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QTc INTERVAL AND RISK AJC 1993; 72:21B. Relative Risk of Arrhythmias = 1.052 x where x = msec increase/10 above QTc 440msec QTc = 440msec Risk = 1.052 0 = 1.0 QTc = 500msec Risk = 1.052 6 = 1.4 QTc = 640msec Risk = 1.052 20 = 2.8. DRUGS AND QTc: ISSUES.
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QTc INTERVAL AND RISKAJC 1993; 72:21B • Relative Risk of Arrhythmias = 1.052x • where x = msec increase/10 • above QTc 440msec • QTc = 440msec Risk = 1.0520 = 1.0 • QTc = 500msec Risk = 1.0526 = 1.4 • QTc = 640msec Risk = 1.05220= 2.8
DRUGS AND QTc: ISSUES • 1. QTc prolongation and risk: exponential • 2. Magnitude of the QTc signal: • mean QTc; range & outliers • 3. Drug effect on QTc: • a. direct: e.g., sotalol, cisapride • b. indirect (interaction): • i) drug-drug: terfenadine + ketoconazole • ii) drug-gene: LQTS mutation/polymorphism
DRUGS AND QTc: Questions • 1. Do the pre-clinical studies indicate an effect on ventricular repolarization? • 2. Do clinical studies indicate a QTc signal? • 3. What is the magnitude of the QTc signal? • 4. Are there potential drug interactions? • 5. Does the drug have unique characteristics?