Table 1.

Study definitions and severity grades for pazopanib-related cardiovascular adverse events

Hypertension

Grade 1: Pre-hypertension (systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg)

Grade 2: Stage 1 hypertension (systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg); medical intervention indicated; recurrent or persistent (≥24 h); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg if previously within normal limits; monotherapy indicated

Grade 3: Stage 2 hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg); medical intervention indicated; more than 1 drug or more intensive therapy than previously used indicated

Grade 4: Life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated

Grade 5: Death

Heart Failure

Grade 1: Asymptomatic with laboratory (e.g., BNP) or cardiac imaging abnormalities

Grade 2: Symptoms with mild to moderate exertion

Grade 3: Severe with symptoms at rest or with minimal activity or exertion, intervention indicated

Grade 4: Life-threatening consequences; urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support)

Grade 5: Death

Electrocardiogram QT corrected interval (QTc) prolonged

Grade 1: QTc 450 – 480 ms

Grade 2: QTc 481 – 500 ms

Grade 3: QTc > = 501 ms on at least two separate ECGs

Grade 4: QTc > = 501 or >60 ms change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.

Atrial flutter

Grade 1: Asymptomatic, intervention not indicated

Grade 2: Non-urgent medical intervention indicated

Grade 3: Symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: Death

Peripheral ischemia

Grade 1: Not defined

Grade 2: Brief (< 24 h) episode of ischemia managed non-surgically and without permanent deficit

Grade 3: Recurring or prolonged (> = 24 h) and/or invasive intervention indicated

Grade 4: Life-threatening consequences; evidence of end organ damage; urgent operative intervention indicated

Grade 5: Death

Adapted from the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [29]. Per the CTCAE original document, a semi-colon indicates ‘or’ within the description of the grade. High-grade adverse events discussed in the text refer to any event assigned a grade of 3, 4, or 5

BP blood pressure, BNP brain natriuretic peptide, IV intravenous, QTc correct QT interval, ECG electrocardiogram