Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

<div><p>Background</p><p>Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis.</p><p>Methods and Findings</p><p>We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I² = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I² = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I² = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I² = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I² = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials.</p><p>Conclusions</p><p>VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.</p></div

Pooled effect of treatment with VEGFi on clinical outcomes.

<p>*For all-cause mortality, the value presented is number needed to treat (NNT); however for all other outcomes number needed to harm (NNH) is presented. # 8 trials presented either only any thrombotic events or specified arterial and/or venous thromosis and/or pulmonary embolism in addition to any thrombotic events; therefore the included trials (in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101145#pone-0101145-g004" target="_blank">figure 4</a>) and number of participants for any thrombotic events differed from the arterial, venous thrombosis or pulmonary embolism events.</p

Risk of bias of included studies.

<p>The responses for each question in this risk of bias tool are represented by different colors, segmented along a horizontal bar. Light gray depicts the percent of studies responding with the smallest risk of bias. Medium gray depicts the percent of studies responding with a moderate or unclear risk of bias. Dark gray indicates the greatest risk of bias. The responses to “Concealed treatment allocation?” are adequate, inadequate and unclear. The responses to “Double-blinded?”, “Intention-to-treat?” and “Interim/preliminary analysis not done?” are yes, unclear and no. The responses to “Withdrawals/dropouts described” are yes, no or partial. The responses to “Total lost to follow up <10%” are yes, no or not reported. The responses to “Funding?” are government, private or mixed/other funding sources.</p

Effect of treatment with VEGFi on hypertension and proteinuria.

<p>Effect of treatment with VEGFi on hypertension and proteinuria.</p

Effect of treatment with VEGFi on all-cause mortality, cardiovascular events and thrombosis.

<p>Effect of treatment with VEGFi on all-cause mortality, cardiovascular events and thrombosis.</p

Brief description of included randomized trials.

<p>NSCLC: non-small-cell lung cancer; RCC: renal cell carcinoma; SCLC: small-cell lung cancer; FOLFOX 4: oxaliplatin, leucovorin, fluorouracil; FU/LV:fluorouracil & leucovorin; IFL: irinotecan, bolus fluorouracil, leucovorin; XELOX: capecitabine & oxaliplatin; HAI Hepatic arterial infusion</p>$<p>Comparison between another arm and control was not eligible.</p><p>There are 74 rows for 72 studies reported in text: two studies, Martin 2011 had two arms Motesanib and bevacizumab comparing with placebo, Robert 2011 had two arms of capecitabine and taxane-based/anthracycline-based comparing bevacizumab versus placebo in each arm.</p><p>*These are two different trials published in the same year by the same author: Spigel et al in 2011 used bevacizumab for extensive stage small cell lung cancer in one trial and sorafenib for advanced non–small-cell lung cancer in another trial. Likewise, Escudier et al in 2007 used neovastat in metastatic renal cell carcinoma in one trial and sorafenib in advanced clear-cell renal-cell carcinoma in another trial.</p

sj-docx-2-cjk-10.1177_20543581221150676 – Supplemental material for Development and Validation of Patient Education Tools for Deprescribing in Patients on Hemodialysis

Supplemental material, sj-docx-2-cjk-10.1177_20543581221150676 for Development and Validation of Patient Education Tools for Deprescribing in Patients on Hemodialysis by Thomas Hyunwoo Cho, Patrick C. K. Ng, Melissa J. Lefebvre, Arlene Desjarlais, Dennis McCann, Blair Waldvogel, Marcello Tonelli, Amit X. Garg, JoAnne Wilson, Monica Beaulieu, Judith Marin, Cali Orsulak, Melanie Talson, Monica Sharma, Jordanne Feldberg, Clara Bohm and Marisa Battistella in Canadian Journal of Kidney Health and Disease</p