Noncardiac QTc-Prolonging Drugs May Increase Risk of Sudden Cardiac Death  CME

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
Disclosures

May 13, 2005 — Noncardiac QTc-prolonging drugs increase the risk of sudden cardiac death almost threefold, according to the results of a population-based case-control study published in the May 11 Advance Access issue of the European Heart Journal.

"The risk of sudden cardiac death was higher among recent starters (within around 90 days) and was significantly increased in users of GI [gastrointestinal] medication and antipsychotics," said Bruno Stricker, from the Erasmus Medical Center in Rotterdam, the Netherlands, in a news release. "Past use was not associated with increased risk. Although the antibiotics have been reported to be linked to sudden cardiac death, we found no statistically significant increase in our study, although that may have been due to the limited number of cases."

Using the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500,000 people, the investigators reviewed all deaths from Jan. 1, 1995, to Sept. 1, 2003. Sudden cardiac death was classified on the basis of time from onset of cardiovascular symptoms to death. Up to 10 random controls were matched to each case on the basis of age, gender, date of sudden death, and general practice. The study sample consisted of 775 cases of sudden cardiac death and 6,297 matched control subjects.

At the index date, the use of noncardiac QTc-prolonging drugs was categorized as current use, past use, or nonuse. Current use of any noncardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted odds ratio [OR], 2.7; 95% confidence interval [CI], 1.6 - 4.7), with risk highest in women and in recent starters.

"Although prolongation of the QTc interval by non-cardiac drugs is not an unusual finding, potentially fatal arrhythmias and sudden cardiac death are relatively uncommon," Dr. Stricker said. "Nevertheless, our results suggest that 320 cases a year of sudden cardiac death can be attributed to QTc-prolonging medication in the Netherlands and, by extrapolation, around 9,000 in Europe and 6,000 [in] the USA."

Study limitations include possible misclassification of outcomes, noncardiac origin of some acute deaths, use of outpatient prescription data rather than records of medication use, and possible residual confounding.

"These findings are important to regulatory authorities because QTc prolongation is used as a surrogate marker for the prediction of serious adverse drug effects and the authorities have to evaluate the clinical significance of QTc prolongation observed in relatively small clinical trials where there were no cases of sudden death," Dr. Stricker concluded.

Eur Heart J. Posted online May 11, 2005.

Clinical Context

Sudden cardiac death is defined as death within one hour of acute onset of cardiac symptoms or an unwitnessed, unexpected death of someone seen in stable medical condition within 24 hours with no evidence of a noncardiac cause. The majority of such deaths are believed to be caused by ventricular fibrillation with a complex interplay between myocardial injury, acute and chronic coronary events, autonomic state, electrolyte balance, and genetic factors. Prolongation of QTc interval has been documented with both cardiac and noncardiac drugs such as cisapride and domperidol (GI), haloperidol (antipsychotic), and macrolides (antibiotics), including erythromycin and clarithromycin, according to the authors of the current study. Current evidence suggests that 5% to 10% of persons in whom cardiac arrhythmias occur carry a silent mutation in one of the genes responsible for the congenital long QTc syndrome.

Using list 1 from the most recent version of the International Registry for Drug-Induced Arrhythmias maintained by Georgetown University, in Washington, DC, the authors conducted a longitudinal case-control study to compare the risk for sudden death in users of these drugs with that for nonusers in the Netherlands using the IPCI database.

Study Highlights

• All data were retrieved during an 8-year period from the IPCI project, an observational database with records of 500,000 patients under the care of 150 general practitioners (GPs).
• Symptoms and diagnoses were classified in free text and using the International Classification for Primary Care. Stored data included prescriptions, laboratory and radiologic tests, and referrals to specialists.
• Inclusion criteria were age older than 18 years and registration with a participating GP in the IPCI project for at least 1 year. Patients with cancer were excluded.
• Case selection was based on the most recent definition of witnessed and unwitnessed sudden death. Index date was the date on which sudden death occurred.
• Use of drugs was considered current if the index date fell within a maximum of 30 days after the end of the last prescription. Use was considered past if the drug was discontinued more than 7 days before a GI or antibiotic medication, or more than 30 days before the index date for an antipsychotic medication. If patients had no prescription for any type of QTc-prolonging drugs, they were considered nonusers.
• Daily dose equivalents (DDDs) as defined by the World Health Organization were calculated, and daily dose was classified as less than 1 or 1 or more DDDs. Among current users, the effect of use duration was assessed.
• Covariates included cardiovascular ischemia, cerebrovascular disease, hypertension, heart failure, diabetes, hypercholesterolemia, arrhythmia, alcohol use, and smoking.
• Relative risk of sudden death during the use of noncardiac QTc-prolonging drugs was estimated with the OR, using logistic regression.
• All subjects were followed up until death, transfer out of practice, date of last data collection, or end of the study period.
• In the source population, 806 sudden cardiac deaths were identified representing an incidence of 1 per 1,000 person-years. 4% of cases for which no controls were found were excluded.
• The study population comprised 775 cases of sudden death and 6,297 matched control subjects (ratio, 1:8).
• Median age was 72 years and 61% were male. 56.4% of sudden deaths were witnessed and 43.6% were unwitnessed.
• Use of cardiovascular medication was associated with sudden death (use of diuretics: OR, 2.5; use of cardiac glycosides: OR, 3.3). Socioeconomic status was not associated with sudden death.
• Risk of sudden death was increased with heart failure (OR, 4.8), smoking (OR, 2.2), ischemic vascular disease (OR, 2.3), diabetes (OR, 2.0), arrhythmia (OR, 1.9), smoking or hypercholesterolemia (OR, 1.7) and hypertension (OR, 1.3).
• Current use of a QTc-prolonging noncardiac drug was associated with an almost threefold increase in risk of sudden death (adjusted OR, 2.7; 95% CI, 1.6 - 4.7).
• The risk was highest in recent starters (</= 90 days), higher in women than in men (OR, 3.1 vs 2.1), and in older patients (OR, 2.7 for those older than 65 years vs 2.3 for those younger than 65 years), but differences were not statistically significant.
• The risk was significantly increased in users of GI and antipsychotic drugs. The risk was higher for users of higher doses and in those who used antipsychotics (OR, 5.0), predominantly haloperidol (OR, 5.6). The risk was higher for those who used domperidol (OR, 3.8) vs cisapride (OR, 1.2).
• For witnessed sudden deaths, the association with current use of noncardiac QTc-prolonging drugs was stronger (OR, 2.9) than those for unwitnessed deaths (OR, 2.3).
• The results suggested that 320 cases of sudden death per year can be attributed to QTc-prolonging drugs in the Netherlands, which extrapolates to 9,000 in Europe and 6,000 in the US.

Pearls for Practice

• Sudden cardiac death is associated with the use of cardiac drugs such as diuretics and glycosides, and noncardiac QTc-prolonging drugs including GI, antipsychotic, and antibiotic drugs.
• Risk of sudden death associated with use of noncardiac QTc-prolonging drugs is higher in women, with higher doses of drugs and for witnessed deaths.

Legal Disclaimer

• This activity has expired.

  The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to the timeliness of expired CME activities.

• CME Information