Hmm
"Peripheral vascular disease (PVD), commonly referred to as peripheral artery disease (PAD) or peripheral artery occlusive disease (PAOD) or peripheral obliterative arteriopathy, refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain." (Wikipedia article opening statement on this disease)
Contrast that with cerebrovascular and cardiovascular events as portrayed in recent FDA statements.
Ponatinib is a more potent inhibitor of VEGFR2 than cabozantanib, sorafenib and sufitinib. These 4 compounds are all associated with an early onset of hypertension followed by a slow build-up of serious cardiovascular events.
Here are some descriptions of the cardiovascular effects of other VEGFR2 inhibitors and a very brief comparison to nilotinib and ponatinib:
Sunitinib [SUTENT] [comment also on sorafenib] (from Schwandt et. al.) :
"VEGF inhibitors appear to have a class effect on the cardiovascularsystem including hypertension and cardiac
toxicity. While the precise mechanism is not clear, hypotheses include pressor stimulation, increased extracellular volume, decreased vascular compliance, increased vascular resistance, endothelial dysfunction and altered nitrous oxide metabolism...
With increased clinical experience and widespread use of sunitinib in patients who may have increased cardiac risk factors or prior cardiac events, information on cardiac toxicities,including heart failure and cardiomyopathy, associated with sunitinib therapy is accumulating (Table 3)...
It is important to note that these patients were prescreened (with inclusion criteria of left ventricular ejection fraction of greater than or equal to the lower limit of normal) and those who had cardiac dysfunction, defi ned as myocardial infarction, unstable angina, coronary or peripheral artery bypass graft, symptomatic congestive heart failure, transient ischemic attack, cerebrovascular accident or pulmonary edema within the past 12 months, were excluded from participation. Other cardiac adverse event data come from experience with sunitinib in patients with gastrointestinal stromal tumors (GIST) in which 11% patients had cardiovascular events including myocardial infarction or congestive heart failure.27 In this phase I/II study of patients with GIST, reductions of at least 10% in ejection fraction occurred in 28% patients treated with sunitinib. A separate retrospective review of 224 patients receiving sunitinib for 10 different malignancies identified 6 patients (3%), 4 of whom had RCC, who developed clinically significant congestive heart failure...
An observational study of sunitinib or sorafenib, another multi-targeted tyrosine kinase inhibitor, for treatment of
metastatic RCC identified 34% of patients as having a cardiac event, defined as increased cardiac enzymes (both symptomatic and asymptomatic), symptomatic arrhythmia, left ventricular dysfunction, or acute coronary syndrome, and 41% having electrocardiogram (ECG) changes...
It is important to assess a patient’s cardiac risk factors and cardiovascular history, and if concern for heart failure is identified, to obtain appropriate cardiac studies and monitor closely for changes in symptoms or functional decline with repeat cardiac evaluation. Congestive heart failure and left ventricular dysfunction generally, though not always, are reversible after discontinuation of sunitinib. Thus patient education and clinical vigilance are paramount to ensure early identifi cation of symptoms with timely clinical assessment and appropriate laboratory and cardiac evaluation in order to initiate aggressive medical intervention when clinically indicated...
Most studies have demonstrated sunitinib-induced increases in mean systolic and diastolic blood pressure, with variable incidences of hypertension ranging from 28% to 47% reported in studies...
Sunitinib can cause QT prolongation and should be given with caution in patients with history of QT prolongation or taking other medications which can prolong the QT interval. Medications affecting the QT interval include, but are not limited to, antiarrhythmics, antipsychotics, some antidepressants, certain antibiotics, some antiemetics, and methadone. Baseline electrocardiograms should be obtained in patients with relevant history or symptoms of arrhythmia. These patients should then be monitored with repeat ECG in each cycle of therapy and in whom clinical symptoms develop..."
From the sorafenib (NEXAVAR) label:
"Sorafenib
hypertension
17% all grades, 3 % grade 3
very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%
Cardiovascular: Common: congestive heart failure,*
Uncommon: hypertensive crisis*, myocardial ischemia and/or infarction.*
Hypertension usually occurred early in the course of treatment and was managed with antihypertensive therapy. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, as required. "
Comment from ga: Given that the median disease progression on renal carcinoma with these compounds is less than 1 year, these numbers will underestimate the cardiovascular effects of sunitinib and sorafenib compared to the 1-3 year readings now coming out for ponatinib....
Cabozantinib (medullary thyroid cancer drug COMETRIQ)
From the US Label:
"COMETRIQ
5.3 Thrombotic Events
COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).
Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
5.4 Wound Complications
Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.
5.5 Hypertension
COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. "
Nilotinib (TASIGNA):
"BLACK BOX WARNING:
WARNING: QT PROLONGATION AND SUDDEN DEATHS
See full prescribing information for complete boxed warning.
Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be
avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
...
ga: In the tables of data from clinical trials no mention of cardiovascular effects whatsoever.
"6.2 Additional Data from Clinical Trials
The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1% -10%), and uncommon (0.1%-1%) adverse reactions single events are captured as Unknown frequency. For adverse drug reactions listed under “Investigations”, very common events (=1/10) not included in Tables 5 and 6 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category
Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. "
Ponatinib label (data as of Dec 2012 or earlier, table greatly abbreviated):
Cardiac or Vascular disorders %s
CPAny, CP3/4, APAny, AP3/4
Hypertension (a) 68 39 71 36
Arterial ischemia (b) 13 7 12 6
Cardiac Failure (c) 6 4 6 2
ga |
