Bruton Tyrosine Kinase Inhibitors (BTKi) (BSH 2021)
Intro
The BTKi’s include ibrutinib alcalabrutinib, zanubrutinib, pirtobrutinib
Used in the treatment of lymphoproliferative disorders, but also potentially in non-haem cancers (JCM 2018)
BSH guideline published to discuss the management of the cardiac side effects related to BTKi use
The greatest experience is with ibrutinib, but the cardiac complications probably are a class-wide concern all though potentially lower risk with the next generation agents.
Non-cardiac side effects / interactions
Acquired platelet function defect: hold for 5-7 days before interventional procedures / surgery
Petechial rash, easy bruising & arthralgia: usually improve with time
Alcalabrutinib: also look for headache, gastritis, drug interaction w/ PPIs.
Avoid CYP3A4 inhibitors - warfarin, anti-arrhythmics, fish oils, Vitamin E, St Johns Wort
Avoid Grapefruit and Seville oranges
hypertension (HTN) (≥160 or ≥100)
30% of patients on BTKi and occurrence proportional to duration of treatment
Rate of new HTN diagnosis double that of non-ibrutinib arms of trials
Major adverse cardiovascular events (MACE) and arrhythmias more like in patients with BTKi-related, vs non-BTKi, hypertension. Treating the HTN reduces this risk.
Aim to avoid BTKi dose modifications by instead treating the hypertension
1st line choice: ACEi or ARB (LV function and renal benefits. No drug interactions)
2nd line choice: Carvedilol, Spironolactone (consider cardiology referral at this stage)
Avoid: Veraparmil, diltiazem due to drug interactions
All patients: Patient education at start of treatment
>140 / >90: Offer ambulatory or home blood pressure monitoring
<80 y.o. and >135/>85: Consider anti-hypertensives, particularly if end organ damage or diabetes
>80 y.o. and >145/>85: Consider starting anti-hypertensives
Asymptomatic >180/>120: Assess end organ damage, start anti-hypertensives and withhold BTKi until BP controlled.
atrial fibrillation
8% patients have AF at time of starting BTKi
6% rate of new onset AF whilst on BTKi (increased compared to rest of population)
Median time to onset 3 months, but risk continues long term whilst on treatment
Risk factors: Older age, male, previous AF, hyperlipidaemia, hypertension, valve disease
Assessment:
Baseline and serial ECG for first 12 months
Baseline Echo if pre-existing AF, heart failure, diabetes, coronary artery disease, hypertension
Management if AF occurs:
Refer to cardiology for joint decision making re: anticoagulation, symptom control
Calculate CHA2DS2-VASc and HAS-BLED scores
In general, consider AC if score 2+ in men, 3+ in women
ABC Pathway of care
Avoid stroke, Better symptom management, Cardiovascular optimisation.
Rate control strategy preferred (avoids drug interactions of anti-arrhythmics)
DOAC preferred over warfarin
Temporary BTKi dose reduction may be necessary in fast AF not controlled with beta-blockers
Stop BTKi in heart failure until stabilised
Lots more detail available in the guideline
Ventricular Arrhythmias & Sudden cardiac death
Increased rate of idiopathic ventricular arrhythmias (600 vs 50 per 100,000 person years in a US registry)
Risk should be specifically discussed in the consent process
Consider an alternative to BTKi at the outset if:
previous VA, structural cardiomyopathy, genetic cardiac arrhythmia syndrome (e.g. Brugarda, long QT) or family history of cardiomyopathy
Stop BTKi if VA occurs. If an convincing alternative cause for VA is found and corrected then weigh the risk/benefits of restarting BTKi.