Upadacitinib in Cardiac Disease
Upadacitinib can be used in patients with pre-existing cardiac disease, but requires careful risk stratification, enhanced monitoring, and should generally be avoided in patients ≥65 years with multiple cardiovascular risk factors unless no suitable alternatives exist. 1, 2, 3
Risk Stratification Framework
High-Risk Patients (Avoid or Use Only When No Alternatives)
- Age ≥65 years with any cardiovascular risk factor 1, 2, 4
- Current or previous long-term smokers with cardiac history 1, 2, 3
- Prior major adverse cardiovascular events (MI, stroke, cardiovascular death) 3
- Active or recent venous thromboembolism 2, 3
Moderate-Risk Patients (Use With Enhanced Monitoring)
- History of coronary artery disease without recent events 1, 2
- Controlled heart failure (prior CHF but currently stable) 2
- Controlled arrhythmias 2
- Age 50-64 years with ≥1 cardiovascular risk factor 4, 3
Lower-Risk Patients (Standard Monitoring)
- Age <50 years without cardiovascular risk factors 2
- Well-controlled hypertension or diabetes as isolated risk factors 2
Regulatory Guidance and Positioning
The FDA recommends JAK inhibitors like upadacitinib only after failure or intolerance to TNF antagonists, while the European Medicines Agency advises cautious first-line use in patients at risk for adverse cardiovascular outcomes. 1, 2
The FDA boxed warning specifically highlights that in RA patients ≥50 years with ≥1 cardiovascular risk factor, another JAK inhibitor showed higher rates of MACE compared to TNF blockers, though this was not directly demonstrated with upadacitinib. 3 However, post-hoc analysis of upadacitinib 15 mg in RA patients at higher cardiovascular risk showed MACE rates comparable to adalimumab. 5
Evidence-Based Safety Profile
Recent large-scale analyses demonstrate reassuring cardiovascular safety data for upadacitinib across multiple indications:
In the SELECT-GCA trial (2025), no major adverse cardiovascular events occurred in patients receiving upadacitinib 15 mg or 7.5 mg over 52 weeks, despite the elderly population (median age 70 years) with giant cell arteritis. 6
Integrated analysis across RA, PsA, and AS programs showed MACE rates of 0.3-0.6 per 100 patient-years and VTE rates of 0.2-0.4 per 100 patient-years with upadacitinib 15 mg, comparable to adalimumab and methotrexate. 7
Systematic review of 45 randomized controlled trials found no statistically significant differences in cardiovascular events or death between upadacitinib and comparators. 8
Most patients experiencing MACE or VTE events had ≥2 baseline cardiovascular risk factors, emphasizing the importance of pre-existing risk. 7
Specific Cardiac Conditions
Heart Failure
Patients with prior heart failure can receive upadacitinib with close monitoring, as congestive heart failure is uncommon with JAK inhibitors. 2 Ensure heart failure is optimally managed with standard medical therapy including diuretics before initiating treatment. 9 Monitor for signs of fluid retention or worsening heart failure at each visit. 2
Coronary Artery Disease
Stable coronary artery disease is not an absolute contraindication, but requires enhanced cardiovascular monitoring. 1, 2 Avoid in patients with recent MI or unstable angina. 3 Optimize all modifiable risk factors including lipids, blood pressure, and smoking cessation before and during treatment. 4
Arrhythmias
Controlled arrhythmias do not preclude upadacitinib use, but ensure cardiology co-management is in place. 2 No specific arrhythmia signals have been identified in clinical trials. 6, 8
Mandatory Baseline and Monitoring Protocol
Baseline Assessment
- Complete blood count with differential 5, 2
- Comprehensive metabolic panel 5, 4
- Lipid panel 5, 2, 4
- TB screening (QuantiFERON or PPD) 5, 2
- Hepatitis B and C screening 5, 2
- Cardiovascular risk assessment including smoking history, prior CV events, family history 1, 2
Follow-Up Monitoring
- CBC and CMP every 3 months 5, 4
- Lipid panel at 1-2 months, then every 6-12 months 5, 4
- Clinical assessment for cardiovascular symptoms at each visit 4
- Aggressive management of hypertension and dyslipidemia 4
Dosing Considerations in Cardiac Disease
Standard dosing remains appropriate for most cardiac patients: 15 mg daily for RA, PsA, AS; 45 mg induction then 15-30 mg maintenance for UC/CD. 2 Consider dose reduction to 15 mg daily in patients ≥75 years. 2 Maximum dose is 15 mg daily in severe renal impairment (CrCl <30 mL/min). 2
When to Discontinue
Immediately discontinue upadacitinib if the patient experiences:
- Myocardial infarction or stroke 3
- New or worsening heart failure symptoms unresponsive to standard therapy 3
- Deep venous thrombosis or pulmonary embolism 3
- Signs of arterial thrombosis 3
Critical Pitfalls to Avoid
- Do not use upadacitinib as first-line therapy in patients ≥65 years with cardiovascular risk factors when TNF inhibitors remain viable options. 1, 4
- Do not ignore smoking status—current or past smokers with cardiac disease represent the highest-risk population. 1, 2, 3
- Do not fail to optimize cardiovascular risk factors before initiating therapy. 4
- Do not continue therapy after a MACE event—this is an absolute indication for discontinuation. 3