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international Heart and Vascular Disease Journal Volume 2, Number 4, November 2014
Journal of the Cardioprogress Foundation
REVIEW ARTICLES
Tyrosine kinase inhibitors and mammalian
target of rapamycin inhibitors related to
cardiac toxicity
Authors:
Majid Asawaeer, MD, Clinical Assistant Professor, Division of Medical Education, Midwestern University, 300 El Camino Real, Sierra Vista, AZ 85635, USA
Irbaz bin Riaz, MD, Internal Medicine Resident, Internal Medicine Department, University of Arizona,
Samuel Carli, MD, Internal Medicine Resident, Internal Medicine Department, University of Arizona,
Parminder Singh, MD, Assistant Professor, Department of Medicine, University of Arizona Cancer Center, University of Arizona, USA
Abstract Background
Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are emerging as one of the most commonly used targeted chemotherapeutic agents in cancer treatment. As with any other medication, adverse effects are not uncommon, especially cardiac adverse effects. Given the improved survival with the use of these medications, it is anticipated that primary care providers are going to manage them and deal with the adverse effects they developed from using these medications more frequently.
We reviewed comprehensively the cardiovascular adverse effects of the oral TKIs and mTORIs. In addition, we offered the current recommendations regarding management of these cardiovascular adverse effects to help the primary care providers manage these side effects.
Methods and Materials
A formal literature review of PubMed and ClinicalTrials.gov using the following terms: "sunitinib, sorafenib, pa-zopanib, temsirolimus, and everolimus" was used, with only phase 2 and 3 clinical trials in English language and published up to April 5, 2013 were consider in this review article.
Asawaeer M.*, Riaz I.bin, Carli S., Singh P.
USA
USA
Aim
* Corresponding author. Tel. (office): +1-520-251-8593. Fax: +1-520-417-3174. Email: masawaeer@gmail.com
Results
We found that hypertension is the most commonly reported adverse effect with the use of TKIs. Pazopanib was associated with the highest incidence of hypertension. 32% of the patients who received pazopanib developed grade 1/2 hypertension and 6% developed grade 3/4 hypertension. The use of oral mTORIs was associated more with endocrinological derangements including hypertriglyceridaemia and hyperglycaemia, especially with everolimus usage.
Conclusion
It is not uncommon to see cardiac adverse effects with the usage of oral TKIs and mTORIs.
Keywords
Oral TKIs, mTORIs, adverse effects, cardiac
Introduction
It is estimated now that two thirds of patients diagnosed with cancer today will experience at least 5-year survival [1]. This rise in cancer survivors has created new challenges to the primary care providers and internists as they deal more often with patients who are on oral chemotherapy including oral TKIs and mTORIs. In this review article, we will discuss the cardiac toxicity of three oral small molecule TKIs, which are sunitinib, sorafenib, and pazopanib as well as the mTORIs, temsirolimus and everolimus. In addition, we will tailor this review to help the primary care providers and internists manage these side effects.
In the era of targeted cancer chemotherapy, TKIs and mTORIs have been one of the most commonly used targeted chemotherapies. These novel medications play a key role in the transmission of growth, differentiation, and migration and apoptotic signals. However, the use of these agents is not without limitations, including the development of resistance, the financial cost and adverse effects associated with the use of these drugs.
Methods and Materials
A formal literature review of PubMed and Clinical-Trials.gov using the following terms: "sunitinib, sorafenib, pazopanib, temsirolimus, and everolimus" was done. And only phase 2 and 3 clinical trials in
English language completed and published up to April 5, 2013 were considered in this review article.
The TKIs (pazopanib, sorafenib, sunitinib)
There are two classes of tyrosine kinases, receptor tyrosine kinases (extracellular) and cellular tyrosine kinases (intra-cytoplasm or intra-nuclear). Fifty-six receptor tyrosine kinases are expressed, which can be subdivided into 19 families (AATYK, ALK, AXL, DDR, EGFR, EPH, FGFR, INSR, MET, MUSK, PDGFR, PTK7, RET, ROR, ROS, RYK, TIE, TRK and VEGFR family). In addition, 32 cellular tyrosine kinases are expressed, which can be subdivided into 11 families (ABL, ACK, CSK, focal adhesion kinase (FAK), FES, FRK, JAK, SRC-A, SRC-B, TEC and SYK family) [2]. See table 1.
Sunitinib works as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRB), vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib is currently approved for the treatment of gastrointestinal stromal tumour (GIST) after disease progression on or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC), and progressive well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease [3].
Table 1. A list of the oral TKI with their taget receptors and the currently approved targeted tumors
TKI Tyrosine kinase target Neoplasm (s) targeted
Sunitinib PDGFRa, PDGFRB, VEGFR1, VEGFR2, VEGFR3, KIT, FLT3, CSF1R, and RET GIST RCC pNET
Sorafenib KIT, FLT3, RET, VEGFR-1, VEGFR-2, VEGFR-3, PDGFRp CRAF, BRAF, and mutant BRAF of unresectable hepatocellular carcinoma, and advanced RCC
Pazopanib VEGFR-1, VEGFR-2, VEGFR-3, PDGFRa and -p, FGFR -1 and -3, KIT, ITK, Lck, and c-Fms RCC soft tissue sarcoma
Sorafenib works as an inhibitor of KIT, FLT3, RET, VEGFR-1, VEGFR-2, VEGFR-3, PDGFRfl, CRAF, BRAF, and mutant BRAF. Sorafenib is currently approved for the treatment of unresectable hepatocellular carcinoma and advanced RCC, and other trials for thyroid and brain tumours are underway [4].
Pazopanib works as an inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFRa and PDGFRB, fibroblast growth factor receptor (FGFR) -1 and -3, KIT, interleukin-2-inducible T-cell kinase (ITK), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane protein receptor tyrosine kinase (c-Fms). Pazopanib is currently approved for the treatment of patients with advanced RCC, and advanced soft tissue sarcoma who have received prior chemotherapy [5].
The mTORIs (everolimus, temsirolimus)
The mTORIs, including temsirolimus and everolimus, have seen a rapid rise in use for targeted chemotherapy [6]. Mammalian target of rapamycin (mTOR) is one of several kinases that are receptors involved in complex molecular pathways including those of cellular metabolism, growth, and proliferation. Initially discovered as an antibiotic, rapamycin was found to have immunosuppressing effects, shown to inhibit cellular proliferation and cell cycle progression. Continued research and development has led to development of additional mTORIs, which affect the same pathways, particularly with T-cell proliferation and with regard to cancer therapy, showing benefit with increased apoptosis of tumour cell lines and with diminishing tumour vascular angiogenesis [7].
Both temsirolimus and everolimus work in the same manner, all based off the initial immunosuppressive qualities noted of rapamycin, a novel antibiotic isolated from bacteria harvested from the island of Rapa Nui. Rapamycin was found to arrest cell growth and additional studies showed extensive immunosuppressive qualities, which led to creation of analogues that target the mTOR pathway, one that is instrumental in cell proliferation and growth [7]. It has been found that this mTOR pathway is often dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. These mTOR inhibitors bind to kinases and portions of this pathway, limiting angiogenesis (helpful in particularly vascular tumours) as well as inhibiting cellular proliferation.
Everolimus has been approved for the treatment of advanced kidney cancer after failure with approved TKIs; subependymal giant cell astrocytomas associated with tuberous sclerosis not amenable to surgery; pancreatic neuroendrocine tumors not amenable to
surgery; breast cancer in receptor positive, HER2-negative patients in conjunction with exemestane; and in prevention of organ rejection in both renal and liver transplant. Temsirolimus has been approved for use in advance RCC.
Cardiac toxicity
Cardiotoxicity is not uncommon side effect of targeted cancer chemotherapy. Commonly seen cardiac toxicities include: left ventricular (LV) dysfunction, hypertension, QTc prolongation, myocardial ischaemia, arrhythmia and peripheral oedema.
The NCI Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) was the adverse effects grading system in almost all the trials we reviewed. CTCAE classify the severity of adverse events (AEs) in 5 grades. In general, grade 1 encompasses mild AEs, grade 2 - moderate, grade 3 - severe, grade 4 - life-threatening or disabling, grade 5 - death related to AEs, respectively. Table 2 shows the definition of each cardiac AE observed with the use of the oral TKIs and mTORIs [8].
Sunitinib
LV ejection fraction (LVEF) / CHF
In the study for the use of sunitinib in patients with GIST [9], 11% of patients on sunitinib developed decline in LVEF; 59% of these patients required intervention with dose reduction and addition to anti-failure treatment; compared to 3% on placebo. In the same study, 2 (out of 209) patients on sunitinib and 2 patients on placebo died of sudden cardiac arrest. In a recent study by Demetri et al. [10], one patient experienced CHF (grade 2) who was managed clinically with anti-failure treatment.
In the study for the use of sunitinib in patients with RCC, 27% of patients on sunitinib developed decline in their LVEF (grade 1 and 2). Two patients (<1%) developed grade 3 CHF while on sunitinib [11]. Two phase 2 clinical trials, each reported grade 3 CHF in one patient out of total 38 patients [12] and 53 patients [13].
We can conclude from the above studies that the incidence of symptomatic decline in the EF, i.e. CHF, with the use of sunitinib is low. We recommend obtaining a baseline evaluation of EF if patients have any history of cardiac dysfunction. If patients develop any symptoms they can be managed with beta-blockers, diuretics, and ACE inhibitors. Metoprolol is safer as compared with carvedilol which may require monitoring of therapy as sunitinib may increase level of carvedilol. Lisinopril, enalapril and also losartan are all safe with sunitinib.
Table 2. The NCI Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) classification of the cardiac AE observed with the use of oral TKIs and mTORIs
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Prolonged QTc interval QTc >0.45-0.47 second QTc >0.47-0.50 second or s0.06 second above baseline QTc >0.50 second QTc >0.50 second with life-threatening signs or symptoms (e.g., arrhythmia, congestive heart failure (CHF), hypotension, shock syncope) or torsade de pointes Death
Atrial fibrillation (AF) Asymptomatic, intervention not indicated Non-urgent medical intervention indicated Symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker) Life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Death
Hypertension Asymptomatic, transient (<24 hrs) increase by >20 mmHg (diastolic) or to >150/100 if previously within normal limits (WNL); intervention not indicated Recurrent or persistent (s24 hrs) or symptomatic increase by >20 mmHg (diastolic) or to >150/100 if previously WNL; monotherapy may be indicated Requiring more than one drug or more intensive therapy than previously Life-threatening consequences (e.g., hypertensive crisis) Death
LV systolic dysfunction Asymptomatic, resting ejection fraction (EF) <60-50%; shortening fraction (SF) <30-24% Asymptomatic, resting EF <50-40%; SF <24-15% Symptomatic CHF responsive to intervention; EF <4020% SF<15% Refractory CHF or poorly controlled; EF <20%; intervention such as ventricular assist device, ventricular reduction surgery, or heart transplant indicated Death
Limb oedema 5-10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection; pitting oedema >10-30% inter-limb discrepancy in volume or circumference at point of greatest visible difference; readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour >30% inter-limb discrepancy in volume; lymphorrhea; gross deviation from normal anatomic contour; interfering with activities of daily living Progression to malignancy (i.e., lymphangiosarcoma); amputation indicated; disabling Death
Follow-up echocardiogram in 3-6 months based on symptom progression is recommended.
QT interval
Sunitinib related QT prolongation is a dose dependent and may lead to torsade de pointes. Upon reviewing all the phase 2 and 3 studies of sunitinib use, one study had one patient who developed electrocardiogram (ECG) QT prolongation without any clinical sequel [14]. The other one, 4 patients developed grade 1 prolonged QT; 2 patients developed grade 2; 2 patients developed grade 3. None of them developed torsade de pointes [15].
Incidence of clinically significant QT prolongation is very low (0.1%) with sunitinib use. It is recommended to have a baseline ECG prior to initiation. Patients with baseline QTc prolongation should be monitored closely. In patients with no prior abnormality we do not monitor QTc in our practice.
Hypertension
In a large randomized study of patients with RCC, who received sunitinib, 34% experienced hypertension. 13% of total patients developed grade 3 or more hypertension [11].
In the study for the use of sunitinib in GIST, grade 3 hypertension was reported in 4% of patients on sunitinib compared to none on placebo [9].
In the study for the use of sunitinib in pNET, 27% of patients experienced hypertension. Grade 3 hypertension was reported in 10% of total patients on sunitinib. Dose reduction or treatment delay controlled blood pressure (BP) in 80% of patients with hypertension in the RCC study and 86% of patients with hypertension in the pNET study [16].
The reported incidence of hypertension as an adverse effect to the use of Sunitinib was variable among the phase 2 and 3 clinical trials that we reviewed with the incidence of grade 1/2 ranging from (3-71)%. The incidence of grade 3 ranging from (0-17)% and no reported cases of grade 4 or 5. Please refer to figure 1. These patients who developed hypertension while on sunitinib were treated with standard antihypertensive therapy and strict surveillance with weekly visits and early intervention of hypertension [10,11,13,15, 17-29].
Significant number of patients developed hypertension while on sunitinib. Hypertension was treated with standard antihypertensive therapy and strict surveillance with weekly visits and early intervention
Hypertension incidence in patients who received sunitïnib
■^^^grade 1/2 ^^H^grade 3/4 ^^^»grade 4 ^^^All grades
Figure 1. A line-graph diagram showing the incidence of hypertension in paitents who received sunitinib as reported in the phase 2 and 3
clinical trials that we reviewed
of hypertension. None of the patients on sunitinib developed grade 4 or 5 hypertension.
We recommend use of metoprolol, amlodipine, lisinopril, losartan or hydrochlorthiazide based on physician choice. Therapy can be titrated as required. Dose reduction for hypertension is usually not required unless adequate antihypertensive are not able to control BP adequately.
Other reported cardiac AEs
No reported AF or hyperlipidaemia were reported with sunitinib use [12-15,17-22,24-36]. Peripheral oedema grade 1 and 2 was ranging between 13-55% in phase 2 and 3 studies [17,20,22].
In summary, the total number of patients from all the trials we reviewed and reported AEs were 2,795. These who developed hypertension grade 1/2 were 377 patients (13%) and these who developed hypertension grade 3/4 were 129 patients (5%). And none developed grade 5. In regard to the development of reduction in EF, 84 patients (3%) developed grade 1/2, and 14 patients (0.5%) developed grade 3/4, and none developed grade 5. 13 patients (0.5%) developed grade 1/2 clinical CHF, 2 developed grade 3/4, and one patient (~0%) developed grade 5 (Table 3).
Pazopanib
LVEF/CHF
In the study for the use of pazopanib in soft tissue sarcoma (STS) [37], LV dysfunction occurred in 11% of patients on pazopanib. One percent of patients on pa-
Table 3. A table showing the pooled data from all the sunitinib trials we reviewed. A total of 2,795 patients developed AEs. It is evident that hypertension grade 1/2 is the most common observed cardiac AE from the use of sunitinib
Grade 1/2 Grade 3/4 Grade 5
n % n % n %
Hypertension 377 13 129 5 0 0
Reduction in EF 84 3 14 0.5 0 0
Clinical CHF 13 0.5 2 ~0 1 ~0
zopanib in the STS trial had CHF. 88% of patients with LV dysfunction treated with pazopanib in the STS trial had concurrent hypertension which may contribute to the worsening LV function in patients at risk.
Though overall incidence of symptomatic LV dysfunction is low we recommend to carefully monitoring patients on pazopanib for clinical signs or symptoms of CHF in addition to obtaining a baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction including previous anthracycline exposure, and patients with history of coronary artery disease or CHF.
Beta-blockers (metoprolol, carvedilol), ACE inhibitors (lisinopril, enalapril), angiotensin II receptor blocker (ARB) (losartan), diuretics (hydrochlorothiazide (HCTZ)) and calcium channel blockers (Norvasc) are generally safe to use in these patients and do not interact with pazopanib adversely.
QT interval
In the studies for the use of pazopanib in RCC [38-42], QT prolongation was identified on routine ECG moni-
Figure 2. A 3D-column graph showing the incidence of hypertension in paitents who received pazopanib as reported in the phase 2 and 3
clinical trials that we reviewed
toring in 2% of patients. Torsades de pointes occurred in less than 1% of patients who received pazopanib.
In the randomized RCC and STS trials [37-46], 1% (3/290) of patients and 0.2% (1/240) of patients respectively, who received pazopanib had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 268 patients who received placebo on the two trials had post-baseline QTc values more than 500 msec.
None of the clinical trials we reviewed reported prolonged QT internal. This may be attributed to the fact that these studies didn't report AEs with incidence less than 10% unless they were grade 4 or 5.
Until we get more post marketing studies for pazopanib, we recommend periodic monitoring with on-treat-ment ECGs and electrolytes (magnesium, potassium).
Hypertension
In the study for the use of pazopanib in RCC [42], hypertension occurs early in the course of treatment (40% of cases occurred by day 9 and 90% of cases occurred in the first 18 weeks). Approximately 40% of patients who received pazopanib experienced hypertension. Grade 3 hypertension was reported in 4%
to 7% of patients receiving pazopanib. Approximately 1% of patients required permanent discontinuation of pazopanib because of uncontrolled hypertension.
The incidence of hypertension in the phase 2 and 3 studies we reviewed was similar to the incidence of hypertension in a company-sponsored study [42] as shown in figure 2.
Hypertension is a significant AE to the use of pazopanib. Therefore we recommend to treat patients with standard antihypertensive therapy. Drugs, considered safe with pazopanib, are lisinopril, HCTZ, am-lodipine and metoprolol. Patients should be monitored closely early during start of treatment and then with BP check at every visit. The side effect is generally considered to be reversible and BP may return to normal after cessation of therapy.
Other reported cardiac AEs
AF was reported in 6.7% in one trial [44]. Peripheral oedema was reported in 10% [39] in one study and in another 3% [47]. Chest pain was attributed to pazopanib usage. It was reported one patient with grade 1 chest pain and one patient with grade 3 chest pain [44]. 3% (1 patient) developed hyperlipidaemia in one trail [47], and 7 patients developed grade 1 hyperlipidaemia in another study [44].
In summary, the total number of patients who received pazopanib from all the trials we reviewed and reported AEs were 1,244. 400 patients (32%) developed hypertension grade 1/2 and 71 patients (6%) developed grade 3/4. None developed grade 5 hypertension.
Sorafenib
Hypertension
As seen in similar medications above, sorafenib most reported AE was hypertension. For example in one long-term study of patients from the TARGET trial, 95% of patients experienced some type of AEs and 25% experienced new-onset hypertension [48] (Table 4).
Table 4. A table showing the pooled data from all the sorafenib trials we reviewed. A total of 2,625 patients developed AEs in the trials which reported hypertension and a total of 198 patients developed AEs in the trials which reported arrhythmias
Grade 1/2 Grade 3/4 Grade 5
n % n % n %
Hypertension 364 13.8 103 4 0 0
Arrhythmias 11 5.5 0 0 0 0
In addition, as TKIs are often added to other chemotherapy regimens, one study showed a doubling of hypertension (12% vs. 6%) when this TKI was added to cisplatin and paclitaxel regimen in non-small cell lung cancer (NSCLC) [49].
Our recommendations are in line with treating hypertension with the use of the other TKIs. We recommend the use of metoprolol, amlodipine, lisinopril, losartan or hydrochlorthiazide based on physician choice and close monitoring with visits every 6-8 weeks until stable is prudent.
Arrhythmias
Another commonly reported AE of this medication was arrhythmias, typical seen as AF with an average incidence of 5.5% grade 1 or 2 (Table 4). A clinician will need to assess a multitude of factors, including hypertension and LV function (along the lines of Cha2DSVasc2) to determine if a patient will need anticoagulation.
Oedema
In the trials we researched with regard to sorafnib, there were relatively low rates of oedema as a reported AE. In only one trial, 3% of patients developed significant oedema edema which was thought to be secondary to medication use [50].
mTORIs
Cardiovascular side effects found in patients treated with mTORIs differed from those in the TKI population - anaemia, mucositis and rashes were commonly reported AEs and often endocrinological derangements were typical. Serum lipid profiles often worsened and hyperglycaemia was consistently an issue for many. In one study, dyslipidaemia was reported in nearly three-fourths of all patients [51].
Dyslipidaemia
Dyslipidaemia whether elevated in cholesterol or in triglycerides was the most reported event and the percentage affected was marked (Tables 5 and 6). While non-pharmacological interventions such as weight loss in obese patients, aerobic exercise, avoidance of concentrated sugars and medications that raise serum triglyceride levels and strict glycaemic control in diabetics should be suggested as first-line therapy, these metabolic derangements are more likely to be drug-induced and often a pharmacological approach may be needed. While there is evidence that cardiovascular risk is diminished by the use of statins regardless of the elevated lipid type, with moderate to severe elevations in triglycerides (>500 mg/dL [5.7 mmol/L]), our recommendations would be to start a therapy with a fibrate or, possibly, use of fish oil, however fibrates seem to have improved microvascular outcomes in recent trials. Once patient's triglycerides have been brought down to more acceptable levels, a statin can be considered as dual therapy for the overall dyslipidaemia present and as a reduction of cardiovascular risk. Nicotinic acid is not recommended, given the risk of worsening glycaemic control, one of the very side effects of these medications.
Hyperglycaemia
In clinical use of mTORIs, patients are likely to have an increase in serum glucose, which may in turn result in the need to increase the dose or initiate insulin or an oral hypoglycaemic agent. Many of the reviewed studies showed a significant increase in elevated serum glucose (Tables 5 and 6). Clinicians should be aware of this and the myriad complications this may cause. Treatment with mTORIs may be prolonged and thus elevated blood glucose may require closer vigilance. Changes in dietary habits would be recommended and an increase in oral hypoglycaemic dosages or initiation of insulin may be necessary.
Conclusion
With the continued improvements in targeted cancer therapies and recently with much decreasing costs of
Table 5. A table showing the pooled data from all the temsirolimus reviewed trials
Temsirolimus Grade 3/4 All
n (total number of patients who developed AEs) % n (total number of patients who developed AEs) %
Hypercholesterolemia 6 1498) 1.2 85 (498) 17
Hypertriglyceridaemia 20 (608) 3.2 125 (608) 20.5
Hyperglycaemia 32 (608) 5.2 1 1 1 (608) 18.2
Table 6. A table showing the pooled data from all the everolimus reviewed trials
Grade 3/4 All
Everolimus n (total number of patients who developed AEs) % n (total number of patients who developed AEs) %
Hypercholesterolaemia 0 0 633 (1943) 32.5
Hypertriglyceridaemia 2 (985) 480 (985) 49
Hyperglycaemia 66 (1 174) 5 303 (1174) 26
certain therapies, the cost drops from $5,000/month to about $175/month [52]. A primary care provider will begin to see more patients using these medications and with improved survival only to have the more insidious 'daily' effects causing problems. Overall, hypertension was the most commonly reported adverse effect and clinicians will need to encourage closer monitoring and implement aggressive antihypertensive regimens for their patients (Table 7). With closer monitoring, the other effects such as bleeding risk, anaemia and thrombosis may be picked up on sooner and mitigated too much benefit for these patients.
Conflict of interest: None declared References
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Table 7. Table showing a monitoring and intervention plan summary for ae primary care provider to guide him/her when
dealing with TKIs cardiac AEs
Clinical follow-up Sunitinib Sorafenib Pazopanib
CHF/Low LVEF • baseline evaluation of EF if risk factor • monitor for clinical signs and symptoms of CHF • baseline evaluation of EF if risk factor • monitor for clinical signs and symptoms of CHF • baseline evaluation of EF if history or risk factors • monitor for clinical signs and symptoms of CHF
QT prolongation • baseline evaluation monitoring with ECG and electrolytes based on symptoms • not significantly reported • baseline evaluation and periodic monitoring with ECG and electrolytes based on symptoms
Hypertension • treated as needed with standard antihypertensive therapy • dose reduction or delay treatment as clinically warranted • strict surveillance with weekly visits • discontinue in hypertensive crisis or if hypertension is severe and persistent despite antihypertensive therapy and dose reduction • treated as needed with standard antihypertensive therapy • dose reduction or delay treatment as clinically warranted • strict surveillance with weekly visits • discontinue in hypertensive crisis or if hypertension is severe and persistent despite antihypertensive therapy and dose reduction • treated as needed with standard antihypertensive therapy • dose reduction or delay treatment as clinically warranted • strict surveillance with weekly visits • discontinue in hypertensive crisis or if hypertension is severe and persistent despite antihypertensive therapy and dose reduction
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