Tyrosine kinase inhibitors and QTc intervals: A class effect.

Abstract

2590 Background: Tyrosine kinase inhibitors (TKIs) are reported to be associated with prolongation of the QTc interval on the ECG. QTc interval prolongation increases the risk for life threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and consist of small patient numbers. Methods: We screened all patients from 4 centers in the Netherlands and Italy, who were treated with TKIs. To evaluate the effects of TKIs on the QTc interval we investigated ECGs prior to and during treatment with sunitinib, vemurafenib, sorafenib, pazopanib, imatinib, erlotinib, lapatinib or gefitinib. All ECGs were reviewed by a single cardiologist (CN). Outcomes of this study were quantitative change in QTc interval (ΔQTc) after start of TKI treatment and chance of becoming a high risk individual, defined as QTc ≥ 470 milliseconds (ms), adjusted for risk factors such as for K+/Ca2+levels, co-medication, age, gender and co-morbidity. Results: A total of 363 patients had ECGs taken prior to and during TKI treatment and were therefore eligible for the analyses (see Table). In the entire group, start of TKI resulted in a significant increase in QTc interval (QTcbaseline = 401 ms vs QTctreatment= 415 ms, p < 0.0001). After correction for possible confounders (site, tumor type, ethnicity, TKI, time between ECGs), sunitinib, vemurafenib, sorafenib, imatinib and erlotinib showed a significant increase in QTc interval after start of treatment (p < 0.01). Especially patients treated with vemurafenib are at increased risk of having QTc ≥ 470 ms (p < 0.05). Conclusions: These observations show that most TKIs give rise to a significant increase in QTc interval. In vemurafenib treated patients, the incidence of patients who are at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, frequent ECG controls in patients treated with TKIs are required. TKI N QTc (ms) p-value N QTc ≥ 470 ms ΔQTc ≥ 30 ms Baseline Treatment Baseline Treatment N Whole 363 401 415 0.0001 6 21 76 Sunitinib 110 393 406 0.0001 1 3 22 Vemurafenib 67 401 427 0.0001 1 8 23 Sorafenib 52 400 410 0.0015 1 2 11 Pazopanib 46 402 412 0.0792 1 2 6 Imatinib 41 410 425 0.002 1 1 8 Erlotinib 21 412 421 0.0043 0 2 3 Lapatinib 16 413 414 0.9822 1 1 1 Gefitinib 10 403 409 0.92 0 2 2