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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Sep 19;78(4):748–762. doi: 10.1111/bcp.12387

Congestive heart failure risk in cancer patients treated with vascular endothelial growth factor tyrosine kinase inhibitors: a systematic review and meta-analysis of 36 clinical trials

Wei-Xiang Qi 1,✉, Zan Shen 1, Li-Na Tang 1, Yang Yao 1
PMCID: PMC4239969  PMID: 24661224

Abstract

Aims

Congestive heart failure (CHF) associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has emerged as a relevant problem in clinical and scientific communities. We performed an up-to-date, comprehensive meta-analysis to determine the overall incidence and risk of CHF in cancer patients receiving VEGFR-TKIs.

Methods

The databases of PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology up to August 31 2013 were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.

Results

A total of 10 553 patients from 36 clinical trials were included. The overall incidence of all grade and high grade CHF associated with VEGFR-TKIs was 3.2% (95% CI 1.8%, 5.8%) and 1.4% (95% CI 0.9%, 2.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all grade (OR 2.37, 95% CI 1.76, 3.20, P < 0.001) and high grade (OR 3.51, 95% CI 1.74, 7.05, P < 0.001) CHF. In subgroup analyses, the risk of CHF did not significantly vary with tumour types (P = 0.071 for all grade; P = 0.72 for high grade) and VEGFR-TKIs (P = 0.55 for all grade; P = 0.99 for high grade). Meta-regression indicated that CHF might possibly occur early in the treatment of VEGFR-TKIs. No evidence of publication bias was observed.

Conclusion

The use of VEGFR-TKIs is associated with a significantly increased risk of developing congestive heart failure in cancer patients. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies.

Keywords: congestive heart failure, meta-analysis, VEGFR-TKIs

Introduction

In recent years, anti-angiogenesis targeted therapies have proven to be a promising therapeutic strategy in patients with cancer [1,2]. Several newly-developed agents that target the vascular endothelial growth factor (VEGF) signalling pathway, such as the small molecular VEGF receptor inhibitors (e.g. sunitinib, sorafenib, vandetanib, pazopanib, axitinib, cediranib, tivozanib, regorafenib, cabozantinib, brivanib and ramucirumab) and the anti-VEGF monoclonal antibody bevacizumab, have shown encouraging treatment benefits in patients with various types of solid tumours [3–16]. However, as the VEGF pathway is not only essential for normal growth and development, but also critical to physiological response and homeostasis in many organs and functions in adulthood [17], a variety of adverse effects are anticipated with pharmacological blockage of this pathway. Indeed, the clinical adverse event profiles are extensive [18–20]. The adverse effects attributed to VEGF inhibition include hypertension, arterial thromboembolic events (ATEs), proteinuria or renal dysfunction, wound complications, haemorrhage and gastrointestinal perforation, which have been systematically defined in previous studies [21–36].

Congestive heart failure (CHF) is a rare but serious adverse event associated with VEGF-targeted agents. A previous meta-analysis demonstrated that the use of bevacizumab significantly increased the risk of CHF when compared with controls (relative risk (RR) 4.74, 95% CI 1.66, 11.18, P = 0.001) [37]. The VEGFR-TKI agent sunitinib has been also associated with an increased risk of CHF in one meta-analysis [38]. However, that report has several limitations. Although the meta-analysis included 16 clinical trials, most of these were single arm trials, and only four randomized controlled trials (RCTs) were included in the meta-analysis and thus the power to investigate the risk of CHF with sunitinib was small and the combined results might have been affected by a single large RCT. In addition, several newly developed VEGFR-TKIs which share a similar spectrum of target receptors with sunitinib might be also associated with increased risk of developing CHF. Indeed, CHF related to these drugs has been sporadically reported in recent clinical trials [7,39–43]. However the contributions of these newly developed VEGFR-TKIs to CHF are still unknown. As a result, we conducted this meta-analysis of all available clinical trials to determine the overall incidence and risk of CHF associated with VEGFR-TKIs.

Methods

Data sources

We conducted an independent review of citations from PubMed between January 1 1966 and August 31 2013. Keywords were sorafenib, nexavar, BAY43-9006, sunitinib, sutent, SU11248, pazopanib, votrient, GW786034, vandetanib, caprelsa, ZD6474, axitinib, cediranib, tivozanib, regorafenib, cabozantinib, brivanib, ramucirumab, clinical trials and cancer. The search was limited to prospective clinical trials published in English. The search strategy also used text terms such as angiogenesis inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitors to identify relevant information. We also performed independent searches using Web of Science databases between January 1 1966 and August 31 2013, to ensure that no clinical trials were overlooked. Additionally, we searched the clinical trial registration website (http://www.ClinicalTrials.gov) to obtain information on the registered prospective trials. We also searched abstracts and virtual meeting presentations from the American Society of Clinical Oncology (http://www.asco.org/ASCO) conferences that took place between January 2004 and January 2013. Reference lists from relevant primary studies and review articles were also examined to find additional publications. Each publication was reviewed and in cases of duplicate publication only the most complete, recent and updated report of the clinical trial was included in the meta-analysis.

Study selection was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [44]. Clinical trials that met the following criteria were included: (1) prospective phase II and III trials, expanded access protocols (EAPs), (2) participants assigned to treatment with VEGFR-TKIs (alone or in combination at any dosage or frequency) and (3) available data regarding events or incidence of CHF and sample size. Phase I trials were excluded because of inter-study variability in drug dosing as well as the small number of patients in these trials.

Data extraction

Data abstraction was conducted independently by two investigators (WXQ and ZS), and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: first author's name, year of publication, trial phase, number of enrolled subjects, treatment arms, number of patients in treatment and controlled groups, underlying malignancy, median age, median treatment duration, median progression-free survival, number of CHF events, name and dosage of the VEGFR-TKIs agents. We considered the reporting of left ventricular ejection fraction (LVEF) decline or dysfunction and CHF not otherwise specified as CHF-related adverse events. Adverse events of all and high grade (≥ grade 3), as recorded according to the National Cancer Institute's common terminology criteria for adverse events (version 2 or 3), were extracted for analysis [45]. The quantitative five point Jadad scale was used to assess the quality of the included RCTs based on the reporting of the studies' methods and results [46].

Statistical analysis

The principal summary measures were incidence, odds ratio (OR) and corresponding 95% confidence intervals (CIs). For the calculation of incidence, the number of patients experiencing CHF and total number of patients treated with VEGFR-TKIs were extracted from the safety profiles of all selected clinical trials; the proportion of patients with CHF and 95% CI were derived for each study. We used the Peto method to calculate the ORs and 95% CIs because this method provided the best CI coverage and was more powerful and relatively less biased than the fixed or random effects analysis when dealing with low event rates [47]. Between study heterogeneity was estimated using the χ2-based Q statistic [48]. Heterogeneity was considered statistically significant when Pheterogeneity < 0.1. If heterogeneity existed, data were analyzed using a random effects model. In the absence of heterogeneity, a fixed effects model was used. A statistical test with a P value less than 0.05 was considered significant. To assess the stability of the results, sensitivity analysis was carried out by sequential omission of individual studies. Additionally, to test whether effect sizes were moderated by differences in the length of treatment, we had carried out meta-regressions with differences in the median length of experimental treatments (expressed in months) as a predictor and the odds ratio as a dependent variable. The presence of publication bias was evaluated by using the Egger tests. All statistical analyses were performed by using Stata version 12.0 software (Stata Corporation, College Station, Texas, USA) and Open Meta-Analyst software version 4.16.12 (Tufts University).

Results

Search results

Our search yielded 927 clinical studies relevant to VEGFR-TKIs (sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, tivozanib, regorafenib, cabozantinib, brivanib and ramucirumab). After excluding review articles, phase I studies, case reports, meta-analyses and observation studies (Figure 1), we selected 36 clinical trials, including eight phase III, 27 phase II trials and one extended access programme (EAP) trial, for the purposes of analysis (Table 2). A total of 10 553 patients from 36 clinical trials were included for analysis. The characteristics of patients and studies are listed in Table 1. According to the inclusion criteria of each trial, patients were required to have adequate hepatic, renal and haematological function. Underlying malignancies included renal cell cancer [14,15,40,49–57] (12 trials), breast cancer [58–63] (six trials), sarcoma [7,39,64,65] (four trials), thyroid cancer [42,66,67] (three trials), gastro-intestinal stromal tumour (GIST) [13,68] (two trials), primitive neuroectodermal tumour (PNET) [69] (one trial), hepatocellular carcinoma [70] (one trial), pancreatic cancer [43] (one trial), cervical cancer [71] (one trial), colorectal cancer (one trial) [16], gastric cancer [41] (one trial), prostate cancer [72] (one trial), non-small cell lung cancer (NSCLC) [73] (one trial) and advanced neuroendocrine tumours [74] (one trial). The most commonly reported adverse event meeting our criteria was LVEF decline (16 studies), with congestive failure in 12 studies and LV dysfunction in eight studies. The quality of 15 included RCTs was high. Ten trials had Jadad scores of 5 and four trials did not mention the blinding of allocation clearly in the randomization process and thus had Jadad scores of 3. Another one trial had a Jadad score of 2.

Figure 1.

Figure 1

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Selection process for prospective clinical trials included in the meta-analysis

Table 2.

Incidence of CHF based on prespecified subgroups

Grades Subgroup Number of trials CHF events Total number of patients I2 (%) Incidence (95% CI) P for group difference
All grade Overall 27 174 6903 90 3.2 (1.8, 5.8) NA
Tumour types
 RCC 10 119 5228 96 4.5 (1.4, 13.6) 0.52
 Non-RCC 17 55 1675 63 3.0 (1.7, 5.1)
VEGFR-TKIs
 Sunitinib 14 136 5638 94.3 3.6 (1.4, 8.8) 0.025
 Sorafenib 4 9 269 66.2 3.4 (0.9, 12.5)
 Axitinib 2 3 114 0 2.7 (0.9, 8.1)
 Cediranib 2 6 99 48.0 5.9 (1.5, 20.6)
 Vandetanib 1 1 231 0 0.4 (0.1, 3.0)
 Pazopanib 3 18 314 0 6.1 (3.9, 9.5)
Ramucirumab 1 1 238 0 0.4 (0.1, 2.9)
Phase of trials
 Phase II 21 45 1240 32.8 4.5 (3.1, 6.6) 0.42
 Phase III 6 129 5663 97.8 2.4 (0.5, 10.2)
High grade Overall 26 48 6896 58 1.4 (0.9, 2.3) NA
Tumour types
 RCC 10 35 5219 0 1.8 (0.7, 4.4) 0.55
 Non-RCC 16 13 1677 96 1.3 (0.8, 2.0)
VEGFR-TKIs
 Sunitinib 15 37 5724 74.2 1.5 (0.7, 3.1) 0.72
 Sorafenib 3 3 238 0 1.5 (0.5, 4.5)
 Axitinib 1 1 52 0 1.9 (0.3, 12.4)
 Cediranib 2 2 99 0 2.0 (0.5, 7.7)
 Vandetanib 1 1 231 0 0.4 (0.1, 3.0)
 Pazopanib 3 4 314 0 1.5 (0.6, 3.7)
 Ramucirumab 1 0 238 0 0
Phase of trials
 Phase II 19 16 1147 97.4 2.1 (1.4, 3.3) 0.18
 Phase III 7 32 5749 0 0.9 (0.3, 2.8)
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RCC, renal cell carcinoma; NA, not available.

Table 1.

Baseline characteristics of the 36 trials included in the meta-analysis (n = 10 553)

Authors/phase Histology Patients enrolled Treatment arm Number for analysis Median age (years) Median treatment duration (months) Median PFS/TTP (months) Median OS (months) Number of high grade CHF Reported events Jadad score
Demetri et al. [13]/III* GIST 312 Sunitinib 50 mg d1−1-28, q6w 202 58 1.9 6 NR 3 LVEF decline 5
Placebo 102 55 1 1.5 NR 0
Motzer et al. [15]/III* RCC 750 Sunitinib 50 mg d1−1-28, q6w 375 62 6 11 NR 13 LVEF decline 3
INF 9 MUI 3 times weekly 360 59 4 2 NR 4†
Barrios et al. [58]/III* HER-2 negative BC 482 Sunitinib 37.5 mg qd + capecitabine 1 250 mg m−2 d1–14 bid po, q3w.§ 238 53 2 2.8 15.3 1 Congestive failure 3
Capecitabine 1 250 mg m−2 d1–14 bid po, q3w 244 53 2 4.2 24.6 0
Abou-Alfa et al. [70]/II* HCC 96 Doxorubicin + sorafenib 400 mg bid po qd 47 66 4 6 13.7 1 LV dysfunction 5
Doxorubicin + placebo 49 65 1.9 2.7 6.5 0
Raymond et al. [69]/III* PNET 171 Sunitinib 37.5 mg qd po 86 56 4.6 11.4 NR 2 Cardiac failure 5
placebo 85 47 3.7 5.5 NR 0
Kindler et al. [43]/II* Pancreatic carcinoma 632 Axitinib 5 mg bid po + gemcitabine 1000 mg m−2 d 1, 8, 15 q4w. 314 61 2.8 4.4 8.5 1 Cardiac failure 5
Placebo + gemcitabine 1000 mg m−2 d1, 8, 15. q4w. 316 62 2.3 4.4 8.3 0
Bergh et al. [59]/III* MBC 593 Sunitinib 37.5 mg qd po q3w. + docetaxel 296 54 6.1 8.6 24.8 1 Cardiac failure 5
Placebo + ocetaxel 297 56 4.2 8.3 25.5 0
Mulders et al. [57]/II* RCC 71 Cediranib 45 mg qd po 53 60 12 12.1 NR 1 LVEF decline 5
placebo 18 61 NR 2.8 NR 0
Wells et al. [42]/III* Thyroid cancer 331 Vandetanib 300 mg qd po 231 50.7 21 30.5 NR 1 Cardiac failure 5
placebo 100 53.4 9.3 19.3 NR 0
van der Graaf et al. [7]/III* STS 372 Pazopanib 800 mg qd po 246 51.9 3.83 4.6 12.5 3 LVEF decline 5
placebo 123 56.7 1.89 1.6 10.7 0
Cristofanilli et al. [60]/II* Inflammatory BC 163 Pazopanib 800 mg qd po + lapatinib 1500 mg 38 52 2.8 NR 16.2 0 LVEF decline 3
Placebo + apatinib 1500 mg 38 52 3.8 NR 14.7 0
Placebo + apatinib 1500 mg 36 53 3.76 NR 15.9 0
pazopanib 400 mg qd po + lapatinib 1000 mg 38 54 2.96 NR NR 0
pazopanib 800 mg qd po 13 55 1.73 NR NR 0
Curigliano et al. [61]/II* Triple-negative BC 217 Sunitinib 37.5 mg qd po q3w. 113 52 NR 2 9.4 0 Cardiac failure 2
standard of care 104 52 NR 2.7 10.5 1
Fuchs et al. [41]/III* Gastric or gastro-oesophageal junction cancer 355 Ramucirumab 8 mg kg−1 q2w. 238 60 1.87 2.1 5.2 0 Cardiac failure 5
placebo 117 60 1.4 1.3 3.8 0
Hyams et al. [62]/II* MBC 62 Cediranib 45 mg qd po + fulvestrant 500 mg q4w. 31 NR NR 7.4 NR 0 LVEF decline 5
Placebo + ulvestrant 500 mg q4w. 31 NR NR 3.7 NR 0
Johnston et al. [63]/II* HER-2 positive BC 177 Pazopanib 400 mg qd po + lapatinib 1000 mg 69 50 NR NR NR 0 LV dysfunction 3
Placebo + lapatinib 1500 mg 72 54 NR NR NR 0
Lapatinib + pazopanib 800 mg qd po 36 54 NR NR NR 0
Motzer et al. [14]/II RCC 63 Sunitinib 50 mg d1−1-28 q6w 63 60 9 8.7 NR 1 LVEF decline NA
Motzer et al. [49]/II RCC 106 Sunitinib 50 mg d1−1-28 q6w 105 56 7.5 8.3 NR 5 LVEF decline NA
Saltz et al. [16]/II CRC 84 Sunitinib 50 mg d1−1-28 q6w, bevacizumab native 40 56.5 NR 2.3 NR 0 LVEF decline NA
Sunitinib 50 mg d1−1-28 q6w, pretreated with bevacizumab 42 57.5 NR 2.8 NR 0
Rixe et al. [50]/II RCC 52 Axitinib 5 mg bid po qd 52 59 9.4 15.7 29.9 1 LVEF decline NA
Kulke et al. [74]/II pancreatic carcinoid 107 Sunitinib 50 mg d1−1-28 q6w 107 56 12.5 7.7 16.4 1 CHF NA
Dror Michaelson et al. [72]/II prostate cancer 34 Sunitinib 50 mg d1−1-28 q6w 34 71 1.5 NR NR 1 LV dysfunction NA
Escudier et al. [9]/II RCC 107 Sunitinib 37.5 qd po 105 59 8.4 8.2 19.8 1 LVEF decline NA
Gore et al. [53]/II RCC 4564 Sunitinib 50 mg d1−1-28 q6w 4371 59 7.5 10.9 18.4 10 CHF NA
Hensley et al. [64]/II Uterine leiomyosarcoma 25 Sunitinib 50 mg d1−1-28 q6w 23 56 NR 1.54 15.1 0 LVEF decline NA
Kontovinis et al. [54]/II RCC 42 Sunitinib 50 mg d1−1-28 q6w 42 64 NR 8.9 16.23 1 LVEF decline NA
Di Lorenzo et al. [51]/II RCC 52 Sorafenib 400 mg qd po q8w. 52 60 4.1 3.73 7.5 1 LV dysfunction NA
Hoftijzer et al. [66]/II Thyroid carcinoma 31 Sorafenib 400 mg qd po q8w. 31 65 NR 13.5 NR NR CHF NA
Kloos et al. [67]/II Thyroid carcinoma 41 Sorafenib 400 mg qd po q8w. Previously treated 19 67 8.73 16 23 1 LV dysfunction NA
Sorafenib 400 mg qd po q8w. Native 22 56 9.87 10 37.5 0
Maki et al. [65]/II Sarcoma 147 Sorafenib 400 mg qd po q4w. 145 55 NR 3.2 14.3 1 Cardiac ejection fraction NA
Rini et al. [6]/II RCC 62 Axitinib 5 mg bid po qd 62 60 6.2 7.4 13.6 NR CHF NA
MacKay et al. [71]/II Cervical cancer 19 Sunitinib 50 mg d1−1-28 q6w 19 44 NR 3.5 NR 0 LV dysfunction NA
Tomita et al. [56]/II RCC 51 Sunitinib 50 mg d1−1-28 q6w 51 56.6 4.9 12.2 33.1 1 LVEF decline NA
61.1 6.5 10.6 32.5
Matsumoto et al. [68]/II GIST 18 Sunitinib 50 mg d1−1-28 q6w 18 58.7 NR 5.3 NR 0 LVEF decline NA
Hainsworth et al. [40]/II RCC 55 Pazopanib 800 mg qd po q8w. 55 60 6 7.5 NR 1 LV dysfunction NA
Kummar et al. [39]/II STS 46 Cediranib 30 mg qd po q4w. 46 27 1.87 NR NR 1 LV dysfunction NA
Reynolds et al. [73]/II NSCLC 63 Sunitinib 37.5 mg qd po q6w. 63 78.4 2.8 3 NR 0 CHF NA
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*

Randomized controlled trial.

†

Data retrieved from drug package insert.

§

1200 mg m−2 in patients age ≥65 years. PFS, progression-free survival; TTP, time to progression; OS, overall survival; LVEF, left ventricular ejection fraction; CHF, congestive heart failure; RCC, renal cell cancer; STS, soft tissue sarcoma; MBC, metastatic breast cancer; NSCLC, non-small-cell lung carcinoma; GIST, gastrointestinal stromal tumours; CRC, colorectal cancer; HCC, hepatocellular carcinoma; PNET, pancreatic neuroendocrine tumours; NR, not reported; NA, not available. Qd daily; bid twice daily; q2w every 2 weeks; q3w every 3 weeks; q4w every 4 weeks; q6w every 6 weeks; q8w every 8 weeks.

Incidence of CHF

A total of 6903 patients from 27 treatment arms who received VEGFR-TKIs as a single agent were available for all grade CHF analysis. There were 174 total CHF events among these patients. The incidence of all grade CHF ranged between 0% and 11.5%. Using a random effect model (χ2-based Q statistic test: Q = 269.35, P < 0.001, I2 = 90%), the overall incidence of all grade CHF was 3.2% (95% CI 1.8, 5.8%, Figure 2). High grade CHF was associated with increased morbidity and could result in dose modification or treatment interruption. A total of 6896 patients prescribed VEGFR-TKIs as a single agent from 26 treatment arms were included for analysis. The incidence of high grade CHF ranged from 0% to 4.8%. The summary incidence of high grade CHF was 1.4% (95% CI 0.9, 2.3%, Figure 2) according to the random effects model. We also performed a sub-group analysis to investigate the incidence difference according to tumour types, VEGFR-TKIs and phase of trials. Our results demonstrated that the incidence of CHF did not significantly vary with tumour types and phase of trials (Table 2). The incidence of all grade CHF associated pazopanib (6.1%) and cediranib (5.9%) was higher than that of vandetanib (0.4%) and ramucirumab (0.4%), and there were significant variations in the incidence of all grade CHF among different VEGFR-TKIs (P = 0.025), but not for high grade CHF (P = 0.72).

Figure 2.

Figure 2

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Incidence of all and high grade CHF associated with VEGFR-TKIs

Odds ratio of CHF

A meta-analysis of the OR for all grade CHF attributable to VEGFR-TKIs compared with controls was performed on 12 randomized controlled trials. The overall OR for all grade CHF was 2.37 (95% CI 1.76, 3.20, P < 0.001, Figure 3), according to the fixed effects model. As for high grade CHF, 15 RCTs were available for analysis. The combined OR also demonstrated that VEGFR-TKIs significantly increased the risk of developing CHF (OR = 3.51, 95% CI 1.74, 7.05, P < 0.001, Figure 3) using a fixed effects model. We also did a sensitivity analysis to examine the stability and reliability of pooled ORs by sequential omission of individual studies. The results indicated that the significance estimate of pooled all grade ORs was not significantly influenced by omitting any single study. As for high grade ORs, there was a non-significantly increased risk of developing high grade CHF after excluding the trial conducted by Motzer et al. [15] (Figure 4). Since in three studies, data on the length of treatment were not reported, nine of 12 studies were included in the analysis. The result indicated that the OR tended to be lower in the studies in which the experimental treatment was longer, and this effect was statistically significant (β = 1.15, P = 0.13, Figure 5). As for high grade CHF, a similar result was also observed (β = 1.26, P = 0.52, Figure 5). Based on these results, we believe that CHF might possibly occur early in treatment regimens.

Figure 3.

Figure 3

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Odds ratio of all and high grade CHF associated with VEGFR-TKIs vs. control

Figure 4.

Figure 4

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Meta-analysis of all and high grade CHF associated with VEGFR-TKIs vs. control: ‘leave-one-out’ sensitivity analysis

Figure 5.

Figure 5

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Meta-regression analysis of trends between treatment duration (months) and all and high grade odds ratio. Symbols: each study is represented by a circle the diameter of which is proportional to its statistical weight

Risk of CHF according to different tumour types, VEGFR-TKIs and phase of trials

To determine whether the observed increase in ORs of developing all and high grade CHF was the result of confounding bias, we preformed subgroup analyses of renal cell carcinoma (RCC) vs. other malignancies, phase II vs. phase III trials and trials with different VEGFR-TKIs. No significant differences were observed for ORs of all (1.91 vs. 3.36, P = 0.071) or high grade (3.02 vs. 4.31, P = 0.72) between patients with RCC and non-RCC. Similarly, no significant differences in ORs were found among different VEGFR-TKIs (all grade: P = 0.55, high grade: P = 0.99, Table 3). Interestingly, the ORs of all grade CHF were significantly higher in phase II trials than in phase III trials (4.77 vs. 2.01, P = 0.026), but not for high grade CHF (2.21 vs. 3.73, P = 0.67).

Table 3.

Odds ratio of CHF based on pre-specified subgroups

Grades Subgroup Number of trials VEGFR-TKIs Control I2 (%) OR (95% CI) P value P for group difference
Events/total, n Events/total, n
All grade Overall 12 152/1957 56/1407 0 2.37 (1.76, 3.20) <0.001 NA
Tumour types
 RCC 2 83/428 44/378 0 1.91 (1.30, 2.80) 0.001 0.071
 Non-RCC 10 69/1529 12/1029 0 3.36 (2.08, 5.43) <0.001
VEGFR-TKIs
 Sunitinib 3 100/690 48/566 26.0 1.95 (1.37, 2.78) <0.001 0.55
 Sorafenib 1 9/47 1/49 0 6.14 (1.67, 22.59) 0.006
 Axitinib 1 1/314 0/316 0 7.44 (0.15, 374.8) 0.32
 Cediranib 2 19/84 3/49 0 5.37 (2.02, 14.3) 0.001
 Vandetanib 1 1/231 0/100 0 4.19 (0.06, 299.27) 0.51
 Pazopanib 3 21/353 4/210 0 2.40 (1.01, 5.69) 0.047
Ramucirumab 1 1/238 0/117 0 4.44 (0.07, 287.50) 0.48
Phase of trials
 Phase II 7 34/665 6/628 0 4.77 (2.41, 9.43) <0.001 0.026
 Phase III 5 118/1292 50/779 0 2.01 (1.44, 2.81) <0.001
High grade Overall 15 28/2577 5/2056 0 3.51 (1.74, 7.05) <0.001 NA
Tumour types
 RCC 2 15/428 4/378 0 3.02 (1.21, 7.55) 0.008 0.72
 Non-RCC 13 13/2149 1/1678 0 4.31 (1.46, 12.72) 0.018
VEGFR-TKIs
 Sunitinib 6 21/1310 5/1192 0 3.19 (1.46, 6.95) 0.004 0.99
 Sorafenib 1 1/47 0/49 0 7.71 (0.15, 388.9) 0.31
 Axitinib 1 1/314 0/316 0 7.44 (0.15, 374.8) 0.32
 Cediranib 2 1/53 0/18 0 3.82 (0.04, 345.5) 0.56
 Vandetanib 1 1/231 0/100 0 4.19 (0.06, 299.3) 0.51
 Pazopanib 3 3/353 0/233 0 4.52 (0.41, 50.16) 0.22
Ramucirumab 1 0/238 0/117 0 NA NA
Phase of trials
 Phase II 7 3/665 1/628 0 2.21 (0.29, 16.72) 0.44 0.67
 Phase III 8 25/1912 4/1428 0 3.73 (1.77, 7.86) <0.001
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RCC, renal cell carcinoma; NA, not available.

Publication bias

No evidence of publication bias was detected for the OR of all grade and high grade ILD in this study by Egger's test (OR of all grade: P = 0.18, OR of high grade: P = 0.66).

Discussion

CHF is a rare but potentially life-threatening complication during anti-VEGF therapy [75,76]. Concerns have arisen regarding the risk of CHF with the use of these drugs. A previous meta-analysis demonstrated that the incidence of high grade CHF was 1.6% (95% CI 1.0, 2.6%) among patients receiving the VEGF antibody bevacizumab, and patients treated with bevacizumab had a significantly increased risk of developing CHF (RR 4.74, 95% CI 1.66, 11.18, P = 0.001) [37]. However, the association between CHF and VEGFR-TKIs, which also target VEGF signalling pathways, has not been systematically defined. As a result, we conducted this study to investigate the overall incidence and risk of CHF in cancer patients treated with VEGFR-TKIs.

Our study included 10 553 patients from 36 clinical trials and demonstrated that the pooled incidence of VEGFR-TKIs associated all and high grade CHF was 3.2% (95% CI 1.8, 5.8%) and 1.4% (95% CI 0.9, 2.3%), respectively. Additionally, we also found that the use of VEGFR-TKIs was associated with a significantly increased risk of all and high grade CHF when compared with controls. Sensitivity analysis indicated that the significance estimate of pooled all grade ORs was not significantly influenced by omitting any single study. As for high grade ORs, there is a non-significantly increased risk of developing high grade CHF after excluding the trial conducted by Motzer et al. [15]. In addition, the meta-regression indicated that the OR of CHF tended to be lower in studies in which the experimental treatment was longer, and the effect was statistically significant. Based on our findings, we could conclude that while VEGFR-TKIs are associated with an increased risk of developing CHF in cancer patients, the absolute incidence and risk of CHF appears low and the use of VEGFR-TKIs should be considered in the context of overall survival benefits. Moreover, as CHF commonly occurs early in the treatment with VEGFR-TKIs, close cardiac monitoring for patients receiving VEGFR-TKIs is recommended, especially during the initial of the regimens.

We also carried out a subgroup risk analysis stratified according to tumour type, VEGFR-TKIs agents, and phase of trials. Our results show that the incidence and risk of CHF associated with VEGFR-TKIs does not significantly vary with tumour types (all grade: P = 0.071, high grade P = 0.72). Then, we explored the incidence and risk of CHF among different VEGFR-TKIs. The incidence of CHF varied significantly with different VEGFR-TKIs (P = 0.025), reflecting the nature of the underlying tumour biology or the different spectrum of target receptors of VEGFR-TKIs. However, our study shows that the OR of CHF did not vary significantly with VEGFR-TKIs (all grade P = 0.55; high grade P = 0.99), but this is unclear with the sample size in this analysis. Additionally, we found that the risk of CHF was substantially higher in phase II trials than that in phase III trials (P = 0.026), but not for high grade CHF (P = 0.67).

The pathogenesis of angiogenesis inhibitor related CHF is currently unknown, and multiple mechanisms might be involved in the pathogenesis of CHF. VEGFR-TKIs, such as sorafenib, sunitinib, vandetanib, pazopanib, axitinib and regorafenib, have been shown to increase the risk of hypertension. The RR for hypertension with these VEGF-TKIs has been shown to range between 1.71 and 8.06 [23,25,26,30,32,33]. Hypertension is a well-known risk factor for development of CHF, and it is possible that VEGFR-TKIs use increases CHF through this mechanism [77]. Another potential mechanism of cardiotoxicity is through inhibition of the VEGF signal pathway. Inactivation of endogenous VEGF with an adenoviral vector encoding a decoy VEGFR could lead to a net reduction in capillary density, impaired cardiac hypertrophy and loss of contractile function after pressure overload in mice subjected to transverse aortic constriction [78], while micro-vascular plasticity allows adaptation of the vascular network, and thus oxygen supply to enhanced metabolic demand due to pressure overload [79]. Inhibiting the VEGF pathway blocks such plasticity, contributing to maladaptive hypertrophy of cardiomyocytes. Additionally, the platelet-derived growth factor (PDGF) signalling pathway also plays a crucial role in the heart. Inhibition of PDGFR-β in cardiomyocytes has been shown to induce heart failure in mice exposed to high vascular pressures [80].

Meta-analysis is considered as a useful tool for analyzing rare and unintended effects of a treatment because it could allow synthesis of data and achieve more stable estimates of effects. However, there are several limitations needed to be considered in our meta-analysis. First, these studies were conducted at various international institutions by different investigators and may have potential bias in reporting the types of adverse events. In particular, the frequency of CHF is under-reported in clinical trials. Second, although CHF events were prospectively collected for each individual study, this analysis was retrospective, and there are potentially important differences among the studies, including differing tumour types, dosage and administration schedule of VEGFR-TKIs, periods of study conduct and study investigators. All of these would increase the clinical heterogeneity among included trials, which also made the interpretation of a meta-analysis more problematic. Thirdly, VEGFR-TKI treatment has also been associated with a significant increase in the risk of hypertension and ATEs. Therefore, an increase in the risk of CHF may have been secondary to an increased incidence of hypertension and/or ATE [35]. However, we could not correlate the incidence of CHF with secondary hypertension or ATE, as neither the causality nor association was reported in any trial. In addition, we were not able to correlate our data with dose delays/interruptions or discontinuations secondary to CHF in the analysis. Fourthly, all these studies excluded patients with poor renal, haematological and hepatic function, and are performed mostly at major academic centres and research institutions. The analysis of these studies may not apply to patients with organ dysfunction and in the community, and the overall incidence and risk of CHF may be higher in medical practice. Finally, our study was a study-level meta-analysis and individual patient information was not available. Therefore, establishment of risk factors for the development of CHF, including prior exposure to cardiotoxic agents, or of potentially contributing comorbid conditions, including prior cardiovascular disease, was not possible in this analysis. Also, we could not determine the potential association between patients who developed CHF during VEGFR-TKIs treatment and efficacy of these drugs. Thus further studies are recommended to investigate this association.

In conclusion, our study suggests that the use of VEGFR-TKIs is associated with an increased risk of developing CHF. As these drugs are increasingly used in the routine treatment of cancer patients and in the setting of clinical trials in combination with other agents, physicians and investigators should be aware of this adverse effect and should monitor patients receiving VEGFR-TKIs closely to offer early intervention and to optimize the balance between oncologic clinical benefit and life-threatening adverse events.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

We are indebted to the authors of the primary studies, for without their contributions, this work would have been impossible.

Funding

None.

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