Conversion Of Paroxysmal Supraventricular Tachycardia Research Articles

Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial

Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min. RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete. Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66-4·15; p<0·0001). Median time to conversion was 17·2 min (95% CI 13·4-26·5) with the etripamil regimen versus 53·5 min (38·7-87·3) with placebo. Prespecified sensitivity analyses of the primary assessment were conducted to test robustness, yielding supporting results. Treatment-emergent adverse events occurred in 68 (50%) of 99 patients treated with etripamil and 12 (11%) of 85 patients in the placebo group, most of which were located at the administration site and were mild or moderate, and all of which were transient and resolved without intervention. Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%). No serious etripamil-related adverse events or deaths were reported. Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting. Milestone Pharmaceuticals.

Rationale for and design of a multicenter, placebo-controlled, phase 3 study to assess efficacy and safety of intranasal etripamil for the conversion of paroxysmal supraventricular tachycardia

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.

The first second-generation adenosine drug enters the US market

On 10 April 2008, CV Therapeutics, Inc. of Palo Alto, California, USA, received approval from the US Food and Drug Administration (FDA) for the use of Lexiscan® (regadenoson; CVT-3146), an A2A adenosine receptor (A2AAdoR) agonist, as a pharmacological stress agent in conjunction with radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress. Lexiscan® has a higher affinity for A2A adenosine receptors than adenosine and is a more potent coronary vasodilator. It preferentially dilates coronary arteries relative to other vascular beds [1], probably due to the high density of A2AAdoR in the coronary arteries and high receptor reserve at that site [2], resulting in maximal vasodilation induced by the activation of a small percentage of these receptors. MPI is commonly used in the clinical setting for the diagnosis of coronary artery stenosis. The rationale for the use of pharmacologic vasodilators in MPI is based on the differential blood flow response in normal vs. diseased coronary arteries, resulting in a coronary-steal phenomenon. The production of myocardial perfusion defects is reflected in nonhomogeneous distribution of a radiopharmaceutical, which is administered subsequent to the vasodilator agent, detected by a gamma camera, and quantified by a computer utilizing specific software. Adenosine and dipyridamole (an adenosine transport blocker that elevates extracellular adenosine levels) have previously been used as pharmacologic stressors; however, the use of both is associated with adverse effects caused by the activation of A1AdoR in addition to the A2AAdoR. For example, first-degree atrioventricular (AV) block occurs in approximately 10% and second- or third-degree AV block in approximately 4% of patients due to the inhibitory effect of adenosine on the AV nodal conduction [3]. Lexiscan® (Fig. 1), given as a bolus injection, increases coronary blood flow velocity by more than 2.5-fold above baseline for at least 2 min [4], which is ample time for the administration and distribution of a radiopharmaceutical. Fig. 1 Lexiscan® (CVT-3146): Adenosine, 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]-, monohydrate Experience with regadenoson (Lexiscan®) has shown that it is well-tolerated, as effective as adenosine as a pharmacologic stressor in MPI, and associated with less side effects than adenosine [5]. Lexiscan® is approved 19 and 13 years after the approval of Adenocard® (intravenous adenosine) in 1989 for conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm and Adenoscan® in 1995 as a pharmacological stress agent in MPI, respectively. The approval of Lexiscan® represents an important milestone in the adenosine research field. It is the first synthetic adenosine receptor ligand approved for medical use. The approval should serve as an impetus for the development of others adenosine and purine nucleotide analogs as novel diagnostic and therapeutic agents.

Tecadenoson

Tecadenoson is a novel selective A1 adenosine receptor agonist that is currently being evaluated for the conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. By selectively targeting the A1 receptor, tecadenoson may be associated with fewer adverse effects such as flushing, dyspnea, chest discomfort, and hypotension than adenosine, which is a nonselective agonist of all 4 adenosine receptors. Based on the results of phase I and phase II clinical trials, tecadenoson appears to be an effective agent for producing rapid and sustained conversion of PSVT to sinus rhythm. Additionally, the adverse effects that are typically attributed to adenosine's nonselective stimulation of the A2A, A2B, and A3 receptors appear to occur less frequently with the use of tecadenoson. Tecadenoson also appears to be associated with a lower incidence of atrial fibrillation following conversion of PSVT compared with the rates that have been associated with adenosine in the literature. A randomized, prospective trial will need to be conducted in the future to appropriately compare the safety and efficacy of tecadenoson and adenosine.

Termination of paroxysmal supraventricular tachycardia by tecadenoson (CVT-510),a novel A1-adenosine receptor agonist

ObjectivesThe aim of this study was to evaluate tecadenoson safety and efficacy during conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. BackgroundTecadenoson (CVT-510), a novel adenosine receptor (Ado R) agonist, selectively activates the A1Ado R and prolongs atrioventricular (AV) nodal conduction at doses lower than those required to cause A2Ado R-mediated coronary and peripheral vasodilation. Unlike adenosine, which non-selectively activates all four Ado R subtypes and produces unwanted effects, tecadenoson appears to terminate AV node-dependent supraventricular tachycardias without hypotension and bronchoconstriction. MethodsIn this open-label, multicenter, dose escalation study, tecadenoson was administered to 37 patients (AV node re-entrant tachycardia, n = 29; AV re-entrant tachycardia, n = 8) with inducible PSVT sustained for ≥1 min during an electrophysiology study. Seven regimens (0.3 to 15 μg/kg) of up to two identical tecadenoson intravenous bolus doses were administered. ResultsAfter the first or second bolus, PSVT converted to sustained sinus rhythm for ≥5 min in 86.5% (32/37) of the patients, with 91% (29/32) of the conversions occurring after the first bolus (most within 30 s), coincident with anterograde conduction block in the AV node. No effects on sinus cycle length (SCL) or systolic blood pressure were observed. The atrial-His (AH), but not the His-ventricular (HV) interval was prolonged up to 5 min after the final tecadenoson bolus, returning to baseline by 10 min. Tecadenoson was generally well tolerated. ConclusionsIn this study, tecadenoson rapidly terminated sustained PSVT by depressing AV nodal conduction without causing hypotension. After sinus rhythm restoration, there was minimal AH interval prolongation without HV interval or SCL prolongation.

Cost-effective adenosine dosing for the treatment of PSVT

We reviewed our experience with adenosine for the conversion of paroxysmal supraventricular tachycardia (PSVT) to determine whether the recommended dosing strategy of 6 mg, followed by 12 mg, is cost-effective in actual practice. We observed a 65% conversion rate to sinus rhythm with the initial dosage of 6 mg adenosine (95% CI, 54% to 75%), and, based on subsequent cost analysis, conclude that the current strategy should not be replaced by a 12-mg-first strategy. If the packaging of adenosine was changed so that 12 mg cost less than twice 6 mg, this analysis should be revisited.

Conversion of paroxysmal supraventricular tachycardia in a child with a slow verapamil infusion: Case report and literature review

The investigators present the case of a 12-month-old female with Down's syndrome and an endocardial cushion defect who presented acutely ill in paroxysmal supraventricular tachycardia (PSVT). Unsuccessful vagal maneuvers were followed by a slow intravenous infusion of verapamil, during which the rhythm converted. The discussion which follows highlights the many issues to be addressed in the acute management of pediatric PSVT including the varied presentations, underlying etiologies, differential diagnosis, electrocardiographic findings, electrophysiologic mechanisms, and prognosis. The literature review concludes with a discussion of the many different therapies avallable for pediatric PSVT including vagal maneuvers, cardioversion, overdrive pacing, and pharmacologic therapies. In particular, the relative merits of verapamil and adenosine are discussed.

Intravenous diltiazem for the treatment of supraventricular tachycardia.

To determine the effects of diltiazem hydrochloride on patients with paroxysmal supraventricular tachycardia, we administered intravenous diltiazem, 0.25 mg/kg to patients who presented to the Stanford Medical Center Emergency Department with this rhythm. Blood pressure was recorded prior to administration, and monitored for 20 min thereafter. Six of the ten patients converted to sinus rhythm a mean of 7.75 min (+/- 4.4) after drug administration. The remaining four experienced slowing of heart rates from a mean of 177 to 166 beats/min. Systolic blood pressure fell a mean of 12.4 mmHg during treatment, but returned to pretreatment level or higher within 20 min following diltiazem administration. This mean degree of blood pressure reduction compares favorably with effects produced by intravenous verapamil under comparable circumstances. Intravenous diltiazem appears to be a safe and effective drug for the conversion of paroxysmal supraventricular tachycardia.

Conversion of Paroxysmal Supraventricular Tachycardia due to a Concealed Extranodal Pathway with Intravenous Bolus of Lidocaine

Conversion of Paroxysmal Supraventricular Tachycardia due to a Concealed Extranodal Pathway with Intravenous Bolus of Lidocaine

Immediate effects of intravenous verapamil in cardiac arrhythmias.

Verapamil was administered by intravenous injection to 181 patients with various cardiac arrhythmias. The automaticity of the cardiac pacemaker was slowed in sinus, idionodal, and idioventricular tachycardia. In atrial fibrillation the drug usually slowed the ventricular response and often made it regular. In some cases atrial flutter was converted to sinus rhythm, the ventricular response being reduced in the remainder. Conversion of paroxysmal supraventricular tachycardia to sinus rhythm was consistently achieved. A favourable response occurred in four patients in whom arrhythmias were associated with pre-excitation syndromes. There were no adverse clinical side effects.

Paroxysmal supraventricular tachycardia in infancy. Report of a case treated with methacholine.

Digitalis is usually so successful in the conversion of paroxysmal supraventricular tachycardia to normal sinus rhythm in infants that experience with other drugs is infrequently obtained. On rare occasions both digitalis and the subsequent administration of quinidine are ineffective. Not uncommonly so much time has then elapsed that the clinical condition has become critical, and thus need for rapid-acting parasympathomimetic drugs becomes imperative. Because of the infrequent necessity for its use and perhaps also because of its condemnation by several authorities, 1,2 experience with methacholine (Mecholyl) has been limited. Successful utilization in infancy has been recorded in only 7 previous cases 3,4 ; for this reason the following report is presented. Report of a Case A 6-month-old white female was admitted to Montefiore Hospital from another institution on Feb. 24, 1961, because of severe congestive heart failure and a respiratory infection. The weight was 4.8 kg. The characteristic thrills and machinery