QT Interval Prolongation Associated with Intramuscular Ziprasidone in Chinese Patients: A Case Report and a Comprehensive Literature Review with Meta-Analysis

Table 1

Summary of IM ziprasidone trials.

Study	Design	Subjects ()	Dose^1	Main findings
Brook et al., 2000 [9]	International multicenter RCT; (IM ZIP versus HAL^2) 3 d IM then 4 d PO	(90 versus 42)	10–80	No pt in any group had QTc >500 ms; ZIP mean QTc change^3 in ms: 2.14 (versus 2.22 HAL)
Brook et al., 2005 [1]	International multicenter RCT; (IM ZIP versus HAL^2); 3 d IM then 6 wk PO	(427 versus 138)	10–20	No pt in any group had QTc >500 ms; Mean ZIP endpoint QTc in ms: 389.9 (versus 383.7 HAL); Mean ZIP QTc change^2 in ms: 3.2 (versus −3.5 HAL)
Chen et al., 2010^3 [10]	7 d open parallel RCT; (IM ZIP versus HAL^2)	(40 versus 40)	10–60	1 ZIP pt withdrew after a QTc prolongation
Daniel et al., 2001 [11]	24 h double-blind RCT	(38 versus 41)	2, 20	Mean QTc change^3 in ms: 3.5 (2 mg) and −1.3 (20); Maximum QTc recorded was 475 ms
Daniel et al., 2004 [12]	Multicenter RCT; (3 IM ZIP doses versus HAL^2); 3 d IM, then 4 d PO	(69, 71, 66, 100 HAL)	20, 40, 80	No pt in any group had QTc >500 ms; Mean QTc change^3 in ms: 0.7 (20 mg), −2.9 (40), and 0.5 (80); −0.5 (HAL)
Emul et al., 2009 [13]	Open-label prospective trial; (schizophrenia versus healthy; controls; baseline versus 1.4–2 h; after IM ZIP	(11 versus 11)	20	IM ZIP did not appear to influence atrial and; ventricular electrical conduction in drug-free; schizophrenia inpts; schizophrenia may affect; atrial conduction resulting in atrial fibrillation
Jiang et al., 2008^4 [14]	3 d open parallel-group RCT; (IM ZIP versus HAL^4)	(36 versus 35)	10–40	No pt in any group had QTc >500 ms
Lesem et al., 2001 [15]	24 h double-blind RCT	(54 versus 63)	2, 10	Mean QTc change^3 in ms: −3.7 (2 mg) and −1.8 (10)
Li et al., 2010^4 [16]	5 d double-blind parallel-group; RTC (IM ZIP versus HAL^2)	(38 versus 37)	10–30	3 pts experienced QTc prolongation (ms): 430, 450 and, 510
Mautone and Scarone, 2011 [17]	Phase IIIb noncomparative(3 d IM then PO for 8 w)	(150)	10	Mean QTc change^3 in ms in 3 pts: 110 (2 d), 70 (5 d), and 55 (10 d). 2 pts discontinued due to QTc prolongation
Micelli et al., 2005 [18]	Phase I study in healthy volunteers: single 5, 10,; or 20 mg IM dose; HAL^2)	(24)	5–20	ZIP and HAL were associated with modest QTc increases
Miceli et al., 2010 [19]	3 d single-blind parallel-group	(31 versus 27)	20–30	Mean QTc change (ms):^3 1st IV 4.6 (ZIP) and 6.0 (HAL); 2nd IV 12.8 (ZIP) and 14.7 (HAL); No pt had QTc >480 ms; QTc ≥450 ms and QTc changes >60 ms: 2 in ZIP (0 in HAL)
Preval et al., 2005 [20]	Naturalistic study (IM ZIP versus first-generation antipsychotics)	(19 versus 80)	20	No patient in the IM ZIP group had QTc >460 ms
Rais et al., 2010 [21]	A 24 h open-label prospective; study in geriatric population	(16)	10–20	Mean QTc range in ms: baseline 382.0–429.5; versus trial: 428.1–370.0
Tambyraja and Strawn, 2011 [4]	Case report (70 yo vascular dementia)	(1♀)	20	Patient lost consciousness within 45 min of ZIP IM; Pulseless, hypotensive, and poor perfusion signs; ECG: bradycardia (30–40 bpm) with 3rd degree block
Li et al., 2010^4 [16]	3 d double- or single-blind parallel-group RCT (IM ZIP versus HAL^2)	(16 versus 16)	20–40	No significant QTc prolongations in ZIP or HAL
Witsil et al., 2012 [2]	Case report (history of substance abuse)	(1♂)	20	Baseline ECG showed QT/QTc of 484/475 ms. Palpitations and weakness 45 min after IM ZIP; Maximum in repeated ECGs: QT/QTc of 612/517 ms
Yin and Wang, 2012^4 [22]	3 d open parallel-group RCT (IM ZIP versus HAL^2)	(30 versus 30)	10–40	Maximum QTc in ZIP: 461 ms.
Zhang et al., 2013^4 [7]	3 d rater-blind, actively-controlled parallel group multicenter RCT (IM ZIP versus HAL^2)	(189 versus 187)	10–40	ZIP mean QTc change^3 in ms: 0.7 (versus −1.6 HAL)^5; ZIP: 3 pts with QTC ≥450 ms. None with QTC ≥450 ms; HAL: 2 pts with QTC ≥480 ms and 1 with QTC ≥500 ms

bpm: beats per minute; d: day; ECG: electrocardiogram; h: hour; HAL: haloperidol; inpts: inpatients; IM: intramuscular;
IV: intravenous; min: minutes; ms: milliseconds; PO: by mouth; pt: patient; RCT: randomized controlled trial; QTc: QTc interval; wk: week; yo: year-old; ZIP: ziprasidone.
¹Ziprasidone dose in mg/day.
²HAL dose ranged from 5 to 20 mg/day in the various studies.
³QTc change from baseline to end of treatment.
⁴In Chinese.
⁵Effect size of the mean difference = 0.009. It was calculated using Cohen’s method [23].