FormalPara Key Points

A systematic review and meta-analysis synthesizing three randomized controlled trials, including 466 participants and investigating the efficacy and safety of etripamil (70 mg) versus placebo.

Etripamil was effective for paroxysmal supraventricular tachycardia (PSVT) conversion up to 60 min, decreasing medical intervention-seeking and emergency department visits.

Etripamil was also well tolerated, being associated with mild local adverse events such as nasal congestion and discomfort, without any serious adverse events or any cases of severe atrioventricular block.

1 Introduction

Cardiac arrhythmias originating due to the automaticity of structures at or above the level of the atrioventricular (AV) node are defined as supraventricular tachycardias (SVTs). SVTs are temporary arrhythmias, including atrial flutter, atrial fibrillation, AV re-entrant tachycardia (AVRT) [Wolf-Parkinson-White syndrome], and AV nodal re-entrant tachycardia (AVNRT). The most common type of SVTs are AVNRTs, followed by AVRTs [1]. Patients with new-onset paroxysmal SVT (PSVT) or a history of PSVT have symptoms such as palpitations, dizziness, fainting, discomfort or pain in the chest, shortness of breath, anxiety, and nausea [2]. A 12-lead electrocardiography (ECG) reveals a narrow complex tachycardia during an episode of PSVT. These accelerated rhythms with sudden onset can cause significant patient morbidity. In the United States, after adjusting for age and sex, PSVT incidence was last reported at 36/100,000 persons/year [3]. PSVTs cause 50,000 admissions to the emergency room (ER) every year, costing $190 million [2].

The most performed initial treatment for PSVT are the vagal maneuvers, which result in the activation of the parasympathetic nervous system, slowing the heart rate. Another method involves massaging the carotid sinus; failure of these physical therapies is then followed by pharmacological therapies. Administration of AV node-blocking medications, such as the calcium channel blockers verapamil and diltiazem; antiarrhythmic medications that block the AV node and lengthen the AV refractory period, such as adenosine; or cardioversion in hemodynamically unstable patients. The onset of action for oral medications is longer compared with intravenous, intranasal, or sublingual medications [2].

Therefore, there is a need for a well-tolerated PSVT drug that can be self-administered via a quick onset of action. Etripamil is a novel, rapid-acting, L-type calcium channel blocker that is administered as a nasal spray. The compelling advantages of etripamil, including its intranasal delivery, rapid onset of action, and short half-life, make it a promising intervention for patients to self-administer outside of formal healthcare settings [2]. Etripamil has recently demonstrated encouraging safety and efficacy in recent randomized controlled trials (RCTs) [4,5,6]. Thus, we performed a systematic review and meta-analysis to investigate the efficacy and safety of etripamil nasal spray for the treatment of acute PSVT, and to review the current evidence about the possible role of etripamil in unsupervised PSVT management.

2 Methodology

This systematic review and meta-analysis was thoroughly conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [7] and the Cochrane Handbook of Systematic Reviews and Meta-Analysis [8].

2.1 Data Sources and Search Strategy

We conducted a comprehensive search of the following databases: PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane Library through to 1 December 2022, without using any search limits. The comprehensive search terms and findings are elaborated in electronic supplementary Table S1.

2.2 Eligibility Criteria

We included RCTs with the following PICO criteria: population (P): patients with a history of PSVT; intervention (I): etripamil at a dose of 70 mg; control (C): placebo; outcome (O): efficacy outcomes of this review are conversion to sinus rhythm after 15, 30, 60, and 300 min, medical intervention-seeking, and ER visits. The safety outcomes include the incidence of any adverse event, any serious adverse event (SAE), nasal discomfort, nasal congestion, epistaxis, and rhinorrhea.

2.3 Study Selection

Two reviewers (SK and IG) independently screened the titles and abstracts of the articles identified in the search and assessed the full-text articles for eligibility based on predefined inclusion and exclusion criteria. Any disagreement was resolved through discussion or by a third reviewer (BA). The included studies were reported in a PRISMA flow diagram.

2.4 Data Extraction

Two independent investigators (SK and MAE) extracted the summary, baseline, and outcome data from the included RCTs, including study characteristics (country, study design, total participants, main inclusion criteria, the primary outcome, and follow-up duration); baseline characteristics (age, sex, number of patients in each group, mean PSVT confirmation duration, the mean number of PSVT episodes in the past year, lifetime number of emergency department [ED] visits for PSVT, and concomitant drug use); efficacy outcomes data (conversion to sinus rhythm after 15, 30, 60, and 300 min), medical intervention-seeking, and ER visits); and safety outcomes data (incidence of any adverse event, any SAE, nasal discomfort, nasal congestion, epistaxis, and rhinorrhea). Any disagreement was resolved through discussion or by a third reviewer (BA).

2.5 Risk of Bias and Quality Assessment

Two independent investigators (SK and MAE) implemented the Cochrane Collaboration's tool for assessing the risk of bias in RCTs (ROB 1) [9], considering selection, performance, detection bias, attrition, reporting, and other potential sources of biases. Any disagreement was resolved through discussion or by a third reviewer (BA). Furthermore, two independent investigators (BA and MA) used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to evaluate the quality of the evidence [10, 11].

2.6 Statistical Analysis

This meta-analysis was conducted using Revman software version 5.4 [12] to pool dichotomous outcomes using risk ratio (RR) along with the corresponding 95% confidence interval (CI). Pooled analysis was conducted using the fixed-effects model; however, the random-effects model was implemented in case of significant heterogeneity. Heterogeneity was evaluated using the Chi-square test and measured using the I-square test. The Chi-square test was considered significant at an alpha level below 0.1, and heterogeneity was considered significant if the I-square was > 50%. On significant heterogeneity, sensitivity analysis by excluding one study at a time and re-running the analysis was conducted to investigate the source of heterogeneity. Finally, we did not investigate the publication bias by funnel plots as we included fewer than 10 RCTs [13].

3 Results

3.1 Search Results and Study Selection

We retrieved 57 records after searching the databases and 35 duplicates were excluded using Covidence, leaving 22 records to be screened. After title and abstract screening, we proceeded with 16 articles for full-text screening. Finally, we included three RCTs [4,5,6]; two through searching databases [4, 5], and another was added manually from a 2022 American Heart Association (AHA) Scientific Sessions conference presentation [6] (Fig. 1).

Fig. 1
figure 1

PRISMA flow chart of the screening process. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, AHA American Heart Association

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3.2 Characteristics of the Included Studies

The final analysis included three RCTs [4,5,6], with a total of 496 patients: 296 in the etripamil group and 200 in the placebo group. The NODE-1 trial is a multicenter, double-blinded, dose-ranging, phase II RCT [5], and NODE-301 [4] and RAPID [6] are multicenter, double-blinded, phase III RCTs. Only RAPID allowed second dose administration after 10 min in cases of non-response to the first dose, while NODE-1 and NODE-301 administrated a single dose. Furthermore, we only included 23 participants from NODE-1 who were administered etripamil 70 mg. The detailed summary characteristics of the included RCTs and baseline data of the participants are outlined in Tables 1 and 2.

Table 1 Summary characteristics of the included RCTs
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Table 2 Baseline characteristics of the participants
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3.3 Risk of Bias and Quality of Evidence

The included RCTs showed a low risk of bias in selection, performance, attrition, and reporting biases. However, NODE-1 showed an unclear risk of detection bias and all three RCTs showed a high risk of other biases, being funded by the manufacturer’s pharmaceutical company (Milestone Pharmaceuticals) (Fig. 2). The quality of evidence assessment is outlined in Table 3.

Fig. 2
figure 2

Quality assessment of the risk of bias in the included trials. The upper panel presents a schematic representation of risks (low = red, unclear = yellow, and high = red) for specific types of biases of each of the studies included in the review. The lower panel presents risks (low = red, unclear = yellow, and high = red) for the subtypes of biases of the combination of studies included in this review

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Table 3 GRADE evidence profile
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3.4 Efficacy Outcomes

Etripamil was effective for PSVT conversion after 15 min (RR 1.84, 95% CI 1.37–2.48; p = 0.0001) [low-quality evidence], 30 min (RR 1.86, 95% CI 1.42–2.44; p = 0.00001) [low-quality evidence], and 60 min (RR 1.25, 95% CI 1.05–1.50; p = 0.01) [very low-quality evidence] after drug administration; decreasing medical intervention-seeking (RR 0.58, 95% CI 0.37–0.90; p = 0.01) [very low-quality evidence]; and decreasing ER visits (RR 0.61, 95% CI 0.38–0.97; p = 0.04) [very low-quality evidence]. However, there was no difference at 300 min (RR 1.10, 95% CI 0.97–1.25; p = 0.12) [very low-quality evidence] (Fig. 3, Table 3).

Fig. 3
figure 3

Forest plot of the efficacy outcomes. (a) Conversion to sinus rhythm; (b) medical intervention seeking; (c) ER visits. RR risk ratio, CI confidence interval, ER emergency room, M-H Mantel-Haenszel, df degrees of freedom

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Studies were homogenous in PSVT conversion after 15 min (p = 0.56, I2 = 0%), 30 min (p = 0.28, I2 = 14%), 60 min (p = 0.27, I2 = 17%), and 300 min after drug administration (p = 0.29, I2 = 11%); decreasing medical intervention-seeking (p = 0.74, I2 = 0%); and decreasing ER visits (p = 0.64, I2 = 0%).

3.5 Safety Outcomes

Etripamil was associated with higher rates of the incidence of any AEs (RR 3.17, 95% CI 2.15–4.69; p = 0.00001) [low-quality evidence], nasal discomfort (RR 3.82, 95% CI 2.01–7.24; p = 0.0001) [low-quality evidence], nasal congestion (RR 5.89, 95% CI 1.93–17.97; p = 0.002) [low-quality evidence], epistaxis (RR 4.74, 95% CI 1.21–18.50; p = 0.03) [very low-quality evidence], and rhinorrhea (RR 3.53, 95% CI 1.22–10.26; p = 0.02) [very low-quality evidence], with no difference regarding SAE incidence (RR 0.30, 95% CI 0.01–7.21; p = 0.46) [very low-quality evidence] (Fig. 4, Table 3).

Fig. 4
figure 4

Forest plot of the safety outcomes. RR risk ratio, CI confidence interval, M-H Mantel-Haenszel, df degrees of freedom

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Studies were homogenous in the incidence of any AEs (p = 0.61, I2 = 0%), nasal discomfort (p = 0.50, I2 = 0%), epistaxis (p = 0.59, I2 = 0%), and rhinorrhea (p = 0.99, I2 = 0%); however, nasal congestion showed mild heterogeneity (p = 0.13, I2 = 56%).

4 Discussion

Our analysis revealed that etripamil is effective to terminate SVT, converting it to sinus rhythm at 15, 30, and 60 min, decreasing medical intervention-seeking and visits to the ER. However, etripamil has been associated with some adverse events, including nasal discomfort, congestion, epistaxis, and rhinorrhea.

Etripamil is a short-acting calcium channel blocker but its exact pharmacokinetics and pharmacodynamics are yet to be determined. Nevertheless, nasal delivery of drugs improves bioavailability by avoiding first-pass metabolism in the liver, and reduces slow absorption, drug degradation, and gastrointestinal adverse effects [14]. PSVT has a high recurrence rate; hence, treatment with early onset and a long therapeutic effect is necessary, and this is compatible with etripamil’s pharmacokinetic features. Regarding conversion to sinus rhythm, etripamil has variable response rates due to its half-life, which may explain why it can only be detected for up to 300 min. Conversely, adenosine, which blocks calcium influx into cardiac cells, is an effective therapy (86–96%) for the rapid termination of PSVT [15]. However, due to its short half-life (10–30 s), its effect is short-lived and the SVT might recur. However, the half-life of etripamil is around 20 min, which can effectively prevent PSVT recurrence [2]. Thus, Stambler et al. [4] argue that a time point of 30 min is the most appropriate to estimate the half-life of etripamil, suiting its pharmacokinetic properties. Furthermore, follow-up with patients for up to 5 h was conducted to detect any efficacy of etripamil, as NODE-301 and RAPID were conducted outside clinical settings [4, 6]. Moreover, different response rates may be associated with pharmacogenetics, and more research is needed to investigate how genetic differences affect how well a treatment works.

SVT is a common cause of hospital admissions with regard to medical intervention-seeking and ER visits. The incidence of PSVT is about 36/100,000 persons, with a female predominance [15, 16]. As per the editorial by Naccarelli et al. [17], the recurrence of PSVT depends on the frequency of exposure to triggers, the properties of the PSVT-involved pathways, and the amount of their excitable gap. Etripamil could be a potential alternative for aborting PSVT in outpatient settings due to its ease of self-administration and effective response. Furthermore, the availability of outpatient intranasal etripamil may significantly decrease patients’ exposure to inappropriate or excess therapy and unnecessary investigations and procedures, which is supported by our analysis. The study conducted by O’Rourke et al. [18] discovered that 38% of patients in the ED were administered adenosine for sinus, ventricular tachycardia, and atrial fibrillation. Moreover, etripamil can be administered as an adjuvant to oral medications before catheter ablation in case of any delay in getting to the procedure.

Etripamil seems to be a safer, easier, and more effective treatment option than oral or intravenous medications. Vagal maneuvers are recommended as the first line of treatment for acute SVT [2]. The Valsalva maneuver, a type of vagal maneuver, involves patient expiration against a closed glottis to stimulate the vagal nerve [19]. However, the efficacy of the Valsalva maneuver varies widely, from 19.4 to 54.3% [19]. The REVERT trial showed that the modified Valsalva technique, which combines passive leg lifting with supine posture, has higher conversion rates compared with the standard Valsalva technique (43% vs. 17%) [19]. However, this modified technique requires a healthcare practitioner and the conversion rate is not as significant as with etripamil. Other vagal maneuvers involve carotid sinus massaging, which is effective but can lead to stroke in the elderly with a history of cardiovascular disease as it carries a risk of embolization [19]. If the above-mentioned maneuvers fail, the first medication administered is adenosine, which is nearly 90% effective with a rapid onset and a very short half-life [2]. However, adenosine is administered intravenously, requiring hospitalization [20]. Furthermore, intravenous calcium channel blockers, such as verapamil and diltiazem, used in hemodynamically stable SVT patients are associated with an excess decrease in heart rate and contractility [20].

Moreover, etripamil was associated with a small number of mild local adverse events, including nasal congestion, nasal discomfort, rhinorrhea, and epistaxis. There was no evidence of QT interval prolongation or AV block. Only one patient experienced hypotension with type II second-degree AV block, 5 min after receiving etripamil 140 mg in NODE-1 [5], which was avoided by using a lower dosage (70 mg) in NODE-301 and RAPID without a single case of second- or third-degree AV block [4, 6]. Conversely, current intravenous calcium channel blockers and β-blockers have been frequently associated with AV block [21]. Accordingly, etripamil is well tolerated and effective for PSVT conversion without medical supervision.

4.1 Strengths and Limitations

To the best of our knowledge, this is the first systematic review and meta-analysis to assess the safety and efficacy of etripamil for PSVT termination. We compiled each study’s findings, limitations, and conclusions into a thorough quantitative and qualitative analysis following Cochrane [8], GRADE [10, 11], and PRISMA guidelines [7]. In addition, we presented the results of various RCTs, which included the administration of etripamil in clinical and unsupervised settings. Therefore, our study constitutes the gold-standard evidence in this regard.

However, our review has some limitations. First, our analysis is limited by the small number of included RCTs, and NODE-1 included patients under sedation and artificially induced PSVT [5], compared with the alert patients with spontaneous PSVT in NODE-301 and RAPID [4, 6]. Second, significant variations in baseline characteristics, such as the mean number of PSVT episodes in the past year, being higher in the placebo group in both NODE-301 and RAPID, can affect our findings. Furthermore, the age of patients included in the studies was wide (> 18 years); however, the mean age of the included patients was in the 50s, indicating that young patients were underrepresented in the results. Third, we could not do a subgroup analysis for different PSVT subtypes such as AVNRT and AVRT because of the lack of data. Fourth, individuals who were taking certain medications and had structural heart disease were excluded from the trials. This might impede the treatment’s use by a significant number of patients. Finally, all our included outcomes showed low- to very low-quality evidence, which limits the generalizability of our findings.

4.2 Implications for Future Research

Further studies are required to study the long-term safety of etripamil and its efficacy in special populations, such as pediatric subjects. Etripamil may also be beneficial in the treatment of other conditions that respond to calcium channel blockers, such as atrial fibrillation and angina; hence, investigating this can be beneficial. Given the high cost of ED care, antiarrhythmic drugs, and successful ablation, this approach will be significantly less expensive. However, pharmacoeconomic studies are also required.

Moreover, further studies are required to examine the safety of etripamil among patients with pre-excitation in baseline ECG.

5 Conclusion

Etripamil is a promising candidate for self-termination of symptomatic, sustained PSVT in a non-clinical setting, with an acceptable safety and efficacy profile. Large-scale, double-blind RCTs with long follow-up periods are needed to confirm our findings before etripamil clinical endorsement.