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.