  • Stable → rate control; rule out reversible causes
  • Avoid amiodarone/dronedarone (Class III AADs) — major drug interaction
  • Avoid non-DHP CCBs for rate control unless switching to 2nd/3rd-gen BTKi with dose reduction
  • Factor Xa inhibitors preferred anticoagulation; warfarin/LMWH acceptable with monitoring; avoid dabigatran
  • Consider LAA closure if anticoagulation contraindicated; AF ablation in select patients
• Bleeding: Dual antiplatelet therapy generally contraindicated; hold ibrutinib 3 days (minor procedures) or 7 days (major procedures); platelet transfusion for severe bleeding regardless of count
• New/worsening HTN: Follow ACC/AHA BP guidelines; avoid non-DHP CCBs; thiazide+BB effective in prior HTN; thiazide+ACE-I/ARB for new-onset HTN
• New VA: Rule out ischaemia first; beta-blockers with antiarrhythmic properties (sotalol) safe; avoid amiodarone/dronedarone

2.8 Switching and Alternatives

• Second-generation BTKi (acalabrutinib, zanubrutinib) recommended when CV toxicity develops with ibrutinib
• Pirtobrutinib (third-generation reversible) available after ≥2 prior lines
• Ibrutinib's continued use despite available alternatives often reflects insurance/accessibility/provider familiarity rather than clinical superiority

3. Immune Checkpoint Inhibitors (ICIs)

3.1 Drug Profile (Table 6)

• CTLA-4 antibodies: ipilimumab, tremelimumab
• PD-1 antibodies: nivolumab, pembrolizumab, cemiplimab, retifanlimab, dostarlimab, toripalimab, tislelizumab
• PD-L1 antibodies: avelumab, atezolizumab, durvalumab
• LAG3 antibodies: relatlimab
• Combination ICI (especially CTLA-4+PD-1): significantly higher myocarditis risk than monotherapy

3.2 Cardiovascular Toxicity Profile

• ICI myocarditis: Incidence 0.04–1.14%; mortality 20–50%; higher with combination therapy
• Other toxicities: Dyslipidaemia, arrhythmias, pericarditis, vasculitis, atherosclerotic CAD, Takotsubo cardiomyopathy
• Patients with pre-existing autoimmune disease and dual ICI therapy (CTLA-4+PD-1) have substantially higher risk

3.3 Baseline Risk Assessment

• ECG, cardiac troponin, natriuretic peptides (BNP/NT-proBNP), echocardiogram with baseline GLS (high-risk patients only)
• No validated pre-treatment risk stratification tool currently exists
• Baseline troponin establishes reference for detecting subsequent changes

3.4 Diagnosis of ICI-Associated Myocarditis — Biomarkers

Cardiac Biomarkers:

• cTnT elevated in 94–100% of cases; cTnI in 82–83%
• cTnT also reflects "triple M" syndrome (myocarditis + myositis + myasthenia gravis), which occurs in ~1/3 of ICI myocarditis cases
• cTnI is more specific for isolated myocarditis; cTnT better captures triple M overlap
• cTnT level <2× ULN (<28 ng/L): mostly benign and self-limiting
• cTnT >2-fold rise above ULN (>28 ng/L): ~1/3 of patients develop ICI myocarditis
• Peak cTnT >32× ULN: 9-fold greater MACE risk at 100 days post-hospitalisation
• cTnT/cTnI normalisation time: median 133 vs. 17 days, respectively

Non-Cardiac Biomarkers:

• CPK, AST, ALT, LDH elevated in the vast majority of ICI myocarditis cases (≥3 of 4 elevated in 95%)
• CPK: 99% sensitivity (23% specificity) for ICI-associated myocarditis
• Non-cardiac biomarkers rise ~20 days before clinical presentation — potential early screening value
• Absence of elevated CPK/AST/ALT/LDH makes clinically significant ICI myocarditis highly unlikely
• Proposed biweekly CPK/AST/ALT monitoring during first 12 weeks, with hsTnI triggered by elevations

Myocarditis-Myositis-Myasthenia Gravis (Triple M) Overlap:

• Associated with more severe presentation and higher mortality
• Respiratory failure from respiratory muscle myositis is a common cause of death
• All 5 biomarkers elevated → highest mortality; normal CPK → better survival

3.5 Cardiac Imaging

CMR:

• Gold standard; diagnosis by modified Lake Louise criteria: myocardial oedema (T2-weighted) + inflammatory injury (T1-based: LGE, native T1 signal, ECV)
• Low sensitivity of standard CMR criteria in ICI myocarditis: retrospective study (n=103) — only 48% positive LGE, 28% positive T2-STIR (local protocols with qualitative T2-STIR limit sensitivity)
• Quantitative parametric T1/T2 mapping superior: abnormal T1 in 78%, T2 in 43% in confirmed cases (n=136, Thavendiranathan et al.)
• A negative CMR report should be reviewed with an imaging expert; further testing required if clinical suspicion persists
• Quantitative T1/T2 mapping + ECV recommended where available

Echocardiography:

• LVEF often normal in ICI myocarditis — normal LVEF does NOT exclude diagnosis
• GLS (global longitudinal strain): lower in ICI myocarditis regardless of LVEF; below-median GCS associated with 4.9× MACE risk; below-median GRS associated with 3.9× MACE risk (Quinaglia et al.)

Endomyocardial Biopsy:

• For uncertain diagnosis when noninvasive imaging and biomarkers insufficient
• Major complication rate ~0.8% (tamponade/complete AV block); minor ~3.3%
• May change management when noninvasive workup equivocal or concurrent cardiotoxic therapies present

3.6 Diagnostic Criteria — International Cardio-Oncology Society 2022 (Table 7)

Pathohistological diagnosis (EMB): Multifocal inflammatory infiltrates with cardiomyocyte loss by light microscopy

Clinical diagnosis: cTn elevation + 1 major criterion OR 2 minor criteria (after ACS and acute infectious myocarditis exclusion)

• Major: CMR diagnostic by modified Lake Louise criteria
• Minor: Clinical syndrome (fatigue/myalgias/chest pain/dyspnoea/oedema/palpitations/syncope/weakness/cardiogenic shock); ventricular arrhythmia/cardiac arrest/new conduction disease; LVEF decline (non-Takotsubo pattern); other immune-related adverse events (especially myositis/myopathy/MG); suggestive CMR

Severity:

• Fulminant: haemodynamic instability, HF requiring ventilation, complete/high-grade heart block, significant VA
• Non-fulminant: symptomatic but haemodynamically/electrically stable; may have reduced LVEF
• Steroid-refractory: worsening despite high-dose methylprednisolone

3.7 Treatment of ICI-Associated Myocarditis

• ICI discontinuation in all confirmed cases (permanent per NCCN/ASCO for grade ≥2)
• Acute management: High-dose IV methylprednisolone 1,000 mg/day × 3 days, then taper over 5 weeks (10 mg/week reduction of oral prednisolone 1 mg/kg/day)

Steroid-refractory or escalating disease:

• Add: mycophenolate mofetil, tacrolimus, plasmapheresis, ruxolitinib, abatacept
• Avoid infliximab — associated with exacerbation of HF in myocarditis patients

Landmark data — upfront targeted immunomodulation (Salem et al.):

• Prospective observational study: abatacept + ruxolitinib upfront → mortality 3.4% vs. 60% in historical control group receiving conventional high-dose steroids alone
• Ongoing RCTs examining abatacept + steroids will further inform management

Fulminant disease:

• Tertiary care centre with advanced HF expertise
• Mechanical circulatory support (contingent on cancer prognosis)
• Early additional immunosuppressants: abatacept, ruxolitinib, alemtuzumab, antithymocyte globulin, IVIG, plasmapheresis

ICI rechallenge:

• Current guidelines (NCCN/ASCO): permanent ICI discontinuation for grade ≥2 myocarditis
• Case-by-case rechallenge may be considered for low-severity/asymptomatic biomarker elevation if no alternative cancer therapy exists

3.8 Survivorship

• Increasing ASCVD risk among ICI recipients (not captured by traditional ASCVD risk calculators)
• Statins: observational data show attenuation of plaque progression + improved progression-free and overall survival in ICI patients
• Lowered threshold for statin use in primary prevention during ICI survivorship (mindful of heightened myopathy risk with CPK elevation)

4. VEGF Inhibitors

4.1 Drug Profile and Mechanism

Two main targets in VEGF axis:

• VEGF/VEGFR interaction blockers: aflibercept, bevacizumab, ramucirumab
• VEGFR tyrosine kinase inhibitors (TKIs): axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib, and others
• Downstream pathway inhibitors: KRAS (sotorasib), BRAF (dabrafenib), MEK1/2 (binimetinib, trametinib), PI3K (alpelisib, idelalisib)

4.2 Cardiovascular Toxicity Profile (Table 10)

Adverse effects with incidence >10% for each drug class:

• Hypertension (class effect): axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, ponatinib, ramucirumab, regorafenib, selpercatinib, sorafenib, sunitinib, vandetanib, ziv-aflibercept
• HF/LV dysfunction: pazopanib, ponatinib, sunitinib
• Arterial/venous thromboembolism: ponatinib (FDA Boxed Warning)
• QTc prolongation >500 ms: vandetanib

4.3 Risk Factors for CV Toxicity (Table 11)

High risk = ≥2 of: age >60, HTN, DM, prior arterial/VTE (MI/CVA/DVT/PE), HF, CAD, BMI ≥25, smoking
Treatment-related: combination with anthracyclines/platinum/taxanes; prior anthracycline; dose of VEGF-targeted antibody

Contraindications to starting anti-VEGF therapy:

• Uncontrolled arrhythmias
• Uncontrolled HTN (≥180 mmHg systolic or ≥110 mmHg diastolic)
• Baseline clinically significant QTc prolongation
• Poorly controlled angina
• Recent ACS or MI

4.4 Baseline Testing

• All patients: lipid panel, HbA1c, BP, ECG
• High-risk (≥2 risk factors): echocardiography or CMR to assess baseline cardiac function

4.5 Monitoring During Therapy

• BP: Home monitoring during first cycle, after each dose change, every 2–3 weeks thereafter
• ECG: Serial monitoring for agents with high QTc prolongation risk
• TTE + natriuretic peptides: If symptoms of HF develop during treatment

4.6 Hypertension Management (Figure 6)

• Mechanism: ↓eNOS/NO bioavailability, ↑endothelin-1, capillary rarefaction (↑microcirculatory resistance), rightward shift of renal pressure-natriuresis curve
• Severe HTN (≥180/110): Withhold VEGF inhibitor until BP <160/100; resume once consistently <160/100 on antihypertensive therapy
• BP ≥160/100 on presentation: Initiate dual antihypertensives immediately
• Preferred antihypertensives: ACE-I or ARB (preferred; limits HF progression) + amlodipine (DHP CCB; ↓arterial smooth muscle contractility)
• Avoid non-DHP CCBs (diltiazem, verapamil): CYP3A4 inhibition → ↑ VEGF inhibitor levels
• BP target: <130/80 mmHg regardless of CV risk factors
• HTN is dose-related and often reversible after drug cessation

4.7 HF/LV Dysfunction Management

• Treat underlying primary etiology (HTN, arrhythmia)
• GDMT: ARNi/ACE-I/ARB, beta-blockers, MRA, SGLT2i (observational data suggest lower CTRCD risk in TKI patients)
• GLP-1 receptor agonists: promising but require prospective investigation
• Await results of prospective SGLT2i RCTs in VEGF inhibitor-related CTRCD

4.8 Venous Thromboembolism (Figure 7)

• Anticoagulation decision based on individual bleeding + thrombotic risk assessment
• Apixaban generally associated with fewer bleeding events in cancer patients
• LMWH preferred for gastrointestinal and genitourinary malignancies (lower bleeding vs. direct factor Xa inhibitors per ASCO guidelines)
• NCCN guidelines: LMWH specifically in gastric/gastroesophageal tumours; DOACs preferred otherwise
• Drug-drug interactions may necessitate LMWH over DOACs
• Primary thromboprophylaxis: Khorana score or COMPASS-CAT scoring; LMWH reduces symptomatic VTE in ambulatory cancer patients on chemotherapy

4.9 Arterial Thromboembolism

• Present per relevant guidelines; multidisciplinary decision on VEGF inhibitor continuation
• Ponatinib (broad-spectrum kinase inhibitor for Ph+ ALL/CML): FDA Boxed Warning — arterial occlusive events including fatal MI, stroke, peripheral vascular disease
• Ponatinib surveillance: ankle-brachial index, Doppler, antiplatelet therapy + statin + strict BP control

4.10 Survivorship

• Monitor BP after stopping anti-VEGF agents; risk of HTN generally decreases but antihypertensives may still be required
• Limited evidence for long-term cardiac imaging post-VEGF inhibitor therapy

Limitations of the Document

• Concise Clinical Guidance format — not a full guideline; focused on point-of-care applicability
• Evidence base primarily from retrospective studies, real-world data, pharmacovigilance databases; few dedicated RCTs in cardio-oncology
• Most BTK inhibitor CV data from ibrutinib studies; second- and third-generation agents have limited long-term evidence
• ICI myocarditis management extrapolates from small case series and non-ICI scenarios (e.g., transplant rejection protocols)
• No validated pre-treatment risk stratification tools for ICI or BTK inhibitor CV toxicity
• Biomarker-guided management strategies for ICI myocarditis lack prospective RCT validation
• Ibrutinib rechallenge/alternatives and AF ablation in BTKi patients lack prospective data
• Drug-label recommendations may differ from clinical guidance in this document

Key Concepts Mentioned

• concepts/Cancer-Therapy-Related-CV-Toxicity — primary management framework updated with BTK/ICI/VEGF data
• concepts/Cancer-Associated-Arrhythmia — BTK-associated AF management, ibrutinib drug interactions
• concepts/Cardio-Oncology — permissive CV toxicity concept, MDT approach
• concepts/Cancer-Associated-VTE — VEGF inhibitor VTE management

Key Entities Mentioned

• entities/Atrial-Fibrillation — ibrutinib-associated AF management

Wiki Pages Updated

• wiki/concepts/Cancer-Therapy-Related-CV-Toxicity.md — added ACC 2025 BTK/ICI/VEGF management sections
• wiki/concepts/Cancer-Associated-Arrhythmia.md — updated BTK inhibitor AF and drug interaction data