Management of cardiovascular complications of bruton tyrosine kinase inhibitors

This Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at BSH Guidelines Development Process (PDF). (b-s-h.org.uk). The British Society for Haematology produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base, but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Literature search was peformed using PubMed on 2 June 2020, with search terms ibrutinib, Bruton Tyrosine Kinase Inhibitor, atrial fibrillation, hypertension, sudden cardiac death and cardiovascular complications, and confined to publications in English. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It has also been reviewed by UK CLL Forum Executive and British Cardiology-Oncology Society. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised the treatment of chronic lymphocytic leukaemia (CLL). Cardiovascular (CV) adverse events associated with BTKi therapy may interfere with continuation of best possible care, induce life-threatening CV complications or lead to long-term morbidity including worse CLL-related outcomes if optimal BTKi treatment is withheld.1, 2 Correct understanding, interpretation and management of BTKi-related CV adverse events are required and should be placed within the context of the overall care of the individual patient. We aim to provide practical management recommendations for BTKi-associated cardiac toxicity to enhance maintenance on BTKi therapy with minimal disruption. Hypertension is a common cardiovascular adverse event in oncology patients, as recently reviewed.3 In general, BTKi-associated hypertension has an incidence of 30% (systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg in 5%), and is proportional to duration of therapy.4-6 In the larger phase 3 randomised controlled trials (RCT), the rate of new hypertension across all ages is double that in the non-ibrutinib arm.7-10 Dickerson et al.11 reported an increased risk of developing major adverse cardiovascular events (MACE; hazard ratio [HR], 2·17; 95% CI, 1·08–4·38) and of arrhythmia (HR 3·18; CI, 1·37–7·37) with ibrutinib-related hypertension compared to patients with stable or no hypertension. Antihypertensive initiation lowered MACE risk (HR 0·40; 95% CI, 0·24–0·66), suggesting the interaction of hypertension and ibrutinib could increase the risk of atrial fibrillation (AF) and other cardiovascular events.11 Drug treatment should be considered in patients aged over 80 with ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) BP > 145/85 mmHg.12 The incidence of new-onset AF is increased in patients with CLL on BTKi therapy, reported at 6%.13-15 A nationwide Swedish population study demonstrated that the prevalence of AF was already 8% (66/828) at the time of commencement of first line therapy.16 The association between ibrutinib and AF is evident from two meta-analyses demonstrating a higher pooled rate of AF (5·77 per 100 person-years) compared to the age-matched population in the Framingham study (1·8 per 100 person-years).15, 17-19 The median time of onset of AF from initiation of therapy was 2·8 months (range 0·3–17·5). The cumulative rate of AF at 36 months was 11·2% (95% CI: 11·2, 16·8), with new cases of AF occurring at a continuous low rate over time.20 Older age, male sex, past history of AF, hyperlipidaemia, hypertension and valvular heart disease were identified as risk factors for AF development.13, 20-22 Baseline CV risk assessment prior to initiation of BTKi is recommended. Baseline and serial electrocardiograms (ECGs) are recommended, particularly during the first 12 months of treatment.23, 24 A baseline transthoracic echocardiogram should be considered for patients with pre-existing AF, coronary artery disease, heart failure or cardiomyopathy, and hypertension.25-27 Prior history of AF is not a contraindication to BTKi initiation, with the exception of the following: recurrent decompensated cardiac failure secondary to AF, or a contraindication to anticoagulation due to a history of a life-threatening bleed or uncontrolled bleeding. Alternative anti-CLL therapy such as conventional chemotherapy or BCL2 inhibitor (e.g., venetoclax) may be used. BTKi dose modification is not warranted unless a patient has new onset, symptomatic grade 3 AF or haemodynamic instability. Early cardiology opinion should be sought for high-risk patients, ideally from a specialist cardio-oncology service. The side-effect of AF appears to be a class effect, albeit potentially of lower frequency in second generation BTKi (Table I). This hypothesis will be confirmed or refuted in the ongoing ALPINE (zanubrutinib vs. ibrutinib) and ACE-CL-006 (acalabrutinib vs. ibrutinib) RCTs.28 19TN 26 RR In patients with suspected paroxysmal AF undetected by standard 12 lead resting ECG recording, a 48-hour ambulatory ECG monitor, seven-day event recorder or 7–14 day ECG patch recording device should be used based on the frequency of suspected symptomatic episodes.29, 30 A confirmed diagnosis of AF should prompt a cardiology or cardio-oncology referral so that joint decision-making regarding the need for anticoagulation and/or need for interruption of BTKi, rate versus rhythm strategy and pharmacological/non-pharmacological treatment of symptoms can occur. Transthoracic echocardiography (TTE) should be performed to exclude concomitant structural cardiac abnormality and establish cardiac function. If ischaemic heart disease is suspected then a myocardial perfusion scan should be considered, avoiding dobutamine as the stressor. Both the CHA2DS2-VASc (Table II) and HAS-BLED (Table III) scores should be calculated in AF patients, to assess AF-related stroke and bleeding risks, respectively.31, 32 Limited evidence for these scores in cancer patients are available, and specifically in CLL patients receiving BTKi therapy.33-35 Although neither score is fully validated in the CLL patients per se, they are a simple and practical guide to aid risk assessment and decision-making regarding the requirement and safety of anticoagulation for stroke prophylaxis. The HAS-BLED score is the best validated bleeding risk score in AF, while the CHADS2 and CHA2DS2VASc are the best validated common stroke risk scores in AF.36 Both stroke and bleeding risks are dynamic, changing with ageing and incident comorbidities, risk re-assessment should thus be considered at every AF patient contact.37 In general, stroke prevention with oral anticoagulation (OAC) is recommended in patients with a CHA2DS2-VASc score of ≥ 2 in males or ≥ 3 in females, taking the potential cancer-related risks of serious bleeding into consideration.38, 39 Oral anticoagulation should preferably be with a direct oral anticoagulant (DOAC). The HAS-BLED score should be appropriately used to address the modifiable bleeding risk factors (e.g., uncontrolled blood pressure, labile international normalised ratios (INRs) if on vitamin K antagonists (VKA), excessive alcohol or concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, and to ‘flag up’ the high bleeding risk patients for early review and follow-up.40 Such an approach has been shown to mitigate modifiable bleeding risks, leading to lower bleeding rates and an increased OAC uptake, at least in a general AF population.41 A high HAS-BLED score is not a reason to withhold OAC, as the net clinical benefit balancing stroke reduction against serious bleeding is even greater with high HAS-BLED scores.42 There is a dearth of robust data in assessing the safety of combining BTKi and anticoagulants in CLL patients with an inherent high bleeding risk.43-45 Furthermore, substantial DDI occur between anticoagulants and BTKi via CYP3A4 and p-glycoprotein pathways.46 In an integrated analysis of 15 ibrutinib clinical trials including four RCTs, reported low-grade haemorrhage was common (35% vs. 15% in comparator arms) but the incidence of major haemorrhage (MH) was similar between the ibrutinib arm and comparator arm with longer follow-up (3·2 vs. 3·1 per 1000 person-months).47 In multivariate analysis, the use of antiplatelet or anticoagulant (AP/AC) was associated with an increased risk of MH in the total ibrutinib pool (HR, 1·7; 95% CI, 1·0–2·7; P = 0·041) but not in the total randomised pool.48 The risk of MH with the concomitant use of anticoagulants and/or antiplatelets (AP/AC) and ibrutinib from retrospective cohort studies was much higher (16–18%),21, 49, 50 underscoring the need for thejudicious use of these agents in the more vulnerable group.51 Each individual DOAC manifests a different risk-benefit profile, but we recommend the use of a label-adherent dose of DOAC due to its superior safety and efficacy relative to warfarin.52-59 Dabigatran is a reasonable option given the reduced potential of CYP3A4 interaction and availability of an antidote,60 although a specific reversal agent (adexanet alpha) for the oral factor Xa inhibitors is now available. Patients with AF and concomitant coronary disease are complex, and the topic has been recently reviewed.61, 62 The use of dual antiplatelets and OAC in combination should be used for a minimal duration in high thrombotic risk AF patients with a recent coronary stent; in high bleeding risk patients, dual therapy with OAC plus a P2Y12 inhibitor (clopidogrel) may be used judiciously.50, 62 Patients with a stable vascular disease can be managed with an OAC alone in long-term treatment (more than 12 months). The management of these niche patients should be discussed in a multidisciplinary team meeting (MDT) involving the treating haematologist, cardiologist and the haemostasis and thrombosis specialist. Rate control with beta blockade is recommended as the first-line approach in the symptomatic treatment of haemodynamically stable AF for several reasons. First, it is unlikely a rhythm-control strategy will be successful in the face of ongoing long term BTKi therapy. Second, there are multiple drug interactions between ibrutinib and antiarrhythmic agents used for rate and rhythm control (amiodarone, digoxin, verapamil and diltiazem) via CYP3A4 hepatic metabolism.63-65 Atrial fibrillation ablation targeting the pulmonary veins is not recommended as it rarely offers long term AF-free survival. If AF rate control is not possible pharmacologically, then atrioventricular node (AVN) ablation and cardiac resynchronisation therapy (CRT) pacemaker implantation may be considered for symptomatic fast AF when CLL-related prognosis is more than one year.66, 67 Recent studies have shown that the leading cause of death for AF patients already treated with appropriate anticoagulation is heart failure. This may include the direct myocardial toxicity of BTKis, hence the cornerstone of treatment should be directed at prevention and management of cardiac failure.68-70 Other associated cardiovascular risk factors and comorbidities should also be proactively managed, and a holistic and integrated approach to AF care such as the ABC pathway (i.e., ‘A’ Avoid stroke; ‘B’ Better symptom management and ‘C’ Cardiovascular and comorbidity risk optimisation) is recommended in the new 2020 ESC Guidelines for AF management, and importantly, ABC pathway-adherent care has been associated with improved clinical outcomes in general AF populations.39, 71 A suggested algorithm for management of BTKi related AF is outlined below (Fig 1 and Table IV). Isolated infrequent ventricular ectopics on ECGs may simply merit observation, especially if there are no/minimal symptoms and no other significant comorbidities. There is emerging evidence of a causal relationship between ventricular arrhythmia (VA) and sudden cardiac death (SCD) with ibrutinib in recent clinical trials (Table V) and an earlier case report.72 Longitudinal data (2009–2016) from US-based Comprehensive Cancer Registry revealed an increased idiopathic VA 100,000 person-year incidence rate of 596 compared to 48·1 in non-ibrutinib treated patients. This corresponds to a relative risk of 12·4 (P < 0·001) and an absolute excess risk of 548. The VA incidence rate rises to 617 per 100 000 person-year in ibrutinib patients with underlying coronary artery disease and heart failure. Over a median follow-up of 32 months, 11 patients developed symptomatic VA with a median time to event of 16 months.73 Cheng et al. reported 33 cases of ibrutinib-associated VA published through the FDA Adverse Events Reporting System between 2013–2017, the majority of which had no underlying cardiac history. The consequences of VA were serious: fatal in five patients, and a further 10 had life-threatening events.74 Based on this analysis, the FDA has updated the prescribing information for ibrutinib to include information about cardiac arrhythmias and ventricular tachyarrhythmias. A study of mouse models has shown that administration of a high dose of ibrutinib increased susceptibility to both AF and VA induced by intracardiac pacing.75 The rare, but real risk of VA should be included in routine patient consultations, and symptoms of palpitations, dizziness, and syncope must be investigated in detail, including echocardiography and cardiac rhythm monitoring.11 A recent alert from an unpublished clinical trial (FLAIR: a phase III, randomised controlled trial comparing the use of ibrutinib and rituximab [IR] versus FCR versus ibrutinib and venetoclax in treatment naïve CLL patients) reported that patients in the ibrutinib and rituximab (IR) arm have an elevated risk of sudden cardiac death if they were on ACE inhibitor treatment at study entry versus patients not on ACE inhibitors at study entry. Pending further data, patients currently receiving both ibrutinib and an ACE inhibitor should consider stopping the ACE inhibitor and changing to an alternative antihypertensive treatment. Decisions to stop ibrutinib should be clinically driven, with monitoring of disease status when ibrutinib is ceased. A range of other CV complications of ibrutinib have been reported including heart failure and cardiac conduction disease, but these are rarer than hypertension, AF and VAs. Consideration for a causative link if CLL patients present with HF or cardiac conduction disease whilst taking a BTKi should be considered. Bruton tyrosine kinase inhibitors has transformed the treatment landscape of CLL but led to an unfortunate rise in targeted therapy-associated CV complications, including hypertension, AF and ventricular arrhythmias with related SCD. A multidisciplinary input with haematologists and cardiologists is recommended to provide personalised, risk-adapted treatment whilst employing appropriate risk mitigation strategies in order to improve patient outcomes. Referral of complex cases to specialist cardio-oncology services, where available, is recommended, and further preclinical and clinical research is needed to understand the pathophysiology and strategies to prevent and manage BTKi-related CV toxicities. We include, with this good practice paper on management of cardiovascular complications of BTKi, an information sheet for use by Primary Care Physicians (Supplementary) to aid patient management. The BSH Haemato-Oncology task force members at the time of writing this Good Practice Paper were Dr Guy Pratt (chair), Dr Nilima Parry-Jones (secretary), Dr Matthew Cullen, Dr Toby Eyre, Dr Shireen Kassam, Dr Oiliver Miles, Dr Elspeth Payne, Dr Simon Stern and Dr Alastair Whiteway. The authors would like to thank them, the BSH sounding board, the BSH guidelines committee and the UK CLL forum executive members Dr John Riches, Dr Adrian Bloor, Dr Andrew Pettitt, Dr Ben Kennedy, Dr Helen McCarthy, Dr Helen Marr, Dr Feargal, Dr Alison McCaig Queen, Dr Helen Parry and Dr George Follows for their support in preparing this Good Practice Paper. The BSH paid the expenses incurred during the writing of this Good Practice Paper. All authors have made a declaration of interest to the BSH and Task Force Chairs which may be viewed on request. GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally. TM: speaker, advisory board or consultancy fees and/or research grants from Amgen, Bayer, Boehringer Ingelheim, Daichii-Sankyo and Novartis. ARL: speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Astra Zeneca, Amgen, Takeda, Roche, Janssens-Cilag Ltd, Clinigen Group, Eli Lily, Eisai, Bristol Myers Squibb, Ferring Pharmaceuticals, Boehringer Ingelheim, Myocardial Solutions, iOWNA Health and Heartfelt Technologies Ltd. PH: speaker, advisory board or consultancy fees and/or research grants from Astra Zeneca, Abbvie, Roche, Janssen Pharmaceuticals, Gilead and Pharmacyclics. SI: speaker fees, advisory board and educational grants from Gilead, Abbvie, Janssen and Takeda. NMC: speaker fees and travel support from Astra Zeneca and Abbvie. NPJ: speaker fees from Roche, educational grants from Janssen and AbbVie. PP: speaker, advisory board or consultancy fees and/or research grants from Novartis, Astra Zeneca, Abbvie, Roche, Janssens-Cilag Ltd. and Gilead. AS: Honoraria from Janssen, Roche, Abbvie, Astra Zeneca, Beigene. Unrestricted educational grants from Astra Zeneca and Janssen. In-kind contributions from Illumina, Oxford Nanopore Technology. RW: advisory board fees from Astra Zeneca, speaker fees from Janssen and Abbvie and educational grants from Janssen and Abbvie. CPST has no conflicts of interest to declare. Members of the writing group will inform the writing group Chair if any new pertinent evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be archived and removed from the BSH current guidelines website if it becomes obsolete. If new recommendations are made, an addendum will be published on the BSH guidelines website https://b-s-h.org.uk/guidelines. While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BSH nor the publishers accept any legal responsibility for the content of this guidance. 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