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Risk of Hypertension Associated with Antivascular Endothelial Growth Factor Monoclonal Antibodies: A Meta-Analysis From 51088 Patients with Cancer

Weilan Wang #1, Le Cai #1, Bingkun Xiao 2, * and Rongqing Huang 2

  1. Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, China
  2. Department of Antiradiation Drug, Beijng Institute of Radiation Medicine, Beijing, China

*Corresponding author: Department of Antiradiation Drug, Beijng Institute of Radiation Medicine, Beijing, China. Tel/Fax: +86-1066930217, Email: 13161748010@163.com # These authors are contributed equally as the first author.

Received 2020 January 19; Revised 2020 June 05; Accepted 2020 June 14.

 

Abstract

Context: Hypertension events are the dominant adverse events observed in patients receiving the antivascular endothelial growth factor (anti-VEGF) monoclonal antibodies bevacizumab and ramucirumab treatment, which severe hypertension, particularly hy- pertensive emergencies, may cause acute target organ injury and major cardiovascular events, that has limited the administration of anti-VEGF monoclonal antibodies. The current meta-analysis aimed to examine the relative risk (RR) of hypertension associated with anti-VEGF monoclonal antibodies.

Evidence Acquisition: PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library, and Clinical Trials.gov were searched until July 2019 for relevant phase II and III randomized controlled trials (RCTs). Statistical analyses were performed to examine the RR (with 95% confidence intervals (CIs)) of hypertension associated with the anti-VEGF monoclonal antibodies.

Results: Ninety four RCTs and 51088 patients were included in the current meta-analysis. According to the results, compared with the control arms, anti-VEGF monoclonal antibodies increased the risk of all-grade (RR: 3.45, 95% CI: 2.98 - 4.00) and high-grade (RR: 5.63, 95% CI: 5.05 - 6.26) hypertension. In the subgroup analyses, the risk of high-grade hypertension varied significantly with cancer type, so that the highest RR was for patients with ovarian cancer (17.27, 95% CI: 8.50 - 35.08), whereas the risk of all-grade hypertension did not vary significantly. When stratified based on drug types and drug dose, no significant difference was discovered.

Conclusions: Anti-VEGF monoclonal antibodies significantly increased the risk of hypertension. The risk may vary with tumor type. Clinicians should be aware of the adverse reaction and clinical monitoring as well as effective management of such situations, particularly for high-risk patients.

 

Keywords: Anti-VEGF Monoclonal Antibodies, Bevacizumab, Ramucirumab, Hypertension, Meta-Analysis


1. Context

Angiogenesis has an important role in promoting tumor growth, invasion, and metastasis. VEGF-A, one of the members of the vascular endothelial growth factor family, plays a vital role in angiogenesis and tissue neovascularization. Among all receptors, VEGFR-2 is widely considered as the most critical driver of tumor angiogenesis. Therefore, inhibition of angiogenesis via blocking VEGF-A or VEGFR-2 receptor signaling pathway is the key approach in current tumor therapeutics (1).

As a VEGF-A-targeted monoclonal antibody, bevacizumab widely administers in the treatment of various cancers. Ramucirumab is a VEGFR2- targeted monoclonal antibody and inhibits the signaling pathways in endothelial cells that mediate angiogenesis. Ramucirumab is approved for the treatment of advanced gastric, lung, and colorectal cancers.

Hypertension events are the most common adverse events of patients who receive the antivascular endothelial growth factor (anti-VEGF) monoclonal antibodies bevacizumab and ramucirumab treatment, which severe hypertension, particularly hypertensive emergencies may cause acute target organ injury and major cardiovascular events, that has limited the administration of anti-VEGF monoclonal antibodies (2). Previously conducted meta-analyses have investigated the risk of hypertension for bevacizumab or ramucirumab. However, the risk of hypertension caused by the anti-VEGF monoclonal antibodies is not yet evaluated systematically. Therefore, we performed the first meta-analysis to examine the risk of hypertension associated with anti-VEGF monoclonal antibodies.

The current meta-analysis aimed to examine the risk of hypertension associated with anti-VEGF monoclonal antibodies.


2.Evidence Acquisition

2.1. Search Strategy

To conduct the current meta-analysis, using the “bevacizumab”, “Avastin”, “ramucirumab”, “IMC1121B”, “LY3009806”, and “cancer” keywords, the following databases were searched: PubMed, ASCO abstracts, ESMO abstracts, and the clinical trial registration website (https://www.ClinicalTrials.gov) for relevant trials till July 2019. To ensure that all relevant clinical trials are incorporated into the meta-analysis, an independent search was conducted using the Web of Science databases.

2.2. Selection of Trials

The publications and data were reviewed and extracted by two independent investigators. Discrepancies were resolved by consensus with a third researcher. The randomized controlled trials that met the following criteria were included (1) phase II and III randomized controlled trials on cancer patients; (2) having a case group with anti-VEGF monoclonal antibodies treatment alone/concurrent chemotherapy or a control group with placebo/chemotherapy alone; and (3) Events or incidence and sample size available for hypertension.

2.3. Data Extraction

Data on study characteristics, therapeutic strategy, and results and reports of hypertension of all eligible studies were collected. The primary endpoint was the relative risk of hypertension with anti-VEGF monoclonal antibodies. Grading of hypertension events was based on versions 3.0 or 4.0 of Common Terminology Criteria.

2.4. Statistical Analysis

Analyses were performed using the RevMan 5.2. The heterogeneity of eligible studies was assessed by the I2 statistic. If P ≥ 0.1 and I2 ≤ 50%, data were analyzed by the fixed-effects model, the analysis was conducted using the random-effects model. Subgroup analyses were performed separated by the drug type, dosage, and cancer type to explore possible reasons for heterogeneity. We performed a meta-regression analysis to investigate various variables on hypertension events by Stata version 12.0.


3.Results

3.1. Search Results

The initial literature review resulted in 2723 potentially relevant studies, of which 2491 were excluded because of the following reasons: reviews, commentaries, letters, basic studies, case reports, non-randomized controlled trials, irrelevant topics, and duplications. The 232 remaining studies were carefully screened and 138 studies were removed because both control and treatment groups were receiving anti-VEGF monoclonal antibodies or data required for assessment of hypertension were not available. The remaining 94 randomized controlled trials were judged as eligible for the purpose of the analysis (Figure 1).

 



Figure 1. CONSORT flow diagram of the study

 

Figure 1. Outline of the search-flow diagram

3.2. Characteristics of Studies

94 RCTs and 51088 patients were selected for this meta-analysis, which were as follows 80 trials of bevacizumab (3 - 82) and 14 trials of ramucirumab (83 - 96) were investigated (3 - 82). All malignancies, including lung cancer (19 trials), colorectal cancer (22 trials), breast cancer (19 trials), ovarian cancer (4 trials), pancreatic cancer (2 trials), renal cell cancer (4 trials), gastric or gastro-oesophageal junction adenocarcinoma (7 trials), glioblastoma (3 trials), lymphoma (2 trials), melanoma (2 trials), lymphocytic leukemia (one trial), prostate cancer (one trial), two malignant mesothelioma (one trial), leiomyosarcoma (one trial), urothelial carcinoma (2 trials), hepatocellular carcinoma (one trial), multiple myeloma (one trial), and soft tissue sarcoma (one trial). The quality of all the trials included in the meta-analysis was acceptable. The characteristics of 94 trials are listed in Table 1.

Table 1. Characteristics of Studies Included in the Meta-Analysis

Author Year Malignancy Phase No in Intervention/Control Concurrent Treatment Dosemg/kg Per wk No. Hypertension Events Intervention/Control
All GradeGrade ≥ 3
Bevacizumab
Kabbinavar et al. (3) 2003 CRC II 67/35 Fluorouracil + leucovorin 2.5 or 5 13/1 11/0
Hurwitz et al. (4) 2004 CRC III 393/397 Irinotecan + fluorouracil + leucovorin 2.5 88/33 43/9
Kabbinavar et al. (5) 2005 CRC II 100/104 Fluorouracil + leucovorin 2.5 32/5 16/3
Giantonio et al. (6) 2007 CRC III 287/285 Oxaliplatin + fluorouracil + leucovorin 5 NR 18/5
Saltz et al. (7) 2008 CRC III 694/675 Capecitabine + oxaliplatin/Fluorouracil + folinic acid + oxaliplatin 2.5 NR 26/8
Allegra et al. (8) 2009 CRC III 1326/1321 Oxaliplatin + fluorouracil + leucovorin 2.5 NR 159/24
Tebbutt et al. (9) 2010 CRC III 157/156 Capecitabine 2.5 46/19 6/1
Statopoulos et al. (10) 2010 CRC III 114/108 Irinotecan + fluorouracil + leucovorin 2.5 23/0 NR
Guan et al. (11) 2011 CRC III 141/70 Irinotecan + fluorouracil + leucovorin 2.5 NR 4/0
Dotan et al. (12) 2012 CRC II 12/11 Capecitabine + oxaliplatin + cetuximab 2.5 6/2 0/0
de Gramont et al. (13) 2012 CRC III 1145/1126 Oxaliplatin + fluorouracil + leucovorin 2.5 NR 122/12
Bennouna et al. (14) 2013 CRC III 401/409 Fluorouracil/Capecitabine + Oxaliplatin/Irinotecan 2.5 NR 7/5
Cunningham et al. (15) 2013 CRC III 134/136 Capecitabine 2.5 26/7 3/2
Infante et al. (16) 2013 CRC II 41/39 Axitinib + oxaliplatin + fluorouracil + leucovorin 2.5 27/16 6/6
Cao et al. (17) 2015 CRC II 65/77 Irinotecan + fluorouracil + leucovorin 5 NR 8/4
Hegewisch-Becker et al. (18) 2015 CRC III 156/158 None 2.5 28/15 3/2
Passardi et al. (19) 2015 CRC III 176/194 Irinotecan + fluorouracil + leucovorin/oxaliplatin + fluorouracil + leucovorin 2.5 49/21 NR
Koeberle et al. (20) 2015 CRC III 131/131 None 2.5 21/4 6/1
Kerr et al. (21) 2016 CRC III 959/963 Capecitabine 2.5 320/75 36/6
Snoeren et al. (22) 2017 CRC III 39/36 Capecitabine + oxaliplatin 2.5 NR 9/6
Miller et al. (23) 2005 BC III 229/215 Capecitabine 5 54/5 41/1
Miller et al. (24) 2007 BC III 365/346 Paclitaxel 5 NR 54/0
Miles et al. (25) 2010 BC III 499/231 Docetaxel 2.5 or 5 NR 13/3
Brufsky et al. (26) 2011 BC III 458/221 Capecitabine/Taxane/Gemcitabine/Vinorelbine 5 NR 41/1
Robert et al. (27) 2011 BC III 817/403 Capecitabine/Taxane/Anthracycline 5 NR 81/4
Martin et al. (28) 2011 BC II 96/89 None 5 39/13 7/1
von Minckwitz et al. (29) 2012 BC III 956/969 Docetaxel 5 NR 25/4
Gianni et al. (30) 2013 BC III 215/206 Docetaxel + trastuzumab 5 NR 25/1
Cameron et al. (31) 2013 BC III 1288/1271 Anthracycline/Taxane 5 224/41 85/5
Coudert et al. (32) 2014 BC II 47/25 Trastuzumab + docetaxel 5 4/1 0/1
von Minckwitz et al. (33) 2014 BC III 245/238 Taxane/Anthracycline/Capecitabine/Vinorelbine/Gemcitabin/Cyclophosphamide 5 69/42 33/17
Bear et al. (34) 2015 BC III 594/596 Docetaxel-based chemotherapy 5 NR 62/2
Sikov et al. (35) 2015 BC II 215/218 Doxorubicin + cyclophlsphamide ± carboplatin 5 NR 47/4
Earl et al. (36) 2015 BC III 384/391 Docetaxel-Fluorouracil + epirubicin + cyclophosphamide 5 58/42 8/6
Dieras et al. (37) 2015 BC II 55/56 Trebananib + Paclitaxel 5 40/13 18/4
Miles et al. (38) 2017 BC III 238/233 paclitaxel 5 74/31 26/10
Johnson et al. (39) 2004 LC II 66/32 Carboplatin + paclitaxel 2.5 or 5 11/1 2/1
Sandler et al. (40) 2006 LC III 427/440 Paclitaxel + carboplatin 5 NR 30/3
Herbst et al. (41) 2007 LC II 39/42 Docetaxel/pemetrexed 5 6/0 2/0
Reck et al. (42) 2009 LC III 659/327 Cisplatin + gemcitabine 2.5 or 5 NR 49/5
Herbst et al. (43) 2011 LC III 313/313 Erlotinib 5 NR 15/4
Spigel et al. (44) 2011 LC II 51/47 cisplatin/carboplatin + etoposide 5 NR 3/2
Niho et al. (45) 2012 LC II 119/58 Carboplatin + paclitaxel 5 57/6 13/0
Boutsikou et al. (46) 2013 LC III 116/113 Docetaxel + carboplatin ± erlotinib 2.5 5/0 4/0
Seto et al. (47) 2014 LC II 75/77 Erlotinib 5 57/10 45/8
Zhou et al. (48) 2015 LC III 140/134 Carboplatin, paclitaxel 5 20/6 7/1
Pujol et al. (49) 2015 LC II–III 37/37 Cisplatin + etoposide ± epidoxorubicin + cyclophosphamide 2.5 18/5 2/0
Takeda et al. (50) 2016 LC II 50/50 Docetaxel 5 20/12 3/1
Karayama et al. (51) 2016 LC II 45/35 Pemetrexed 5 15/6 7/0
Tiseo et al. (52) 2017 LC III 95/103 Cisplatin + etoposide 2.5 NR 6/1
Wakelee et al. (53) 2017 LC III 735/738 Cisplatin + vinorelbine/docetaxel/gemcitabine/pemetrexed 5 NR 219/60
Spigel et al. (54) 2018 LC II 59/48 pemetrexed 5 11/0 2/0
Yang et al. (55) 2003 RCC II 76/40 None 1.5 or 5 15/2 8/0
Escudier et al. (56) 2007 RCC III 337/304 Interferon alfa 5 88/28 11/2
Rini et al. (57) 2010 RCC III 362/347 Interferon alfa 5 103/13 39/0
Donskov et al. (58) 2018 RCC II 59/59 Interleukin-2 + interferon-a 5 32/10 15/2
Van cutsem et al. (59) 2009 PC III 296/287 Gemcitabine + erlotinib 2.5 60/26 10/3
Kindler et al. (60) 2010 PC III 277/263 Gemcitabine 5 NR 28/8
Perren et al. (61) 2011 OC III 745/753 Paclitaxel + carboplatin 2.5 193/47 46/2
Pujade-Lauraine et al. (62) 2014 OC III 179/181 PLD/paclitaxel/topoteca 5 NR 13/2
Aghajanian et al. (63) 2015 OC III 247/233 Gemcitabine + carboplatin 5 104/20 42/2
Coleman et al. (64) 2017 OC III 330/327 Paclitaxel + carboplatin 5 135/10 39/2
Ohtsu et al. (65) 2011 GC III 386/381 Cisplatin + capecitabine 2.5 NR 24/2
Okines et al. (66) 2013 GC II/III 99/101 Epirubicin + cisplatin + capecitabine 2.5 NR 1/0
Shen et al. (67) 2015 GC, GEJC III 100/101 Capecitabine + cisplatin 2.5 NR 0/1
Cunningham et al. (68) 2017 GEJC II/III 468/477 Epiribicin + cisplatin + capecitabine 2.5 65/33 4/0
Chinot et al. (69) 2014 Glioblastoma III 461/450 Radiotherapy + temozolomide 5 181/57 52/10
Gilbert et al. (70) 2014 Glioblastoma III 260/233 None 5 NR 11/2
Balana et al. (71) 2016 Glioblastoma II 48/45 Temozolomide 5 NR 2/0
Hainsworth et al. (72) 2014 Lymphoma II 29/31 Rituximab 5 NR 3/0
Seymour et al. (73) 2014 Lymphoma III 395/386 Rituximab + doxorubicin + vincristine + cyclophosphamide + prednisone 5 64/14 NR
Kay et al. (74) 2016 lymphocytic leukemia II 33/32 Pentostatin + cyclophosphamide + rituximab 5 NR 7/1
Kim et al. (75) 2012 Melanoma II 143/69 Paclitaxel + carboplatin 5 NR 5/0
Corrie et al. (76) 2014 melanoma III 671/672 None 2.5 216/41 41/1
Kindler et al. (77) 2012 MM II 53/55 Gemcitabine + cisplatin 5 NR 12/5
Zalcman et al. (78) 2016 MM III 222/224 Pemetrexed + cisplatin 5 125/3 51/0
Kelly et al. (79) 2012 Prostate cancer III 504/505 Docetaxel + prednisone 5 NR 36/7
Hensley et al. (80) 2015 uLMS III 52/51 Gemcitabine + docetaxel 5 NR 4/0
Chisholm et al. (81) 2017 STSs II 71/79 Cyclophosphamide + Vinorelbine 2.5 NR 0/0
White et al. (82) 2013 multiple myeloma II 50/50 Bortezomib 5 11/2 8/0
Ramucirumab
Garon et al. (83) 2014 LC III 627/618 Docetaxel 3.3 68/30 35/13
Doebele et al. (84) 2015 LC II 67/69 Pemetrexed + carboplatin/cisplatin 3.3 13/4 7/1
Yoh et al. (85) 2016 LC II 76/81 Docetaxel 3.3 6/0 4/0
Petrylak et al. (86) 2016 UC II 46/45 Docetaxel 3.3 11/3 3/0
Petrylak et al. (87) 2017 UC III 258/265 Docetaxel 3.3 29/12 15/5
Tabernero et al. (88) 2015 CRC III 529/528 Irinotecan + fluorouracil + leucovorin 4 138/45 59/15
Moore et al. (89) 2016 CRC II 52/49 Oxaliplatin + fluorouracil + leucovorin 4 15/1 7/1
Mackey et al. (90) 2015 BC III 752/382 Docetaxel 3.3 203/44 51/7
Yardley et al. (91) 2016 BC II 69/65 Eribulin 3.3 9/1 3/1
Vahdat et al. (92) 2017 BC II 52/49 Capecitabine 3.3 16/1 4/1
Fuchs et al. (93) 2014 GC or GEJC III 236/115 None 4 38/9 18/3
Wilke et al. (94) 2014 GC or GEJC III 327/329 Paclitaxel 4 78/16 46/8
Yoon et al. (95) 2016 GC, EC,or GEJC II 82/80 Oxaliplatin + fluorouracil + leucovorin 4 31/10 13/3
Zhu et al. (96) 2015 HC III 277/276 None 4 56/20 35/10

Abbreviations: BC, breast cancer; CRC, colorectal cancer; EC, esophagus cancer; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HC, hepatocellular carcinoma; LC, lung cancer; MM, malignant mesothelioma; NR, not reached; OC, ovarian cancer; PC, pancreatic cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; STSs, soft tissue sarcomas; UC, urothelialcarcinoma; uLMS, uterine leiomyosarcoma.

3.3. RR of All-Grade Hypertension Events

To assess the relative risk of all-grade hypertension 58 RCTs were reviewed. The random-effects model (I2 = 72%) revealed that anti-VEGF monoclonal antibodies significantly increased the relative risk of all-grade (3.45, 95% CI: 2.98 - 4.00, P < 0.00001) hypertension compared to control arms (Figure 2).

 



Figure 2. Forest plot of the relative risk of all-grade hypertension

 

3.4. RR of High-Grade Hypertension Events

The relative risk of high-grade hypertension was assessed by 91 RCTs. Using a fixed-effects model (I2 = 46%), anti-VEGF monoclonal antibodies significantly increased the relative risk of high-grade hypertension (5.63, 95% CI: 5.05 - 6.26, P < 0.00001) (I2 = 46%). (Figure 3).

 



Figure 3. Forest plot of the relative risk of high-grade hypertension

 

3.5. Subgroup Analysis According to Drug Type

To explore the association between risk of hypertension events and drug type, a subgroup analysis was performed according to the type of the administered drug, which indicated the relative risk of all-grade hypertension events for bevacizumab (3.57: 95% CI: 2.98 - 4.28, P < 0.00001) and for ramucirumab (2.92: 95% CI: 2.42 - 3.52, P < 0.00001). No significant difference was observed between the subgroups (P = 0.571, Table 2).

 

Table 2. Relative Risk of All-Grade Hypertension Associated with Angiogenesis Inhibitors in the Subgroup Analysis

CI
HypertensionNumber of TrialsNumber of Events/TotalRR, 95% CIPP Value for Group Difference
PP Value for Group Difference
TreatmentControl
Type of drug           0.571
Bev 44 2853/10487 738/10185 3.57 [2.98, 4.28] < 0.00001  
Ram 14 711/3450 196/2951 2.92 [2.42, 3.52] < 0.00001  
Drug dosage, mg/kg/week           0.408
Bev 2.5 19 1232/4773 351/4803 3.13 [2.51, 3.91] < 0.00001  
Bev 5 27 1620/5677 389/5449 4.06 [3.09, 5.34] < 0.00001  
Ram 3.3 8 355/1947 95/1574 2.53 [2.02, 3.17] < 0.00001  
Ram 4 6 356/1503 101/1377 3.21 [2.46, 4.18] < 0.00001  
Tumor types           0.074
OC 3 432/1322 77/1313 6.15 [3.34, 11.35] < 0.00001  
RCC 4 238/834 53/750 4.02 [2.35, 6.87] < 0.00001  
Other tumor 51 2894/11781 804/11073 3.23 [2.76, 3.76] < 0.00001  

Abbreviations: Bev, bevacizumab; OC, ovarian cancer; Ram, ramucirumab; RCC, renal cell carcinoma.

 

For high-grade hypertension events, the relative risk (RR) was 6.04 (95% CI: 5.37 - 6.80, P < 0.00001) for bevacizumab and 3.83 (95% CI: 2.96 - 4.96, P < 0.00001) for ramucirumab. There was no significant difference (P = 0.224) between bevacizumab and ramucirumab (Table 3).

 

Table 3. Relative Risk of High-Grade Hypertension Associated with Angiogenesis Inhibitors in the Subgroup Analysis

Hypertension Number of Trials Number of Events/Total RR, 95% CI P P Value for Group Difference
TreatmentControl
Type of drug           0.224
Bev 77 1970/22533 296/20781 6.04 [5.37, 6.80] < 0.00001  
Ram 14 300/3450 68/2951 3.83 [2.96, 4.96] < 0.00001  
Drug dosage, mg/kg/week           0.369
Bev 2.5 30 619/9562 104/9461 5.70 [4.66, 6.97] < 0.00001  
Bev 5 51 1351/12934 201/11945 6.16 [5.34, 7.11] < 0.00001  
Ram 3.3 8 122/1947 28/1574 3.39 [2.26, 5.08] < 0.00001  
Ram 4 6 178/1503 40/1377 4.17 [2.98, 5.83] < 0.00001  
Tumor types           0.003
OC 4 140/1501 8/1494 17.27 [8.50, 35.08] < 0.00001  
RCC 4 73/834 4/750 13.29 [5.44, 32.50] < 0.00001  
Other tumors 83 2057/23648 352/21488 5.27 [4.72, 5.88] < 0.00001  

Abbreviations: Bev, bevacizumab; OC, ovarian cancer; Ram, ramucirumab; RCC, renal cell carcinoma.

3.6. Subgroup Analysis According to Drug Dose

In the stratified analysis, which was performed according to the dose of anti-VEGF monoclonal antibodies, RR of all-grade hypertension for bevacizumab at 2.5 mg/kg/week was 3.13 (95% CI: 2.51 - 3.91), for bevacizumab at 5 mg/kg/week was 4.06 (95% CI: 3.09 - 5.34), for ramucirumab at 3.3 mg/kg/week was 2.53 (95% CI: 2.02 - 3.17), and for ramucirumab at 4 mg/kg/week was 3.21 (95% CI: 2.46 - 4.18). No significant difference was found by various drug doses (P = 0.408, Table 2).

For high-grade hypertension events, RR for bevacizumab at 2.5 mg/kg/week was 5.70 (95% CI: 4.66 - 6.97), for bevacizumab at 5mg/kg/week was 6.16 (95% CI: 5.34 - 7.11), for ramucirumab at 3.3mg/kg/week was 3.39 (95% CI: 2.26 - 5.08), and for ramucirumab at 4 mg/kg/week was 4.17 (95% CI: 2.98 - 5.83). No significant difference was observed by various drug dose (P = 0.369, Table 3).

3.7. Subgroup Analysis According to Cancer Type

In the subgroup analysis, which was performed according to the cancer type (i.e., ovarian cancer, renal cell carcinoma, and other cancer types), the risk of all-grade hypertension events was higher for these cancers. RR for ovarian cancer patients was 6.15 (95% CI: 3.34 - 11.35), for renal cell carcinoma patients was 4.02 (95% CI: 2.35 - 6.87), and for other tumor patients was 3.23 (95% CI: 2.76 - 3.76). However, RR of all-grade hypertension events did not vary significantly according to the cancer type (P = 0.074, Table 2).

For high-grade hypertension events, RR varied significantly (P = 0.003), the highest and lowest RR was for ovarian cancer patients (17.27, 95% CI: 8.50 - 35.08) and for other cancer patients (5.27, 95% CI: 4.72 - 5.88, Table 3), respectively.

3.8. Publication Bias

Funnel plots were performed to assess publication bias. No apparent publication bias was detected for all-grade and high-grade hypertension by the funnel plots.


4.Discussion

To the best of our knowledge, this is the first meta-analysis that examined the risk of hypertension events associated with anti-VEGF monoclonal antibodies.

Analysis of the data from RCTs demonstrated that anti-VEGF monoclonal antibodies increase the risk of all-grade (RR: 3.45, 95% CI: 2.98 - 4.00) and high-grade (RR: 5.63, 95% CI: 5.05 - 6.26) hypertension compared to control arms. The mechanisms of hypertension induced by angiogenesis inhibitor included increasing cell apoptosis, decreasing endothelial renewal capacity, suppressing the production of nitric oxide in vessels, and decreasing the number of capillaries and arterioles (2).

Because severe hypertension, particularly hypertensive emergencies, may cause acute target organ injury and major cardiovascular events, which in turn leads to limited administration of the anti-VEGF monoclonal antibodies. So, clinical monitoring and effective management might be important ways for the safe application of these agents.

To explore possible risk factors, subgroup analysis was performed according to the types of administered drugs. In the current meta-analysis, there was a higher risk of high-grade hypertension in patients using bevacizumab compared with ramucirumab (RR: 6.04 VS 3.83). However, no significant difference (P = 0.224) was discovered between bevacizumab and ramucirumab.

As a VEGF-A-targeted monoclonal antibody, bevacizumab prevents the activation of VEGFR-1 and VEGFR-2, whereas ramucirumab only inhibits the VEGFR-2 receptor. VEGFR-2 is a critical receptor for angiogenesis, and blockade of the VEGF-A/VEGFR-2 signaling may result in endothelial dysfunction and hypertension (2). The precise mechanism of VEGFR-1 is not entirely understood, and the study showed that VEGFR-1 tyrosine kinase signaling also had an effect on angiogenesis (97). Blockade of the VEGF-A/VEGFR-1 signaling resulted in the endothelial dysfunction and hypertension, but simultaneously played only a minor role compared with VEGF-A/VEGFR-2 signaling (98). This may be the reason for the higher risk of high-grade hypertension in patients who were receiving bevacizumab compared to those who were receiving ramucirumab; however, the difference was not statistically significant. The difference between bevacizumab and ramucirumab was more obvious for the risk of ATE, VTE, and high-grade bleeding (99).

Based on the results, all doses of angiogenesis inhibitors increase the risk of all-grade and high-grade hypertension events, but no significant difference was found between various doses of antiangiogenic monoclonal antibodies bevacizumab (2.5 mg/kg/week and 5 mg/kg/week) and ramucirumab (3.3 mg/kg/week and 4 mg/kg/week), no matter for the risk of all-grade hypertension (P = 0.408) or the risk of high-grade hypertension (P = 0.369), suggesting that the risk of hypertension events may not be dose-dependent.

In a meta-analysis on angiogenesis inhibitors, patients with renal cell carcinoma or ovarian cancer had a high risk of hypertension. Therefore, we performed subgroup analysis according to renal cell carcinoma, ovarian cancer, and other cancer types to identify potential risk factors. The risk of high-grade hypertension varied significantly according to the cancer type, with the highest and lowest RR was for ovarian cancer and other types of cancer. The underlying mechanisms of these differences are still unclear. A possible explanation is that patients with hypertension were not excluded from ovarian trials, despite antihypertensive treatment. Also, hypertension events are relatively common in women with ovarian cancer. The high incidence rate of hypertension may be related to cancer or its ovariectomy treatment. The depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension. For example, at least 40% of the participants of the OCEANS trial had baseline hypertension, and according to the literature, pre-existing hypertension predicts the increased risk for anti-VEGF therapy-induced hypertension (63). Besides, the RR of patients with renal cell carcinoma was times higher than those with other cancers. Although nephrectomy performed among renal cell carcinoma patients can decrease glomerular filtration, the concentration of antiangiogenic monoclonal antibodies is not be influenced by a decreased GFR likely, because the metabolism and elimination of these agents primarily rely on proteolytic catabolism throughout the body, and does not depend primarily on elimination through the kidneys and livers (2100). Thus, the possible explanation for this phenomenon is that post nephrectomy glomerular hypertrophy may be more dependent on VEGF to keep structural completeness than a normal kidney, leading to increased sensitiveness to angiogenesis inhibitors (101). So, patients with ovarian cancer or renal cell carcinoma should pay more attention to hypertension when receiving antiangiogenic monoclonal antibodies.

4.1. Limitations

One limitation of this meta-analysis is that we conducted subgroup analysis only for ovarian cancer, renal cell carcinoma, and other cancer types, mainly because it was difficult to assess so many cancer types included in the current meta-analysis. Besides, except for drug type, drug dose, and cancer type, other potential risk factors, such as age, race, sex, and treatment duration, could increase clinical heterogeneity and, therefore, were not evaluated in the study. Finally, the literature search was limited to articles published in English, which may have led to selection bias.


5.Discussion

In conclusion, the results showed that anti-VEGF monoclonal antibodies significantly increased the risk of hypertension. The risk may vary with cancer type, in which the highest RR was for patients with ovarian cancer (17.27, 95% CI: 8.50 - 35.08). When patients were stratified based on the type of administered drugs and dosage, no significant difference was observed. Clinicians should be aware of the adverse reaction and clinical monitoring as well as effective management of such situations, particularly for high-risk patients.


Acknowledgments

Thanks to the Gastroenterology Clinic of Taleghani Hospital in Tehran for identifying and referring patients with reflux and all the participants who participated in this study.


Footnotes


References

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