Ziprasidone and the Corrected QT Interval: A Comprehensive Summary of Clinical Data
CNS Drugs,  Clinical Article

Camm AJ et al. – The analyses provide the first comprehensive summary of QT interval (QTc) changes associated with ziprasidone based on Pfizer–sponsored phase II–IV randomized controlled trials (RCTs), safety reports and post–marketing surveillance. The results of the analyses of pooled data from phase II–IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60 ms and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post–marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Methods
  • The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone:
    • Post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies
    • Post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults
    • Post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects
    • Cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia
    • A large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18,154 subjects with schizophrenia (the only previously reported results included here); and
    • Cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007.

Results
  • A total of 4306 adults received ziprasidone in placebo- and active-comparator phase II–IV RCTs and had evaluable QTc data.
  • One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms.
  • QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%).
  • In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms.
  • Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects.
  • A scatter-plot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms.
  • The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration.
  • The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use.
  • Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs.

Please login or register to follow this author.
► Click here to access PubMed, Publisher and related articles...
<< Previous Article | Next Article >>

Your Unread Messages in Cardiology

See All >> Messages include industry-sponsored communications and special communications from MDLinx

Most Popular Cardiology Articles

1 Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation European Heart Journal, September 16, 2014    Clinical Article

2 Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized, controlled trials Hypertension, September 29, 2014    Evidence Based Medicine    Review Article

3 Effects of tea intake on blood pressure: A meta-analysis of 21 randomized controlled trials JACC - Journal of the American College of Cardiology, October 22, 2014    Clinical Article

4 A systematic review of statin-induced muscle problems in clinical trials American Heart Journal, October 7, 2014    Review Article

5 Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy EP Europace, September 19, 2014    Clinical Article

6 Effect of statins in preventing contrast-induced nephropathy: an updated meta-analysis Coronary Artery Disease, October 2, 2014    Clinical Article

7 Comparison of safety of sotalol versus amiodarone in patients with atrial fibrillation and coronary artery disease The American Journal of Cardiology, September 5, 2014    Clinical Article

8 Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population American Heart Journal, October 6, 2014    Clinical Article

9 Effect of Nicorandil in patients with heart failure: A systematic review and meta-analysis Cardiovascular Therapeutics, October 17, 2014    Evidence Based Medicine    Review Article    Clinical Article

10 New oral anticoagulants for the treatment of venous thromboembolism: understanding differences and similarities Drugs, October 10, 2014    Review Article

11 The effect of indapamide versus hydrochlorothiazide on ventricular and arterial function in patients with hypertension and diabetes: Results of a randomized trial American Heart Journal, October 1, 2014    Clinical Article

12 Effect of different dose aspirin on coronary artery lesions in the acute phase of Kawasaki disease JACC - Journal of the American College of Cardiology, October 21, 2014    Clinical Article

13 Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid Journal of Thrombosis and Haemostasis, September 25, 2014    Clinical Article

14 Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion Clinical Therapeutics, August 19, 2014    Clinical Article

15 Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: A subanalysis of the apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial American Heart Journal, October 13, 2014    Clinical Article

16 Tea consumption is inversely related to 5-year blood pressure change among adults in Jiangsu, China: A cross-sectional study Full Text Nutrition Journal, October 24, 2014    Free full text    Clinical Article

17 Endovascular versus medical therapy for atherosclerotic renovascular disease Current Atherosclerosis Reports, October 23, 2014    Clinical Article

18 Starting primary prevention earlier with statins The American Journal of Cardiology, October 15, 2014    Clinical Article

19 Ischemic postconditioning versus remote ischemic conditioning in patients treated with primary percutaneous coronary intervention: A Bayesian network meta-analysis JACC - Journal of the American College of Cardiology, October 16, 2014    Clinical Article

20 Prasugrel vs. clopidogrel in acute coronary syndrome patients treated with prasugrel Journal of Clinical Pharmacy and Therapeutics, September 24, 2014    Clinical Article

Indexed Journals in Cardiology: American Heart Journal, American Journal of Cardiology, Circulationn, Heartmore