Anthracyclines |
Cardiac toxicity associated with anthracyclines |
Antimetabolites |
Capecitabine |
Thought to be coronary artery vasospasm |
Ranges from 3-9%r
Commonly occurs in cycle one, but can occur at any stage of treatment
|
Most frequent clinical manifestation is angina (4.6%)r
Other symptoms include MI, arrhythmias and death
|
Previous cardiac toxicity during chemotherapy with fluorouracil
Concurrent chemotherapy with cardiotoxic drugs
Presence of coronary artery disease
Prior radiation therapy
|
Cease capecitabine, referral to a cardiologist for symptomatic treatment may be necessary
Re-challenge is controversial and generally not recommended
Cardiac symptoms recur in up to 62% of patients and are not influenced by dose reduction or medical prophylaxis with vasodilatorsr
|
Fluorouracil |
Thought to be coronary artery vasospasm |
Ranges from 1-19%r
The mean onset of cardiac symptoms is 3 days (range 2 to 5 days), with the majority of patients experiencing angina within hours of administrationr
|
Most common symptom is chest pain (non specific or angina) normally associated with ECG changes
Other symptoms include angina (45%), MI (22%), arrhythmias (23%), acute pulmonary oedema (5%), cardiac arrest (1.4%) and pericarditis (2%)r
|
Method of administration (infusional over bolus)
Presence of coronary artery disease
Prior radiation therapy
Prior chemotherapy with anthracyclines and other cardiotoxic regimens
|
Cardiac symptoms usually resolve with cessation of fluorouracil
Referral to a cardiologist for symptomatic treatment may be necessary
Re-challenge is controversial and generally not recommended
Cardiac symptoms recur in up to 47% of patients and may occur with lower doses or different schedulesr
|
Microtubule targeting agents |
Paclitaxel/docetaxel |
Impaired cell division |
Transient asymptomatic bradycardia occurred in 29% of patients in a small phase II trialr
MI has been reported in ~5% of patients in a retrospective studyr
|
Bradycardia and heart block are the most frequent cardiac effects although usually asymptomatic
Other symptoms include arrhythmias and myocardial ischaemia
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Cardiomyopathy has been reported when combined with doxorubicin |
Note: nab-paclitaxel has the same cardiac toxicity profile as the non-albumin bound formulation |
Alkylating agents |
Cyclophosphamide |
Direct oxidative cardiac injury
Impaired protein synthesis
|
Ranges from 7-28% and normally occurs within 10 days after administration of the first doser |
Acute cardiomyopathy including HF, acute pericarditis and haemorrhagic myocarditis |
Dose related (>150 mg/kg and 1.5 g/m2/day)r
Correlated to prior anthracycline or mitozantrone therapy and mediastinal radiation therapy
|
Note: not cumulative dose related
Ifosfamide can induce the onset of HF, with a dose-response trend (doses >12.5 g/m2)r
|
Monoclonal agents |
Bevacizumab |
Uncontrolled hypertension and inhibition of VEGF/VEGFR signalling |
9.2% hypertension 3.8% thromboembolic eventsr
Can occur at any time throughout treatment
|
HF or arterial thromboembolic events (ATEs) or venous thromboembolism and severe hypertension |
Elderly patients
Prior arterial thromboembolic event
|
Bevacizumab should be discontinued in patients who develop severe ATEs during treatment |
HER-2 monoclonal antibodies targeted agents |
Cardiac toxicity associated with HER-2 targeted agents |
Tyrosine kinase inhibitors (TKIs) and other targeted agents |
Crizotinib |
Unknown |
31% sinus bradycardiar |
Sinus bradycardia
QTc prolongation
|
Heart failure, bradyarrhythmias, electrolyte abnormalities, or patients who are taking other medications known to prolong the QTc interval or that cause bradycardia
Use with caution in patients who are receiving other drugs that inhibit CYP3A4
|
Dose adjustment for symptomatic bradycardia and QTc prolongationr
Monitor heart rate and blood pressure regularly during treatment
Consider baseline ECG for patients with risk factors or that develop bradycardia
|
Dasatinib |
Inhibition of the hERG K+ channel and action potential prolongation has the potential to prolong cardiac ventricular repolarisation
|
7% cardiac conduction disturbance
4% ischaemic heart disease (IHD)
<4% cardiac disease
<4% pericardial effusionr
|
CHF/cardiac dysfunction
Pericardial effusion
IHD
Arrhythmias
QT prolongation
HT
|
Pre-existing cardiac disease, bradycardia, electrolyte imbalance or taking medications which prolong the QTc interval |
Patients with risk factors or history of cardiac disease should be monitored carefully for signs or symptoms of cardiac dysfunction and should be treated appropriatelyr |
Ibrutinib |
Unknown |
1-9% atrial fibrillation (AF)r |
Atrial flutter and fibrillation
Mild QTc shortening |
Cardiac risk factors, acute infections or prior history of atrial fibrillation
Unknown clinical relevance |
The development of arrhythmic symptoms or new onset dyspnoea should be clinically evaluated and, if indicated, an ECG performedr
For persistent AF, consider risks/benefits of treatment and follow dose modification guidelinesr
|
Imatinib |
Impaired cell signal transduction |
~1-2% HF
0.7% cardiac failure and LVDr
|
QTc prolongation
|
Elderly age, dose |
Monitor for signs and symptoms of HF |
Lapatinib |
Unknown |
1.6% reduced LVEF by at least 20%r
0.2% symptomatic HFr
|
Asymptomatic decline in LVEF or rarely symptoms of a decline in cardiac function
QTc prolongation
|
Female gender, elderly age, myocardial ischaemia/infarction, HF, electrolyte imbalance, bradycardia and medications which prolong the QTc intervalr |
Dose adjustment or discontinuation of therapy may be necessary if QTc prolongation occurs or decrease in LVEFr
|
Lenvatinib |
Unknown |
72.8% HT
3.8% venous thromboembolic eventsr
2.7% arterial thromboembolic eventsr
8.8% QTc prolongation
1.5% pulmonary embolismr
<1% MI/AMI, right bundle branch block, cerebral ischaemia, cerebrovascular accident, ischaemic stroke, transient ischaemic attack
|
HT
Venous thromboembolism (VTE) or arterial thromboembolism (ATE)
QTc prolongation
|
Congenital long QT syndrome, electrolyte imbalance or taking medications which prolong QTc intervalr |
Blood pressure should be monitored after 1 week of treatment, then every 2 weeks for the first 2 months, and monthly thereafter
Do not administer in patients with QTc interval >450 milliseconds (ms). Dose interruption in patients who develop QTc interval >500 ms until QTc returns to <450 ms
Periodic monitoring of ECG and electrolytes, correction of electrolyte imbalances prior to commencement
|
Nilotinib |
Potential to prolong cardiac ventricular repolarisation |
10-11% HT
5-9% IHD
1-3% cerebral ischaemiar
|
HT
IHD
Cerebral ischaemia
Arrhythmias
QTc prolongation
|
Pre-existing cardiac disease, bradycardia, hypokalaemia or taking medications which prolong the QTc interval
Concomitant treatment with potent CYP3A4 inhibitors
|
ECG at baseline, after 7 days of treatment, then as clinically indicatedr
Monitor for hypokalaemia or hypomagnesaemia and correct deficienciesr
Use with caution in uncontrolled or significant cardiac disease
Withhold if QTc exceeds 480 msecr
|
Ponatinib |
Unknown |
53-71% HT
>23% vascular occlusion
12% MI
8% HF (including fatal)r
|
HT
Left ventricular dysfunction
Vascular occlusion
QTc prolongation
Arrhythmias
|
Increasing age
Increasing dose
Prior history of ischaemia, hypertension, diabetes or hyperlipidaemiar
|
Assess all patients' cardiovascular status before commencing treatment and manage cardiovascular risk factorsr
Blood pressure should be monitored at each clinic visitr
Monitor for signs and symptoms of HF and treat as clinically indicatedr
Interrupt or stop ponatinib for new or worsening HFr
|
Regorafenib |
Possibly the inhibition of VEGF receptors |
30% HT typically within the first cycle of treatmentr |
Myocardial ischaemia and infarction
Arterial hypertension
|
Uncontrolled hypertension |
Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle or more frequently as clinically indicatedr |
Sorafenib |
Possibly the inhibition of RAF1, PDGFRs and VEGF receptors |
17-43% hypertension
2.9% acute coronary syndrome including MIr
Hypertension normally occurs early in treatment
|
Hypertension is the most common cardiac sign
QTc prolongation
|
Pre-existing cardiac disease, bradycardia, electrolyte imbalance or taking medications which prolong the QTc interval |
Blood pressure should be monitored and treated (if required) throughout treatmentr |
Sunitinib |
Mechanism unknown, may be inhibition of a number of receptors including VEGF, PDGF, c-Kit, FLT3, CSF1R and RET |
28% asymptomatic LVEF reduction of at least 10%r
11% cardiovascular events including MI
47% hypertensionr
|
Most commonly HT
Arrhythmias, LVEF dysfunction, HF, acute coronary syndrome have been reported
QTc prolongation
|
Pre-existing cardiac disease, bradycardia, electrolyte imbalance or taking medications which prolong the QTc interval
Concomitant treatment with potent CYP3A4 inhibitors
|
Blood pressure should be monitored and treated (if required)
Monitor for clinical signs and symptoms of CHF
Consider LVEF monitoring
|
Trametinib |
Unknown |
11% cardiomyopathy (decrease in LVEF)r |
LVEF dysfunction |
Pre-existing cardiac disease |
Monitor LVEF prior to commencement, after one month and three monthly thereafter
Withhold treatment if LVEF decreases by 10% from pre-treatment level to less than lower limit of normal
Permanently discontinue for symptomatic HF or decrease in LVEF >20%rr
|
Vandetanib |
Unknown |
32% HT
14% QTc prolongation
<1% ischaemic cerebrovascular events, arrhythmias, heart failure
Torsades de Pointesr
|
HT
QTc prolongation
|
Pre-existing cardiac disease
Congenital long QT syndrome, electrolyte imbalance or taking medications which prolong the QTc interval
|
Blood pressure should be monitored regularly in the first few months of treatment and control as appropriate
Do not administer in pts with QTc interval > 450 milliseconds (ms)
Dose interruption in pts who develop QTc interval > 500 ms until QTc returns to <450 ms
ECG and electrolytes (potassium, calcium and magnesium) should be performed at baseline, 1, 3, 6, and 12 weeks after starting treatment and every 3 months for at least a year thereafter
|
Immune modulators |
PD1/PDL1 and CTLA4 checkpoint inhibitors – class effectrr
Ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab
|
Immune response activation:
- PD-1 is known to protect against tissue inflammation and myocyte damage
- PD-L1 may regulate potentially autoreactive lymphocytes at effector sites, thus playing a role in limiting activities of T cells in the heart, where PD-L1 is highly expressed
|
Overall incidence of cardiac AEs is <1%
Variable onset: Early myocarditis (0.09%) can occur at median onset 17 days after first treatment
Combination therapy with dual-immunotherapy associated with more severe and frequent myocarditis than single-agent immunotherapy
|
Myocarditis, myositis, heart failure, pericarditis, heart block, arrhythmias, myocardial fibrosis, cardiomyopathy |
Pre-existing cardiac/pre-existing autoimmune disease |
Withhold therapy
Start high dose steroids (methylprednisolone intravenously)
Echocardiogram
Cardiac MRI if stable enough
Consider endomyocardial biopsy (EMB) if needed and feasible
ATG or IVIg and plasma exchange for unstable patients
Consider alternative immunosuppressive therapy if high grade myocarditis on EMB or failure to respond to steroids e.g. infliximab (if no HF), mycophenolate mofetil
Appropriate treatment of HF/cardiomyopathy
If unstable consider heart failure consult to discuss mechanical support
|
Cyclin-dependent kinase 4/6 inhibitors |
Ribociclibrrr |
PI3K signalling inhibition, with effects on many ion channels |
Median onset 15 days, occurring in 3.3% |
QTc interval prolongation |
Pre-existing cardiac disease |
ECG monitoring QTc at baseline, mid-cycle 1 and beginning of cycle 2
If QTcf 480-500 ms: Interrupt dose until recovery to <481 ms. If first occurrence: resume at same dose
If recurs: resume at next lower dose
If QTcf >500 ms: Interrupt dose until recovery <481 ms then resume at next lower dose
Permanently discontinue if QTcf interval prolongation is either >500 ms or >60 ms change from baseline AND associated with Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope or signs/symptoms of serious arrhythmias
Monitor electrolytes prior to each of the first 6 cycles
|
Other |
Arsenic |
Unknown |
74% QTc interval prolongationr |
QTc interval prolongation
Torsade de pointes
|
Heart failure, bradyarrhythmias, electrolyte imbalance, or taking other medications known to prolong the QTc interval or that cause bradycardia |
Maintain potassium concentrations above 4.0 mmol/L, magnesium concentrations above 0.8 mmol/L and QTc less than 500 msec.
Monitor twice weekly (more frequently in unstable patients) during treatmentr
|