. Author manuscript; available in PMC: 2019 Dec 1.

Published in final edited form as: Lancet Oncol. 2018 Nov 12;19(12):1579–1589. doi: 10.1016/S1470-2045(18)30608-9

Table 2. Reporting Odds-Ratio (ROR) and its 95% confidence interval (CI), comparing selected cardiovascular adverse events (detected as signals) in overall immunotherapy (IMU) vs. full database (full); combined immunotherapy (COMB) vs. monoimmunotherapy (MONO); mono-immunotherapy with anti-PD-1/PD-L1 (PD1) vs. mono-immunotherapy with anti-CTLA-4 (CTLA4) from VigiBase (time period: 01/2008 to 01/2018).

Significant over-reporting are in bold after Bonferroni-adjustment for multiple tests within immunotherapy subgroups (p≤(0.05/10 tests)=> p≤0.005). First reports of ICSRs associated with ICI started in 2008.

	Overall immunotherapy (IMU; n: 31,321)
Total number of ICSRs	MONO (n: 28,909)		COMB (n: 2,412)	Full database (full; starting 2008; n: 12,455,401)	ROR and 95% CI [,] PD1 vs. CTLA4	ROR and 95% CI [,] COMB vs. MONO	ROR and 95% CI [,] IMU vs. full
Total number of ICSRs	MONO-PD1 (n: 20,643)	MONO-CTLA4 (n: 8,266)	COMB (n: 2,412)	Full database (full; starting 2008; n: 12,455,401)	ROR and 95% CI [,] PD1 vs. CTLA4	ROR and 95% CI [,] COMB vs. MONO	ROR and 95% CI [,] IMU vs. full

Number of ICSRs by CV-ADR subgroup
Myocarditis	84 (0.41%)	6 (0.07%)	32 (1.3%)	4,454 (0.04%)	5.62 [2.46–12.88]	4.31 [2.86–6.38]	11.21 [9.36–13.43]
Pericardial diseases	74 (0.36%)	13 (0.16%)	8 (0.33%)	10,009 (0.08%)	2.28 [1.27–4.12]	1.1 [0.53–2.24]	3.8 [3.08–4.62]
Vasculitis	56 (0.27%)	18 (0.22%)	8 (0.33%)	20,987 (0.2%)	1.25 [0.73–2.12]	1.3 [0.62–2.67]	1.56 [1.25–1.94]
Number of ICSRs in vasculitis-ADR subgroup
Temporal arteritis	7 (0.03%)	10 (0.12%)	1 (0.04%)	568 (<0.01%)	0.28 [0.11–0.74]	0.71 [0.07–3.94]	12.99 [8.12–20.77]
Polymyalgia rheumatica	14 (0.07%)	1 (0.01%)	1 (0.04%)	1254 (0.01%)	5.61 [0.74–42.66]	0.8 [0.08–4.62]	5.13 [3.13–8.40]

Overall immunotherapy (IMU): Any individual case safety report related to nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab or tremelimumab.

Mono immunotherapy (MONO):

Any individual case safety report related to any of the following 7 drugs only when used alone (monotherapy) =>

Anti PD-1/PD-L1 monotherapy: any of nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab used alone (MONO-PD1)
Anti CTLA-4 monotherapy: ipilimumab or tremelimumab alone (MONO-CTLA4)

Combination immunotherapy (COMB):

Any individual case safety report related to at least one drug from Anti PD-1/PD-L1 inhibitors combined to an Anti CTLA-4

Abbreviations: ICSRs, individual case safety reports