Longitudinal study based on a safety registry for malaria patients treated with artenimol–piperaquine in six European countries

Vignier, Nicolas; Bouchaud, Olivier; Angheben, Andrea; Bottieau, Emmanuel; Calleri, Guido; Salas-Coronas, Joaquín; Martin, Charlotte; Ramos, José Manuel; Mechain, Matthieu; Rapp, Christophe; Nothdurft, Hans-Dieter; Velasco, Maria; Bardají, Azucena; Rojo-Marcos, Gerardo; Visser, Leo G.; Hatz, Christoph; Bisoffi, Zeno; Jelinek, Tomas; Duparc, Stephan; Bourhis, Yann; Tommasini, Silva; Iannucelli, Maurizio; Bacchieri, Antonella; Mattera, Giovan Giuseppe; Merlo Pich, Emilio; Behrens, Ronald H.

doi:10.1186/s12936-021-03750-x

Table 5 Factors associated with the change in QTcF and QTcB from baseline to the final treatment day or strict final treatment day

From: Longitudinal study based on a safety registry for malaria patients treated with artenimol–piperaquine in six European countries

	QTcF population (N = 143)				Strict QTcF population (N = 60)		QTcB population (N = 143)				Strict QTcB population (N = 60)
	n	Change in QTcF value from baseline to the final treatment day (ms): mean [CI95%]	ANOVA: p-value and R-squared	Multivariate analysis (ANOVA, backward selection process)	n	Change in QTcF value from baseline to the strict final treatment day (ms): mean [CI95%]	n	Change in QTcF value from baseline to the final treatment day (ms): mean [CI95%]	ANOVA: p-value and R-squared	Multivariate analysis (ANOVA, backward selection process)	n	Change in QTcF value from baseline to the strict final treatment day (ms): mean [CI95%]
Total	143	18.9 [14.8; 23.0]			60	17.5 [12.6; 22.4]	143	3.3 [− 0.8; 7.4]			60	2.6 [− 3.3; 8.5]
Sex
Male	98	18.7 [14.1; 23.4]	p = 0.90		42	17.4 [10.9; 23.8]	98	3.9 [− 1.0; 8.8]	p = 0.67		42	2.9 [− 4.4; 10.3]
Female	45	19.3 [10.9; 27.6]	R² = 0.0%		18	17.7 [10.4; 25.0]	45	2.0 [− 6.0; 10.0]	R² = 0.1%		18	1.7 [− 9.0; 12.5]
Age category
< 18 years old	6	26.5 [1.0; 52.0]	p = 0.44		3	14.0 [_34.0; 62.0]	6	− 0.5 [− 19.6; 18.6]	p = 0.71		3	− 13.0 [− 35.0; 9.1]
≥ 18 years old	137	18.6 [14.4; 22.8]	R² = 0.4%		57	17.6 [12.6; 22.7]	137	3.5 [− 0.8; 7.7]	R² = 0.1%		57	3.4 [− 2.7; 9.5]
≤ 65 years old	139	18.4 [14.3; 22.6]	p = 0.19	Not retained	58	17.0 [12.0; 22.0]	139	2.5 [− 1.6; 6.7]	p = 0.03	Not retained	58	1.6 [− 4.3; 7.4]
> 65 years old	4	35.0 [20.9; 49.1]	R² = 1.2%	Not retained	2	31.0 [− 57.9; 119.9]	4	30.5 [4.4; 56.6]	R² = 3.4%	Not retained	2	32.0 [− 120.5; 184.5]
Ethnicity
African	118	18.3 [13.7; 23.0]	p = 0.54		51	17.2 [11.6; 22.7]	118	2.3 [− 2.5; 7.0]	p = 0.29		51	1.6 [− 5.1; 8.3]
Others	25	21.6 [13.1; 30.2]	R² = 0.3%		9	19.2 [7.9; 30.5]	25	8.1 [0.2; 16.0]	R² = 0.8%		9	8.1 [− 4.2; 20.4]
Smoking status
Never smoked	101	17.1 [12.3; 21.9]	p = 0.18	Not retained	40	15.0 [10.3; 19.7]	101	0.2 [− 4.7; 5.1]	p = 0.02	p = 0.0204	40	− 0.0 [− 6.2; 6.2]
Previous, current smoker or missing information	42	23.2 [15.3; 31.1]	R² = 1.3%	Not retained	17	22.4 [10.6; 34.2]	42	10.8 [3.4; 18.2]	R² = 3.8%	R² = 3.8%	20	7.8 [− 5.5; 20.9]
Alcohol consumption
Never/on special occasions	115	19.3 [14.6; 23.9]	p = 0.74		45	19.3 [14.1; 24.6]	115	3.2 [− 1.4; 7.8]	p = 0.92		45	3.7 [− 2.7; 10.0]
Ex- or current consumer or missing information	28	17.5 [8.3; 26.7]	R² = 0.1%		15	11.9 [− 0.7; 24.5]	28	3.8 [− 6.3; 13.8]	R² = 0.0%		15	− 0.8 [− 16.1; 14.5]
APQ administered at least 3 h from any meal
Yes	95	19.1 [14.2; 24.1]	p = 0.87		41	20.8 [14.3; 27.2]	95	1.9 [− 3.3; 7.1]	p = 0.35		41	5.3 [− 2.3; 13.0]
No or missing information	48	18.4 [10.9; 26.0]	R² = 0.0%		19	10.4 [3.9; 16.8]	48	6.0 [− 0.9; 13.0]	R² = 0.6%		19	− 3.4 [− 12.5; 5.6]
Patient having taken other treatments known to prolong QTc
Yes	33	20.6 [12.0; 29.3]	p = 0.65		13	17.7 [8.0; 27.3]	33	7.3 [− 0.8; 15.4]	p = 0.30		13	8.7 [− 4.4; 21.8]
No	110	18.4 [13.7; 23.1]	R² = 0.1%		47	17.4 [11.6; 23.2]	110	2.1 [− 2.7; 6.9]	R² = 0.8%		47	0.9 [− 5.9; 7.6]
Liver abnormalities at baseline
Yes	25	15.9 [5.9; 25.9]	p = 0.51		12	11.8 [− 3.0; 26.6]	25	1.9 [− 6.9; 10.6]	p = 0.76		12	2.3 [− 13.1; 17.8]
No or missing information	118	19.5 [15.0; 24.1]	R² = 0.3%		48	18.9 [13.7; 24.0]	118	3.6 [− 1.1; 8.3]	R² = 0.1%		48	2.6 [− 4.0; 9.2]
Renal abnormalities at baseline
Yes	3	27.7 [2.8; 52.5]			2	32.5 [27.0; 38.0]	3	23.7 [− 27.3; 74.6]			2	34.0 [− 93.1; 161.1]
No or missing information	140	18.7 [14.6; 22.9]			58	16.9 [11.9; 22.0]	140	2.9 [− 1.3; 7.0]			58	1.5 [− 4.4; 7.4]

QTcF/B: corrected QT interval with Fridericia’s or Bazett’s formulae, QTcF/B population: patients with corrected QT interval calculated using Fridericia’s formulae/Bazett’s formulae, ms: millisecond, CI95%: 95% confidence interval, R²: R-squared, APQ: artenimol-piperaquine; Strict QTcF/B population: patients with corrected a QT interval calculated at the strict final treatment day

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