Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis of randomized controlled trials

Figures & data

Table I. National Cancer Institute’s common terminology criteria versions 1-3 for arterial thromboembolic events.

Grade	Version 1	Version 2	Version 3
1	Cardiac: non-specific T wave flattening or changes	Cardiac: Non-specific T wave flattening or changes, Troponin > = 0.03–<0.05	Cardiac: Asymptomatic. Arterial narrowing no ischemia, Troponin > = 0.03–<0.05
	CNS: none.	CNS: none.	CNS: none.
	Peripheral and visceral artery: none.	Peripheral and visceral artery: none.	Peripheral and visceral artery: none.
2	Cardiac: asymptomatic ST-T changes s/o ischemia	Cardiac: Asymptomatic ST-T changes s/o ischemia, Troponin >=0.05–<0.1	Cardiac: Stable Angina Troponin >=0.05–<0.1
	CNS: none.	CNS: none.	CNS: none.
	Peripheral and visceral artery: none.	Peripheral and visceral artery: Brief episode, no surgery	Peripheral and visceral artery: brief episode, no surgery
3	Cardiac: angina without infarction	Cardiac: Angina without infarction, Troponin >=0.1–<0.2	Cardiac: Unstable angina, Troponin >=0.1–<0.2
	CNS: none	CNS: Transient ischemic attack (TIA)	CNS: transient ischemic attack (TIA)
	Peripheral and visceral artery: none	Peripheral and visceral artery: requires surgery	Peripheral and visceral artery: requires surgery
4	Cardiac: acute myocardial infarction	Cardiac: Acute MI, troponin >or = 0.2	Cardiac: Acute MI, troponin >or = 0.2
	CNS: none	CNS: Permanent Stroke	CNS: Permanent Stroke
	Peripheral and visceral artery: none	Peripheral and visceral artery: life – threatening or with permanent functional deficit	Peripheral and visceral artery: life – threatening or with permanent functional deficit
5	None	Death	Death

Abbreviations: CNS, central nervous system; MI, myocardial Infarction; n/a, not applicable

Figure 1. Selection process for randomized controlled trials (RCTs) included in the meta-analysis.

Table II. Characteristics of randomized controlled trials included in the meta-analysis.

Study Name	Trial phase	No. Enrolled	No. for Analysis	Duration of Follow-up, Median (Range), mo	Underlying malignancy	Concurrent Treatment	Bevacizumab Dose, mg/kg per wk(b)	CTC version
Allegra et al. [6], 2008	3	2 710	2 710	22.4 (NA)	Colorectal cancer	Fluorouracil, oxaliplatin, and leucovorin	2.5	3
Escudier et al. [21], 2007	3	649	641	13.3 (0–25.6)	Renal Cell Carcinoma	Interferon Alfa	5	3
Giantonio et al. [31], 2007	3	829	572	28 (NA)	Colorectal cancer	Oxaliplatin, fluorouracil, and leucovorin	5	2
Herbst et al. [36], 2007	2	122	81	15.8 (NA)	NSCLC	Docetaxel or pemetrexed	5	2
Hurwitz et al. [11], 2004	3	813	790	18.0 (NA)	Colorectal cancer	Irinotecan, bolus fluorouracil, and leucovorin	2.5	2
Johnson et al. [28], 2004	2	99	98	14.7 (NA)	NSCLC	Docetaxel or pemetrexed	2.5 or 5	1
Kabbinavar et al. [27], 2003	2	104	102	17.6 (NA)	Colorectal cancer	Fluorouracil and leucovorin	2.5 or 5	1
Kabbinavar et al. [30], 2005	2	209	204	14.8 (NA)	Colorectal cancer	Bolus fluorouracil and leucovorin	2.5	2
Karrison et al. [7], 2007	2	115	108	15.1 (NA)	Mesothelioma	Cisplatin and gemcitabine	5	NA
Kindler et al. [8], 2007	3	602	523	11.3 (NA)	Pancreatic cancer	Gemcitabine	5	NA
Miles et al. [24],2008	3	736	736	10.2 (0-17.5)	Breast cancer	Docetaxel	2.5 or 5	NA
Miller et al. [37], 2005	3	462	445	14.8 (NA)	Breast cancer	Capecitabine	5	2
Miller et al. [34],2007	3	722	711	25.9 (NA)	Breast cancer	Paclitaxel	5	2
Price et al. [33],2008	3	400	400	NA	Colorectal cancer	Capecitabine or mitomycin	2.5	NA
Reck et al. [23], Jco, 2009	3	1 043	986	NA	NSCLC	Cisplatin and gemcitabine	2.5 or 5	3
Rini et al. [32],2008	3	732	715	NA	Renal Cell Carcinoma	Interferon Alfa	5	3
Saltz et al. [26], 2008	3	1 401	1 369	27.6 (NA)	Colorectal cancer	Oxaliplatin, fluorouracil, and leucovorin or capecitabine and oxaliplatin	2.5	3
Sandler et al. [35], 2006	3	878	868	19.0 (NA)	NSCLC	Paclitaxel and carboplatin	5	2
Van Cutsem et al. [22], 2009	3	607	583	6.7 (NA)	Pancreatic cancer	Gemcitabine and erlotinib	2.5	3
Yang et al. [29], 2003	2	116	116	27	Renal Cell Carcinoma	None	2.5 or 5	2.0

Abbreviations and notes: NA, data not available; NSCLC, non-small cell lung carcinoma.

(a) Funding sources: Seven trials were sponsored by Genentech [11,27,28,30,34,36,37]. Five trials were sponsored by Hoffman-LaRoche [21–24,26]. Seven trials were supported by National Cancer Institute and National Institute of Health [6,8,29,31,32,34,35]. One trial was supported by Mesothelioma Applied Research Foundation [7]. One trial was supported by Australian Gastrointestinal Trials Group [33].

(b) The dose schedule was converted from mg/kg per schedule.

Table III. Incidence and relative risk (RR) of all-grade arterial thromboembolic events (ATE) with bevacizumab according to tumor types.

	No. of Studies	All-Grade ATE (No./Total No.) Bevacizumab	All-Grade ATE (No./Total No.) Control	Incidence (95% CI),%	RR (95% CI)
Overall	8	58/1 853	23/1 720	3.3 (2.0–5.6)	2.08 (1.28–3.40)
Colorectal cancer	3	33/560	11/536	6.1 (4.4–8.5)	2.79 (1.42–5.49)
Breast cancer	2	8/594	1/561	1.6 (0.8–3.2)	3.49 (0.48–25.49)
Renal Cell Carcinoma	1	5/337	2/304	1.5 (0.6–3.5)	2.26 (0.44–11.54)
NSCLC	1	3/66	1/32	4.5 (1.5–13.2)	1.46 (0.16–13.44)
Pancreatic Cancer	1	9/296	8/287	3.0 (1.6–5.7)	1.09 (0.43–2.79)

Abbreviations and notes: CI, confidence interval; NSCLC, non-small cell lung carcinoma. The incidence and RR were calculated from the trials included in this study by meta-analysis as described in the “Methods” section.

Table IV. Incidence and relative risk (RR) of high-grade arterial thromboembolic events (ATE) with bevacizumab according to tumor types.

	No. of Studies	High-Grade ATE (No./Total No.) Bevacizumab	High-Grade ATE (No./Total No.) Control	Incidence (95% CI),%	RR (95% CI)
Overall	15	98/5 558	60/4 812	2.0 (1.7–2.5)	1.29 (0.86–1.94)
Colorectal Cancer	5	47/2 531	27/2 472	1.9 (1.4–2.5)	1.57 (0.98–2.53)
Colorectal Cancer-metastatic	4	22/1 205	8/1 151	1.9 (1.2–2.8)	2.18 (0.99–4.80)
Renal cell cancer	3	16/779	2/693	2.2 (1.4–3.6)	5.14 (1.35–19.64)
NSCLC	3	20/1 125	16/809	11.3 (4.7–24.8)	0.64 (0.34–1.22)
Pancreatic Cancer	2	14/573	14/550	2.5 (1.5–4.1)	0.96 (0.46–2.0)
Breast Cancer	1	0/497	1/233	1.0 (0–1.6)	0.18 (0.01–3.83)
Malignant Mesothelioma	1	1/53	0/55	1.9 (0.3–12.2)	3.11 (0.13–74.72)

Abbreviations and notes: CI, confidence interval; NSCLC, non-small cell lung carcinoma. The incidence and RR were calculated from the trials included in this study by meta-analysis as described in the “Methods” section.

Figure 2. Relative risk (RR) of arterial thromboembolic events (ATE) associated with bevacizumab versus controls. Overall summary RR of ATE was calculated using a fixed-effects model. RR for each study is displayed numerically on the left and graphically on the right. Total events and sample sizes are also displayed for each study. For study name, the first author’s name was used to represent each trial. If the same first author was involved in two trials, then the publication year was also included to identify the trial. For each trial the position of the square denoted incidence, horizontal lines represent 95% CI, and diamond plot represents overall results of the included trials. The size of the squares is directly proportional to the amount of data in each trial.

Table V. Incidence and Relative Risk (RR) of arterial thromboembolic events (ATE) with bevacizumab according to organs.

ATE	No. of Studies	All-Grade thrombosis (No./Total No.) Bevacizumab	All-Grade thrombosis (No./Total No.) Control	Incidence (95% CI),%	RR (95% CI)
Cardiac	5	33/2 322	12/2 151	1.5 (1–2.1)	2.14 (1.12–4.08)
CNS (Stroke)	5	20/2 288	13/2 253	1.2 (0.8–1.9)	1.37 (0.67–2.79)
Extremities (Peripheral)	1	0/1 326	3/1 321	0 (0–0.6)	0.14 (0.01–2.75)
Viscera	1	1/67	0/35	0.4 (0.1–2.1)	3.71 (0.20–69.79)

Abbreviations and notes: CI, confidence interval; RR, relative risk, N/A: not applicable, NSCLC, non-small cell lung carcinoma. The incidence and RR were calculated from the trials included in this study by meta-analysis as described in the “Methods” section.

Figure 3. Relative risk (RR) of cardiac ischemia or stroke associated with bevacizumab versus controls. Overall summary RRs of high grade cardiac ischemic events (A) or stroke (B) were calculated using a fixed-effects model. RR for each study is displayed numerically on the left and graphically on the right. Total events and sample sizes are also displayed for each study. For study name, the first author’s name was used to represent each trial. If the same first author was involved in two trials, then the publication year was also included to identify the trial. For each trial the position of the square denoted incidence, horizontal lines represent 95% CI, and diamond plot represents overall results of the included trials. The size of the squares is directly proportional to the amount of data in each trial.

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