Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis

Our plain-English summary of Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis, by V. Ranpura, B. Pulipati, D. Chu, et al (American Journal of Hypertension, 2010).

The study

• Authors: V. Ranpura, B. Pulipati, D. Chu, X. Zhu, S. Wu
• Journal: American Journal of Hypertension
• Published: 2010;23(5):460-8
• Type of article: Meta-analysis, Systematic review
• Cited by: 185 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Hypertension is associated with the use of bevacizumab, an angiogenesis inhibitor widely used in cancer therapy. Currently, the risk of severe hypertension associated with bevacizumab is unclear. We performed a systematic review and meta-analysis of published randomized-controlled clinical trials (RCTs) to assess the risk of high-grade hypertension in cancer patients treated with bevacizumab.

Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which bevacizumab was directly compared with controls in cancer patients receiving concurrent antineoplastic therapy. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies.

Results: A total of 12,656 patients with a variety of tumors from 20 studies were included for the analysis. The incidence of all-grade hypertension in patients receiving bevacizumab was 23.6% (95% CI: 20.5-27.1) with 7.9% (95% CI: 6.1-10.2) being high-grade (grade 3 or 4). Patients treated with bevacizumab had a significantly increased risk of developing high-grade hypertension with an RR of 5.28 (95% CI: 4.15-6.71, P < 0.001) in comparison with controls. Even though not statistically significant, there was a trend suggesting that bevacizumab may increase the risk of hypertensive crisis (grade 4) with an RR of 3.16 (95% CI: 0.91-10.90). The increased risk of high-grade hypertension was observed in patients receiving bevacizumab at 2.5 mg/kg/week (RR = 4.78, 95% CI: 3.59-6.36) as well as 5 mg/kg/week (RR = 5.39, 95% CI: 3.68-7.90). The risk of high-grade hypertension may vary with tumor types, with RRs ranging from 2.49 (95% CI: 0.94-6.59) in patients with mesothelioma to 14.80 (95% CI: 0.92-238.51) in patients with breast cancer.

Conclusion: Bevacizumab may significantly increase the risk of high-grade hypertension in cancer patients. Close monitoring and adequate management are highly recommended to decrease cardiovascular complications.

In plain English

This systematic review and meta-analysis studied a cancer drug, not asbestos exposure. The authors pooled 20 randomized trials found in searches to May 2009. These trials included 12,656 cancer patients (6,754 given bevacizumab, 5,902 controls); in nearly every trial both groups received other cancer treatment. The aim was to estimate the risk of high-grade (grade 3 or 4) hypertension. In bevacizumab patients, pooled incidence was 23.6% (95% CI 20.5 to 27.1) for any-grade hypertension (11 trials) and 7.9% (95% CI 6.1 to 10.2) for high-grade hypertension. Versus controls, the relative risk of high-grade hypertension was 5.28 (95% CI 4.15 to 6.71). For hypertensive crisis (grade 4, five trials) the relative risk, 3.16 (95% CI 0.91 to 10.90), was not statistically significant. In the single malignant mesothelioma trial, high-grade incidence among bevacizumab patients was 22.6% (95% CI 13.3 to 35.8), but the relative risk of 2.49 (95% CI 0.94 to 6.59) was not significantly increased. The authors concluded that bevacizumab may significantly increase the risk of high-grade hypertension in cancer patients. They noted the trials may have underestimated hypertension.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review and meta-analysis of randomized controlled clinical trials
• Who was studied: 12,656 cancer patients (6,754 given bevacizumab, 5,902 controls) from 20 phase II and phase III randomized trials. Tumor types were colorectal cancer (7 trials), non-small-cell lung cancer (4), breast cancer (3), pancreatic cancer (3), renal cell cancer (3) and malignant mesothelioma (1). The trials were identified in PubMed (January 1966 to May 2009), Web of Science, and American Society of Clinical Oncology abstracts (January 2000 to May 2009).
• Exposure: Bevacizumab, an anti-VEGF angiogenesis inhibitor, compared with control (placebo or best supportive care). The inclusion criteria required concurrent chemotherapy or a biological agent. However, Table 2 lists no concurrent treatment ('None') for one trial, the Yang renal cell carcinoma trial. Doses were grouped as low dose (2.5 mg/kg/week) and high dose (5 mg/kg/week). Asbestos exposure was not studied.
• Main results:
  • Among patients given bevacizumab, the pooled summary incidence of all-grade hypertension was 23.6% (95% CI: 20.5–27.1), based on 11 trials with 3,679 patients. The relative risk of all-grade hypertension versus controls was 3.02 (95% CI: 2.24–4.07, P < 0.001).
  • Among the 6,754 patients given bevacizumab, the pooled summary incidence of high-grade (grade 3–4) hypertension was 7.9% (95% CI: 6.1–10.2).
  • Across all 20 trials, the relative risk of high-grade hypertension for bevacizumab versus controls was 5.28 (95% CI: 4.15–6.71, P < 0.001).
  • Five trials reported grade 4 hypertension (hypertensive crisis) separately. Its incidence was 0.5% (95% CI: 0.3–0.8) among 2,771 bevacizumab patients. The relative risk versus controls was 3.16 (95% CI: 0.91–10.90; P = 0.069), which was not statistically significant. No grade 5 hypertension (death) was reported.
  • The relative risk of high-grade hypertension was 4.78 (95% CI: 3.59–6.36) for low-dose bevacizumab (10 trials, 7,208 patients). It was 5.39 (95% CI: 3.68–7.90) for high-dose bevacizumab (14 trials, 6,096 patients).
  • The relative risk of high-grade hypertension was significantly increased in four tumor types: renal cancer (RR 8.99; 95% CI: 2.72–29.72), non-small-cell lung cancer (RR 7.06; 95% CI: 3.66–13.62), pancreatic cancer (RR 5.52; 95% CI: 2.12–14.35) and colorectal cancer (RR 5.24; 95% CI: 3.89–7.05). It was not significantly increased in mesothelioma (RR 2.49; 95% CI: 0.94–6.59) or breast cancer (RR 14.80; 95% CI: 0.92–238.51).
  • In the single malignant mesothelioma trial, the incidence of high-grade hypertension among bevacizumab patients was 22.6% (95% CI: 13.3–35.8), the highest of the tumor types.
  • Efficacy data from the included studies showed that bevacizumab did not improve progression-free or overall survival in pancreatic cancer or malignant mesothelioma. At study level, high-grade hypertension was not significantly correlated with progression-free survival or overall survival.
• The authors' conclusion: The authors concluded that bevacizumab may significantly increase the risk of high-grade hypertension in cancer patients. They found the risk with both low and high doses, and said it may vary by tumor type.
• Limitations the authors state:
  • The trials defined hypertension as blood pressure above 150/100 mm Hg rather than the standard 140/90 mm Hg, so they may have underestimated its incidence.
  • Blood pressure instruments, recording and protocols differed across institutions, and reported incidence of high-grade hypertension varied significantly between studies.
  • The trials enrolled patients with adequate organ function at major academic institutions, so the results may not apply to general community patients or patients with organ dysfunction.
  • The analysis was done at study level, so patient-level confounding variables could not be assessed.
  • Publication bias may not have been eliminated despite the tests and the search of unpublished abstracts.
  • The hypertensive crisis result rests on a small number of studies.
  • The study may have lacked power to detect a small difference in risk between doses.

Topics

Medical terms in this study, explained in our Lexicon: Bevacizumab, Meta-Analysis, Angiogenesis, Systematic Review, Clinical Trial, Relative Risk, confidence interval, Mesothelioma.

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