Update 1
Myocarditis is a rare but highly fatal adverse effect of immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs) have transformed cancer care and improved outcomes across a growing number of malignancies.1,2 As ICI treatment expands across tumor types and earlier lines of therapy, hospitalizations for immune-related adverse events (irAE) – including cardiovascular (CV) toxicities – have risen accordingly.3 Led by the International Cardio-Oncology Society (IC-OS), this review provides a broad overview of cardiovascular toxicities associated with ICI therapy, with a particular emphasis on myocarditis.4 This position statement was authored by a multidisciplinary panel and synthesizes basic science research, registry findings, and expert consensus, limited by lack of randomized trial data in this space.
Although ICI myocarditis is rare, occurring in roughly 0.75% of patients on single-agent therapy and 1–2% of those on combination therapy, it is the most fatal irAE with an estimated mortality of 23%.5–7 Other CV complications - pericarditis, acute coronary syndromes, stroke, tachyarrhythmias, heart failure, and pericardial effusion - occur more frequently but are less fatal.6,7
Diagnostic evaluation for myocarditis includes cardiac biomarkers (cardiac troponin, BNP, and NT-proBNP), electrocardiography, echocardiography, cardiac MRI (CMR) and potentially coronary angiography/cardiac computed tomography (CT) to evaluate for coronary artery disease. Endomyocardial biopsies may be pursued when there is diagnostic uncertainty, particularly as diagnosis may impact candidacy for future ICI treatment. Hospitalists should be aware of possible overlapping syndromes with ICI myocarditis (including hepatitis, myositis, or myasthenia gravis), pursuing additional diagnostic evaluation and involving multidisciplinary teams as indicated. Diagnosis of ICI myocarditis is based on European Society of Cardiology (ESC)-ICOS 2021 Diagnostic Criteria and includes either histopathological diagnosis or clinical diagnosis. Clinical diagnosis requires cardiac troponin elevation with either 1 major criteria or 2 minor criteria (Table 1).8
Management of myocarditis depends on the degree of severity. Non-severe myocarditis (symptomatic but hemodynamically and electrically stable) warrants ICI discontinuation and prompt treatment with high-dose corticosteroids (500-1000 mg of intravenous (IV) methylprednisolone daily) after diagnosis is confirmed. Steroids are transitioned to oral prednisone (1-2 mg/kg daily) once cardiac troponins begin to decline, followed by a taper of roughly 10 mg/week. Some patients may have steroid-refractory disease and can be managed with additional immunosuppression (abatacept, ruxolitinib, mycophenolate). Infliximab should be avoided given an association with higher rates of CV death.9
Patients with severe myocarditis (characterized by conductional abnormalities or hemodynamic instability, heart failure requiring non-invasive or invasive ventilation) should have ICI therapy discontinued and receive immediate initiation of high-dose steroids (IV methylprednisolone 500-1000mg daily) in addition to stabilization with vasopressors, temporary pacing, and/or cardioversion/defibrillation as indicated. Patients who present with severe myocarditis or triple M syndrome (myocarditis, myositis, and myasthenia gravis) often require multidisciplinary consultation, with additional consideration for possible transfer to specialized facilities capable of managing potential complications. These patients may require treatment with additional upfront immunosuppression as well as potentially a JAK inhibitor, antithymocyte globulin, intravenous immunoglobulin and/or plasma exchange.10
The principal limitation of this position statement is the absence of randomized trials. Recommendations rely heavily on registry data, case reports/case series, and expert consensus. The authors identify several knowledge gaps requiring further investigation. Topics that may be relevant to hospital medicine include the further refinement of CMR diagnostic criteria, the role of additional immunosuppressive therapy earlier in treatment, as well as the optimal dose, taper, and duration of steroids.
Take-away: Myocarditis remains the most fatal ICI cardiovascular toxicity and requires prompt recognition and treatment. Hospitalists should have a low threshold to evaluate for myocarditis in patients on ICI therapy who present with new cardiopulmonary symptoms, conduction abnormalities, or arrythmias. Management should include multidisciplinary collaboration with cardiology and oncology. Corticosteroids are the mainstay of treatment for both non-severe and severe cases with or without the addition of adjunctive immunosuppressants.
Update 2
Extended reduced-dose apixaban is non-inferior to full-dose apixaban for prevention of recurrent venous thromboembolism in patients with active cancer
The incidence of venous thromboembolism (VTE) in patients with active cancer is three to ninefold higher than that of the general population.11,12 The risk of VTE may increase depending on the cancer type (pancreatic cancer typically having the highest risk) as well as treatment modality (i.e. immunotherapy vs. chemotherapy).11,13 Conventional practice is to continue indefinite therapeutic anticoagulation for patients with active cancer and VTE. However, patients with cancer are also at an increased risk of major bleeding events.14,15
The Apixaban for Cancer-Associated Thrombosis (API-CAT) trial aimed to determine if reduced-dose apixaban would be noninferior to full-dose apixaban for prevention of recurrent VTE in patients with active cancer.15 This prospective, randomized, double-blind, noninferiority trial included patients with active cancer who had completed at least 6 months of treatment for VTE. The primary outcome was fatal or nonfatal recurrent VTE, including both incidental and symptomatic events. A key secondary outcome was clinically relevant bleeding. All outcomes were confirmed by a blinded central adjudication committee.
A total of 1,766 patients were randomly assigned to receive reduced-dose (2.5 mg twice a day) or full-dose (5.0 mg twice a day) apixaban after completion of at least 6 months of therapeutic anticoagulation (with low-molecular-weight heparin, vitamin K antagonists or direct oral anticoagulant). Median age was 69 years old with 43.4% men. The vast majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (92.6%), meaning that most patients were independent in their activities of daily living. Patients with ECOG of 3 or 4 were excluded from this study. Additional exclusion criteria included patients with creatinine clearance <30 mL/min, isolated upper extremity deep vein thrombosis (DVT), hemoglobin <8 g/dL and platelets <75/mm3, amongst others.
Ultimately, in an intention-to-treat analysis, there was similar cumulative incidence of recurrent VTE (2.1% in reduced-dose group vs 2.8% in full-dose group, p=0.001 for noninferiority). There was a significantly lower incidence of major bleeding in the reduced-dose group compared to the full-dose group (12.1% vs 15.6%, p=0.03). Most major bleeding was due to gastrointestinal sources in both groups. There were equal numbers of fatal bleeding events between groups (two in each group).
Key limitations to generalizability to an inpatient population include exclusion of patients with ECOG >2, upper extremity DVT, and reduced creatinine clearance. Additionally, this study did not look at dose reduction with other DOACs so cannot be extrapolated to use with rivaroxaban.
Take-away: Reduced-dose apixaban (2.5 mg twice a day) was shown to be non-inferior to full-dose apixaban in prevention of recurrent VTE in patients with cancer after 6 months of initial treatment. The reduced-dose group had lower rates of clinically relevant bleeding. Hospitalists may have opportunities to discuss apixaban dose reduction in appropriate inpatients, especially those who have already had or may be at increased risk for bleeding complications.
Update 3
Incidental splenomegaly on imaging increases risk of hematological cancer and liver disease
Splenomegaly on imaging is a common incidental finding encountered by hospitalists. Etiologies of splenomegaly in hospitalized patients can include serious conditions like hematologic malignancies and liver disease.16 However, the threshold for defining pathologic “splenomegaly” is uncertain, and spleen size varies with sex, body height, and weight.17
To better understand the risks of incidental splenomegaly, Juhl et al. performed a large prospective cohort study determining the spleen size at which individuals are at increased risk for hematologic cancer or liver disease.18 Adult patients were randomly invited for imaging as part of larger cohort studies: 8,556 Danish participants underwent CT and 38,996 UK participants underwent magnetic resonance imaging (MRI) scans. Patients were followed for a median of 5 years; those with pre-existing hematologic disorders were excluded (Juhl et al 2026). Subsequent diagnoses of liver and hematologic diseases were obtained from registries using ICD-10 codes. Co-variates investigated included age, sex, alcohol use, smoking, and comorbidities.
Baseline characteristics were similar between Danish and UK cohorts, with median ages in the 60s and approximately half female; most patients in the larger cohorts were self-reported White race (99 and 95%, respectively). 55% and 39% were ever-smokers, and 24% and 20% had a notable comorbidity, respectively. The median spleen volume differed between the cohorts (161 and 154 ml, respectively), so Danish and UK populations were considered separately.
As expected, larger spleens portended higher risk for developing hematologic cancer. Individuals with spleen volume greater than the 99th percentile (>433 mL in Danish or >386 mL in UK individuals) had approximately 11-fold increase in relative risk for hematologic cancer compared to individuals with volumes in the 26th to 74th percentile. For the Danish cohort (who had both spleen volume and length available), volume performed better than length for estimating risk of hematologic cancer. Interestingly, risk estimation based on spleen size was not compellingly improved by accounting for height, weight, or BMI.
Evaluating commonly used cut-offs for “splenomegaly”, individuals with spleen length of 130-139 mm and volume of 400-499 ml had moderately increased risk of hematologic cancer. Individuals with spleen length of 140 mm or greater or volume of 500 ml or greater had a large jump in risk; e.g. Danish men over 70 years of age with spleen volume ≥ 500 ml had a 46% chance of developing a hematologic malignancy in 5 years.
Risks of liver cirrhosis and cancer were limited to the UK cohort due to lower statistical power in the Danish cohort. Individuals with spleen volume greater than the 90th percentile had increased risk of cirrhosis compared to individuals with volumes in the 26th to 74th percentile, with the risk rising further with volume. For liver cancer, an increased risk was observed only among patients with spleen volumes above the 99th percentile (HR 6.3).
There are several limitations. Although the general population design is useful to target incidental splenomegaly, this population is likely healthier and younger on average than admitted patients encountered by hospitalists. Additionally, a follow-up period longer than 5 years may have unmasked additional diseases of interest.
Take-away: If hospitalized patients have incidentally detected splenomegaly on CT or MRI, defined as spleen length ≥ 130 mm or volume ≥ 400 ml, consider further evaluation for hematologic malignancy and liver disease. Older patients with spleens ≥140 mm length or ≥ 500 ml volume are particularly high risk for hematologic cancer.
Disclosures/Conflicts of Interest
The authors declare they have no conflicts of interest.
Corresponding author
Andrew Lyu, MD
Division of Hospital Medicine, Department of Medicine,
MaineHealth Maine Medical Center, Portland, ME 04102
Email: andrew.lyu@mainehealth.org