Presenter: Kenneth Ellenbogen, MD, Professor of Medicine, Virginia Commonwealth University Medical College of Richmond
Tecadenoson (CT-510) is a selective A1-adenosine receptor agonist currently under clinical investigation for the treatment of supraventricular tachyarrhythmias. Tecadenoson is believed to prolong AV nodal conduction by selective activation of the A1-adenosine receptors without causing the A2-adenosine receptor-mediated reductions in blood pressure or the A2B-, A3-adenosine-mediated bronchospasms that are seen with adenosine, the commonly used treatment. Although adenosine also has potential benefit in preventing recurrent arrhythmias, tecadenoson appears to have a longer elimination half-life. The drug is under development by CV Therapeutics (Palo Alto, California) and is not yet approved for marketing in the United States or elsewhere.
As presented at a special session of the 2002 AHA Scientific Sessions, the results of the Trial to Evaluate the Management of PSVT during Electrophysiologic Study with Tecadenoson (TEMPEST), the first phase 3 study with tecadenoson, show that 5 different dosing regimens were able to rapidly convert paroxysmal supraventricular tachycardia (PSVT) in up to 90% of patients without significant adverse symptoms or hemodynamic effects.
TEMPEST was an international, multicenter, randomized, double-blind, placebo-controlled study carried out at 34 sites in the United Kingdom and the United States. It included 181 patients with ≥ 1 documented episode of spontaneous symptomatic tachyarrhythmia consistent with PSVT. After PSVT was induced and sustained for ≥ 2 minutes, tecadenoson or placebo was administered as rapid intravenous bolus in 151 and 30 patients, respectively. If PSVT persisted for 1 minute after administration of the study drug, a second dose was administered. Five active tecadenoson regimens were evaluated:
75 mcg/150 mcg (first dose/second dose)
150 mcg/300 mcg
300 mcg/300 mcg
450mcg/900 mcg
900 mcg/900 mcg
Each tecadenoson regimen resulted in significantly higher therapeutic conversion rates compared with placebo (intent-to-treat in 181 patients, P < .0005) (Table). Median time to conversion for regimens C, D, and E was ≤ 1 minute. PSVT recurred in 0%, 0%, 6%, 7%, 12%, and 7% on placebo and regimens A, B, C, D, and E, respectively. Conversion arrhythmias were transient and did not require treatment in regimens A-D. In addition, 10 patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without experiencing bronchospasm.
Table. TEMPEST: Primary Efficacy Assessment
| Treatment | 1st Dose/ 2nd Dose |
Patients Converted |
Therapeutic conversion (ITT, %) |
P |
|---|---|---|---|---|
| Placebo | Placebo/placebo | 22/30 | 7 | - |
| Tecadenoson | ||||
| Regimen A | 75 mcg/150 mcg | 16/32 | 50 | < .0005 |
| Regimen B | 150 mcg/300 mcg | 17/29 | 59 | < .0005 |
| Regimen C | 300 mcg/300 mcg | 28/31 | 90 | < .0001 |
| Regimen D | 450 mcg/900 mcg | 24/29 | 83 | < .0001 |
| Regimen E | 900 mcg/900 mcg | 26/30 | 87 | < .0001 |
As expected, based on the pharmacology of the study drug, transient postconversion atrioventricular block increased with dose (P < .0001), occurring with regimens C (2 patients), D (4 patients), and E (7 patients). There was no decrease in blood pressure after tecadenoson, and heart rate increased by a significantly lesser degree on tecadenoson than on placebo. The main side effect was paresthesia, experienced in 9 (6%) patients on tecadenoson compared with 6 (3%) on placebo. Other side effects with tecadenoson included flushing in 6 patients (3%) and tachycardia, headache, and dyspnea in 4 patients (2%) each. There was no apparent dose-dependent relationship between any adverse event after tecadenoson.