Potential Drawbacks of ICS/LABA/LAMA Triple Fixed-Dose Combination Therapy in the Treatment of Asthma: A Quantitative Synthesis of Safety Profile

Figures & data

Figure 1 PRISMA 2020 flow diagram for the identification of Phase III RCTs included in the meta-analysis concerning the safety profile of triple FDC in asthma.

Note: Adapted from Moher D, Shamseer L, Clarke M, et al.Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcod.⁶

Abbreviations: FDC, fixed-dose combination; ICS, inhaled corticosteroid; LABA, long-acting β₂-adrenoceptor agonist; LAMA, long-acting muscarinic antagonist; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomized controlled trial.

Table 1 Level of ICS Doses in Agreement with the Daily Doses of Medications in Adults in the Phase III RCTs Included in the Meta-Analysis as Reported by Current GINA Recommendations¹⁰ and NICE Guidelines.¹¹

Treatment	Regimen of Administration	Daily Dose	Level of ICS Dose
BDP	200 µg b.i.d.	400 µg	Medium-dose
	400 µg b.i.d.	800 µg	High-dose
FF	100 µg q.d.	100 µg	Medium-dose^a
	200 µg q.d.	200 µg	High-dose^a
MOM	80 µg q.d.	80 µg	Medium-dose^b
	160 µg q.d.	160 µg	High-dose^b
	320 µg q.d.	320 µg	High-dose^b

Notes: ^aThe dose levels refer to those reported in the NICE guidelines.¹¹ bThe medium-dose 80 µg and the high-dose 160 µg of MOM delivered via Breezhaler^® device correspond to the medium-dose 400 µg and the high-dose 800 µg of MOM delivered via the approved Twisthaler^® formulation.²⁶.

Abbreviations: b.i.d., bis in die (twice-daily); BDP, beclomethasone dipropionate; FF, fluticasone furoate; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; MOM, mometasone furoate; NICE, National Institute for Health and Care Excellence; q.d., quaque die (once-daily); RCT, randomized controlled trial.

Figure 2 Forest plot of meta-analysis concerning the impact of triple FDC vs ICS/LABA FDC on the risk of total SAEs. The effect estimates resulting from the meta-analysis are reported in bold.

Abbreviations: BDP, beclomethasone dipropionate; BID, bis in die (twice daily); DPI, dry powder inhaler; FDC, fixed-dose combination; FF, fluticasone furoate; FOR, formoterol fumarate; GLY, glycopyrronium bromide; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-adrenoceptor agonist; MOM, mometasone furoate; pMDI, pressurized metered dose inhaler; QD, quaque die (once daily); SAE, serious adverse event; UMEC, umeclidinium bromide; VI, vilanterol.

Figure 3 Forest plots of meta-analysis concerning the impact of triple FDC vs ICS/LABA FDC on the risk of cardiac SAEs (A) and vascular SAEs (B). (B’) reports the overall sensitivity meta-analysis by excluding the comparison (FF/VI/UMEC 200/25/31.25 vs FF/VI 200/25) that introduced substantial heterogeneity in the subgroup high-dose ICS. The effect estimates resulting from the meta-analysis are reported in bold.

Abbreviations: BDP, beclomethasone dipropionate; BID, bis in die (twice daily); DPI, dry powder inhaler; FDC, fixed-dose combination; FF, fluticasone furoate; FOR, formoterol fumarate; GLY, glycopyrronium bromide; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-adrenoceptor agonist; MOM, mometasone furoate; pMDI, pressurized metered dose inhaler; QD, quaque die (once daily); SAE, serious adverse event; UMEC, umeclidinium bromide; VI, vilanterol.

Figure 4 Forest plots of meta-analysis concerning the impact of triple FDC vs ICS/LABA FDC on the risk of pneumonia reported as SAE. The effect estimates resulting from the meta-analysis are reported in bold.

Abbreviations: BDP, beclomethasone dipropionate; BID, bis in die (twice daily); DPI, dry powder inhaler; FDC, fixed-dose combination; FF, fluticasone furoate; FOR, formoterol fumarate; GLY, glycopyrronium bromide; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-adrenoceptor agonist; MOM, mometasone furoate; pMDI, pressurized metered dose inhaler; QD, quaque die (once daily); SAE, serious adverse events; UMEC, umeclidinium bromide; VI, vilanterol.

Table 2 Pooled Analysis of Total SAEs, Cardiovascular SAEs, and Pneumonia with Number of Events, Frequency, and Rank According to EMA Guidelines.¹⁴

	Medium-Dose ICS/LABA/LAMA FDC (N=2004; CAPTAIN, IRIDIUM, TRIMARAN)			High-Dose ICS/LABA/LAMA FDC (N=1999; CAPTAIN, IRIDIUM, TRIGGER)			Medium-Dose ICS/LABA FDC (N=1589; CAPTAIN, IRIDIUM, TRIMARAN)			High-Dose ICS/LABA FDC (N=1592; CAPTAIN, IRIDIUM, TRIGGER)
	Events	Frequency	Rank	Events	Frequency	Rank	Events	Frequency	Rank	Events	Frequency	Rank
Total SAEs	118	5.89	Common	118	5.90	Common	85	5.35	Common	106	6.66	Common
Cardiovascular SAEs	14	0.70	Uncommon	17	0.85	Uncommon	13	0.82	Uncommon	12	0.75	Uncommon
Cardiac SAEs	10	0.50	Uncommon	8	0.40	Uncommon	12	0.76	Uncommon	9	0.57	Uncommon
Angina unstable	1	0.05	Rare	1	0.05	Rare	2	0.13	Uncommon	0	0.00	FNK
Myocardial infarction	2	0.10	Uncommon	1	0.05	Rare	2	0.13	Uncommon	1	0.06	Rare
Acute coronary syndrome	2	0.10	Uncommon	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK
Acute myocardial infarction	2	0.10	Uncommon	2	0.10	Uncommon	0	0.00	FNK	1	0.06	Rare
Angina pectoris	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Atrial fibrillation	2	0.10	Uncommon	1	0.05	Rare	1	0.06	Rare	1	0.06	Rare
Atrial flutter	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Acute cardiac event	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Arrhythmia	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Atrioventricular block complete	0	0.00	FNK	1	0.05	Rare	1	0.06	Rare	0	0.00	FNK
Cardiac failure	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Cardiac failure congestive	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Cardiac tamponade	0	0.00	FNK	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK
Myocardial ischaemia	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Palpitations	0	0.00	FNK	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK
Supraventricular tachycardia	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Ventricular extrasystoles	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Cardiovascular death due to heart failure	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK
Heart failure due to left ventricular dysfunction	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare	0	0.00	FNK
Sudden cardiac death	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Worsening of heart failure	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Vascular SAEs	4	0.20	Uncommon	9	0.45	Uncommon	1	0.06	Rare	3	0.19	Uncommon
Circulatory collapse	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Hypertensive crisis	0	0.00	FNK	2	0.10	Uncommon	0	0.00	FNK	0	0.00	FNK
Angiopathy	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Aortic dissection	0	0.00	FNK	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK
Aortic dissection rupture	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK
Deep vein thrombosis	0	0.00	FNK	2	0.10	Uncommon	1	0.06	Rare	0	0.00	FNK
Hypertension	2	0.10	Uncommon	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK
Thrombophlebitis	0	0.00	FNK	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK
Varicose vein	0	0.00	FNK	2	0.10	Uncommon	0	0.00	FNK	0	0.00	FNK
Acute ischaemic stroke	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK	1	0.06	Rare
Death due to haemorrhagic stroke	0	0.00	FNK	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK
Ischaemic stroke	1	0.05	Rare	0	0.00	FNK	0	0.00	FNK	0	0.00	FNK
Pneumonia	5	0.25	Uncommon	11	0.55	Uncommon	8	0.50	Uncommon	9	0.57	Uncommon

Notes: Rank: common ≥1/100 to <1/10, uncommon ≥1/1000 to <1/100, rare ≥1/10,000 to <1/1000. Treatments and high-level categories used to group adverse events are reported in bold.

Abbreviations: EMA, European Medicine Agency; FDC, fixed-dose combination; FNK, frequency not known; ICS, inhaled corticosteroid; LABA, long-acting β₂-adrenoceptor agonist; LAMA, long-acting muscarinic antagonist, SAEs, serious adverse events.

Figure 5 Traffic light plot for assessment of the risk of bias of each included Phase III RCT (A) and weighted plot for the assessment of the overall risk of bias (B) via the Cochrane RoB 2 tool (n=4 Phase III RCTs). The overall risk of bias resulting from the Cochrane RoB 2 tool is reported in bold.

Abbreviations: D1, bias arising from the randomization process; D2, bias due to deviations from intended intervention; D3, bias due to missing outcome data; D4, bias in measurement of the outcome; D5, bias in selection of the reported result; RCT, randomized controlled trial; RoB, risk of bias; robvis, risk of bias visualization tool. Green circle represents low risk of bias.

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