Intranasal etripamil for rapid treatment of paroxysmal supraventricular tachycardia

Abstract

Paroxysmal supraventricular tachycardia (PSVT) is a common arrhythmia that, although usually benign, can occur unpredictably, cause disabling symptoms and significantly impair quality of life. If spontaneous resolution does not occur, the only current self-treatment is for the patient to attempt vagal maneuvers, however, these are frequently unsuccessful. Hospital attendance is then required for intravenous therapy. Etripamil, an intranasal calcium channel blocker similar to verapamil, may be able to fill this therapeutic gap, allowing rapid self-treatment of PSVT at home. This narrative review discusses the latest evidence for etripamil and its potential role in future clinical practice.

Plain language summary

Paroxysmal supraventricular tachycardia (PSVT) is an abnormal heart rhythm, causing the heart to beat rapidly. There are several ways to treat PSVT. This article discusses a new therapy, etripamil. One treatment involves breathing techniques called ‘vagal maneuvers’. These avoid medication and sometimes stop the abnormal rhythm, however, in many cases, this does not work. An alternative is a tablet taken when symptoms occur. Unfortunately, tablets take time to absorb, meaning symptoms may continue until the medication takes effect, and this approach does not work for everyone. If these approaches fail, patients suffering from PSVT may need to seek treatment at a hospital. This may involve intravenous therapy, with certain drugs causing unpleasant sensations of chest discomfort. Some patients may also be kept in the hospital for monitoring. Although PSVT can often be cured via a catheter ablation procedure, this is invasive (involving wires inserted via veins in the groin), so not everyone wishes to pursue this, and in some cases, it cannot be performed safely. There is a need for a rapid, safe, and effective treatment that patients can administer at home when PSVT occurs. Etripamil shows promise. Because it is a nasal spray, etripamil allows rapid absorption into the body – much faster than a tablet. Etripamil is not yet available on the market; however, several studies have demonstrated its effectiveness and safety, so it may be available in the near future. Promising evidence for etripamil in certain groups, such as elderly patients, is still lacking.

TWEETABLE ABSTRACT

Intranasal etripamil shows promise in at-home self-management of paroxysmal supraventricular tachycardia.

Article Highlights

Background

• Paroxysmal supraventricular tachycardia (PSVT) is a common arrhythmia which may significantly affect quality of life and is responsible for many emergency department attendances and hospitalizations. Simple therapies for PSVT, such as vagal maneuvers and pill-in-the-pocket oral medications are frequently ineffective.

Treatment of PSVT

• There are limited options for rapid, at-home treatment of PSVT. These include vagal maneuvers, which are often ineffective, or as-needed oral antiarrhythmics, which have a slow onset and may also be ineffective.

• Although catheter ablation is frequently curative, this approach may not be acceptable to all patients, and in some may be unsafe due to the proximity of the arrhythmic mechanism to critical cardiac structures, such as the AV node.

The role of etripamil

• There is a clear need for a treatment that is both rapid in absorption and onset, efficacious in terminating PSVT, and safe to administer in a medically unsupervised setting.

• Etripamil is an intranasal L-type calcium channel blocker related to verapamil. It is not yet commercially available; however, several phase 3 studies have recently concluded. These studies demonstrate that etripamil can efficaciously terminate PSVT with no significant adverse safety signals.

Remaining uncertainties

• The evidence for etripamil in very elderly patients, those with heart failure, and those with significant polypharmacy are currently lacking. Real-world studies (phase 4) following approval of the drug will be of great interest to the cardiac electrophysiology community.

Keywords: :

• calcium channel blocker
• etripamil
• paroxysmal
• PSVT
• supraventricular tachycardia
• SVT

1. Background

Supraventricular tachycardia is an umbrella term for tachyarrhythmias arising above the level of the ventricles. The term ‘paroxysmal supraventricular tachycardia’ (PSVT) describes episodes that abruptly start and stop; in most cases, PSVT refers to reentrant tachyarrhythmias involving the atrioventricular node, specifically atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT). PSVT, although usually benign, causes symptoms such as palpitations, breathlessness and presyncope. Episodes may occur without warning and thus significantly impair quality of life. In the USA alone, PSVT affects as many as 1 in 300 people [1] and results in ~50,000 US emergency department (ED) visits per year, with almost a quarter of these resulting in hospitalization [2]. Prior estimates suggest that these admissions may cost up to US $190 million per year [2].

At present, there are limited options for rapid, at-home, self-treatment of PSVT to avoid hospital or urgent care centre attendance. Etripamil (Milestone Pharmaceuticals, Quebec, Canada), a self-administered intranasal calcium channel blocker (CCB), may provide a solution to this therapeutic gap. In this narrative review, we discuss the treatment options for PSVT and provide an update on the latest evidence supporting the use of etripamil.

2. Therapeutic options for paroxysmal supraventricular tachycardia

Broadly, most medical treatments can be divided into conservative measures, medical therapy with drugs, or interventional procedures. The approach to treating PSVT, along with the putative role of etripamil, is summarized in Figure 1.

Figure 1. Guideline recommended treatment of paroxysmal supraventricular tachycardia and the potential role of etripamil.

Etripamil may be suitable for immediate use in those with good responses, especially in those for whom vagal maneuvers are known to be ineffective. Alternatively, the benefit may be seen after failed vagal maneuvers or in the hospital before intravenous access, which may be obviated if PSVT is terminated by etripamil. Further, etripamil may be useful when IV adenosine has failed to terminate PSVT.

BB: Beta-blocker; CCB: Calcium channel blocker; DCCV: Direct current cardioversion; IV: Intravenous; PIP: Pill-in-the-pocket (e.g., Flecainide); PSVT: Paroxysmal supraventricular tachycardia.

3. Conservative measures

For patients preferring to avoid oral medications or interventional procedures, the only current options are tolerance of symptoms in expectation of spontaneous termination or vagal maneuvers. Vagal maneuvers are noninvasive, can be performed at home, and are generally safe. Although there are case reports of complications arising in relation to valsalva maneuvers [3,4], these are speculative in their accounts of causal relationships. Carotid sinus massage may cause cardiac or neurological complications, but fortunately these are rare, occurring in 0.1–1% of cases [5]. Unfortunately, vagal maneuvers are frequently ineffective [6,7]. Although the modified ‘REVERT’ technique may improve success, conversion may still occur in less than half of cases [8]. If vagal or spontaneous termination does not occur, it is likely that intravenous therapy will be required. This situation may provoke anxiety and impair quality of life, both due to fear that symptoms may arise at unpredictable times and during unplanned ED visits. Hence, a long-term conservative approach to PSVT is generally not favored.

3.1. Medical therapy

Long-term drug therapy is frequently unappealing to patients. Although daily medications, such as beta-blockers, CCBs, or antiarrhythmics may suppress PSVT, they may also be associated with side effects. An alternative approach is the ‘pill-in-the-pocket’, in which the patient does not take regular medication but takes a dose when symptoms occur. Unfortunately, due to gastroenteric transit, absorption time and first-pass hepatic metabolism, it may take 30 min or more for plasma levels to accumulate sufficiently to terminate the arrhythmia [9]. Flecainide as a pill-in-the-pocket for PSVT has an efficacy of ~50%, which was similar to placebo in one study [9]. Such an approach may be acceptable for selected patients, with shared decision-making; however, it is likely that many will seek medical review if their symptoms do not rapidly resolve, and many would likely prefer a more effective solution.

Intravenous therapy with adenosine, beta-blockers, or CCBs is highly effective [10] and recommended by international guidelines [11,12]. However, this necessitates hospitalization. Hence, there is a clear gap for a medical therapy that can provide safe, rapid, and efficacious termination of PSVT in the outpatient setting. The intranasal route is a compelling option because the posterior nasal mucosa is well suited to rapid drug absorption [13].

3.2. Interventional procedures

Percutaneous catheter ablation is considered first-line therapy for PSVT in international guidelines [11,12]. Although the invasive nature of this approach may be off-putting to some patients, the procedure is usually curative, eliminating the need for drug therapy [14]. This results in better quality-of-life outcomes and improved long-term cost–effectiveness [15,16]. Catheter ablation is, however, not suitable for all. As mentioned, some patients may prefer to avoid an invasive approach, even when PSVT is causing significant issues. Furthermore, some patients are unsuitable for ablation, either because of contraindications to invasive therapy or due to the inability to safely perform ablation (e.g., para-Hisian pathways). Still others may have unsuccessful ablation, even after multiple attempts.

4. Etripamil: filling the gap

Etripamil is a short-acting, nondihydropyridine, L-type CCB similar to verapamil. Unlike verapamil, etripamil has a rapid onset (time to peak plasma concentration approximately 8 min) and short half-life (accounts in the literature indicate varying half-lives of from 10–30 s up to 20 min [17]; formal pharmacological data has yet to be published). It is rapidly metabolized by serum esterases to an inactive carboxylic acid, and it has a shelf-life of more than 1 year.

An abstract reported in 2019 demonstrated that 15 min after administration, etripamil significantly prolonged the AV-nodal effective refractory period and Wenckebach cycle length, with minimal effect on the AH-interval, compared with baseline measurements [18]. A case study undertaken during the NODE-1 trial used 3D electroanatomic mapping of the slow pathway to further our understanding of this mechanism. The investigators demonstrated that after etripamil administration, slow pathway voltages decreased to a level comparable with postablation status [19]. Concurrently, there was an increase in the AV cycle length from 330 to 550 ms after 3 min, recovering back to 350 ms after 30 min. It is notable that, although providing fascinating mechanistic insights, these are only case reports, and such studies have not been repeated in a large cohort. Here we discuss the studies performed to date on etripamil.

4.1. Phase 1 studies: preliminary safety

To briefly summarize, phase 1 studies of etripamil established that the drug is feasible to administer via the intranasal route and was not associated with any significant adverse outcomes [20]. These studies also helped determine appropriate doses for subsequent phase 2 dose-finding studies. We focus our attention on the more recent clinical studies.

4.2. Phase 2 studies: dose finding & efficacy

NODE-1 was a randomized, double-blind, placebo-controlled dose-finding trial performed in the electrophysiology lab setting [17]. Patients received one of four doses of etripamil (or placebo) after induction of sustained PSVT. 199 patients were randomized, although 95 were withdrawn primarily because PSVT could not be induced or sustained in the lab. Almost 90% of patients had AVNRT, confirmed by an electrophysiology study. The primary outcome was conversion to sinus rhythm at 15 min.

NODE-1 found that etripamil significantly outperformed placebo at all doses except 35 mg (65–95% conversion with 70–140 mg vs 35% with placebo) with a median conversion time of <3 min. Efficacy >70 mg appeared to plateau. Adverse effects were generally mild, and most related to the intranasal administration route (e.g., congestion, lacrimation, cough). These events were not uncommon in the placebo arm and could be reduced with improved administration techniques. Adverse events included flushing and breathlessness, nausea and vomiting, and cough. One patient given the 140 mg dose had a second-degree AV block associated with hypotension, which resolved in under 45 min. Higher doses were associated with larger decreases in blood pressure 6 min postdose, although this returned to baseline by 15 min. NODE-1 concluded that etripamil was safe and effective overall. The optimal dose for subsequent phase 3 studies was selected as 70 mg.

4.3. Phase 3 studies – larger scale evidence

The studies discussed in this section reflect the potential real-world application of etripamil. These are summarized in Table 1.

Table 1. Phase 3 studies of etripamil.

Study	Summary of findings	Status	Ref.
NODE-301 Part 1	Etripamil did not outperform placebo for termination of PSVT at 5 h, but significance was suggested for earlier time points. No serious safety concerns were raised	Complete, published	[21]
NODE-302	Open-label extension of NODE-301, confirmed consistent findings and no significant adverse safety signals	Complete, published	[22]
RAPID	Etripamil outperformed placebo for termination of PSVT at 30 min, with significant reductions in patients attending the emergency department or seeking medical attention. No serious safety concerns were raised	Complete, published	[23]
NODE-303	Safety study of etripamil completed in January 2023; results are not yet available	Complete, results awaited	[24]
Open-label extension study	An open-label extension study of NODE 301, 302 and 303 is underway	Ongoing; completion expected April 2024	[25]

4.4. NODE-301 part 1

NODE-301 was a phase 3 multicenter, double-blind, randomized, placebo-controlled trial [21]. The full article was published in December 2022, although the results have been known since late 2021. This study was conducted in two parts: part 1 recruited up to 150 positively adjudicated PSVT episodes. The study continued into part 2, known as the RAPID study, which is discussed later in this section.

Patients enrolled in part 1 underwent a supervised test dose of etripamil and, if tolerated, were randomized to therapy versus placebo for home self-administration in the event of PSVT. 419 patients were randomized in a 2:1 manner to etripamil or placebo. Patients were analyzed in two populations. The efficacy population consisted of 156 patients with a self-treated positively adjudicated episode of PSVT (107 etripamil and 49 placebo). The safety population included all patients who received the test dose only (233 patients) and 198 patients who passed the test dose and also self-administered etripamil.

Unfortunately, NODE-301 chose a primary end point of termination of PSVT by 5 h, which is far beyond the pharmacological timeframe of etripamil. Because many PSVTs terminate spontaneously, it is unsurprising that etripamil did not outperform the placebo (hazard ratio [HR]: 1.086; 95% CI: 0.726–1.623; p = 0.12). Similarly, the choice to randomize 2:1 with relatively low patient numbers meant that by 2 h, there were almost no patients left in the placebo arm's Kaplan–Meier curve. This strongly suggests statistical underpowering.

Subanalysis of earlier, more appropriate time points in NODE-301 demonstrated more compelling results. Conversion by 30 min occurred in 54% of etripamil patients versus 35% of placebo patients (HR: 1.87; 95% CI: 1.09–3.22; p = 0.016).

Despite these limitations, NODE-301 demonstrated that etripamil was safe and well tolerated. The most common side effects were similar to earlier studies, relating to intranasal administration. These effects were more common with etripamil than placebo; for example, epistaxis occurred in 6.5% of etripamil patients and no placebo patients. No serious adverse events were reported. Overall, NODE-301 suggests potential benefits to etripamil, but flaws in the design, acknowledged by the authors, rendered this an underpowered and negative study.

4.5. NODE-302

Following the completion of NODE-301 Part 1, 169 patients were enrolled into NODE-302, an open-label extension study [22]. Patients in NODE-302 were allowed to treat up to 11 episodes during study participation, and this occurred over a median of 223 days. Most patients had just one episode (56.5%) or 1–3 episodes (88%), with a minority having as many as 10 episodes (n = 1).

Because NODE-302 was open-label, there was no placebo comparator. Overall, a similar performance to NODE-301 was seen, with 60% of patients cardioverting by 30 min and 75% by 60 min, with a median time to conversion of 15.5 min (95% CI: 11.3–22.1). More importantly, no significant adverse safety signals were seen despite multiple episodes treated with etripamil 70 mg. Treatment-related adverse events occurred in 32.4% of patients but were largely mild and transient. Only 1.9% of events (n = 2) were classified as severe, both involving epistaxis.

4.6. RAPID

Following on from NODE-301 part 1, the same investigators designed the RAPID study [26]. RAPID was similar to NODE-301 but with randomization 1:1 and the choice for patients to self-administer a second 70-mg dose of etripamil in the event of ongoing symptoms 10 min after the first dose. The primary outcome was time until PSVT termination within 30 min. All patients attempted a vagal maneuver before administering the study drug.

The results of the RAPID study were presented in a late-breaking clinical trial session at the American Heart Association Scientific Sessions in November 2022 [23]. The study randomized 692 patients, of whom 255 were treated. The trial met its primary end point: 64.3% of etripamil patients experienced PSVT termination by 30 min compared with 31.2% of placebo patients (HR: 2.62; 95% CI: 1.66–4.41; p < 0.001). The median time to conversion was also significantly better with etripamil (17.2 vs 53.5 min).

A pooled analysis of NODE-301 and RAPID showed that etripamil also resulted in fewer patients seeking medical attention (25% vs 15%; p = 0.013) or presenting to the ED (22% vs 14%; p = 0.035). Although treatment-related adverse events were more common with etripamil (50% vs 11%), the majority were mild and transient. No significant safety concerns were reported, despite increased exposure to the drug given the double-dosing aspect of the protocol.

4.7. NODE-303 – safety study

NODE-303 is an open-label safety study that began in September 2019 and was completed in January 2023. NODE-303 differed from prior studies in that a test dose was not required. The study originally reported that recruitment would be up to 3000 patients; however, at the study's end, 1118 participants were enrolled. The reasons for this have not been made public. The primary outcome was adverse events reported by participants. As of the time of writing, the results have not yet been released.

4.8. Future studies

An open-label extension study allowing patients to have continued access to the study drug from prior participation in NODE 301, 302, and 303 is ongoing and due to end in April 2024 [25]. Regulatory approval is likely to be sought soon after.

Although outside of the scope of this review, it bears mention that etripamil is now also being studied for acute rate control of atrial fibrillation (AF). The recently completed ReVeRA-201 study randomized 69 patients, of whom 56 received either etripamil or placebo for rapidly conducted AF. Etripamil resulted in greater heart rate reductions and better treatment satisfaction [27]. Adverse events were rare; although one patient suffered severe bradycardia with syncope, underlining the potential for complications.

5. The role of etripamil in real-world clinical practice

5.1. Benefits

As described earlier, there is a clear need for a rapid, safe, and effective treatment for PSVT at home. This could improve patient quality of life and reduce healthcare expenditures. The current evidence base for etripamil suggests that it may well be able to fill this gap. The studies described here demonstrate that etripamil can efficaciously terminate PSVT, with rapid onset, short half-life and no significant safety concerns. It is hoped that the results of NODE-303 and the open-label extension study will support this.

Aside from simply providing treatment at home, etripamil may have other uses. For example, for patients on a waiting list for ablation, etripamil may improve the quality of life in the intervening time. Furthermore, it may be useful for those in whom ablation is unsuccessful or prohibitively high risk. Etripamil may also be useful in the ED for acute termination of PSVT, potentially avoiding the need for intravenous cannulation and facilitating early discharge. There are a few potential issues to consider with etripamil in the real world, however. We discuss these concepts next.

5.2. Cost–effectiveness

The cost of etripamil has yet to be determined. It is worth considering that, given the long shelf life (>1 year) combined with potentially minimal uses per patient, the price required to render the drug financially beneficial to the pharmaceutical company may be high. Too high a cost will result in the drug not being cost-effective and hence seeing minimal real-world usage. Too low a cost will fail to provide profit and render it nonviable. This may be offset by the reduction in hospital and urgent care attendance due to etripamil allowing rapid and effective at-home treatment, especially in those patients for whom catheter ablation is not feasible. As mentioned earlier, ablation tends to outperform medical therapy for cost-effectiveness in the long term [15,16]. Whether this holds for etripamil remains to be seen in future cost-effectiveness analyses.

5.3. Patient preferences

Although we can theorize that patients may prefer the option of etripamil over other treatment modalities, this has yet to be confirmed in a non-trial setting. Although many people prefer to avoid invasive therapy, it may be that the anxiety of knowing PSVT may occur at any time, even with etripamil available, may not be preferable to undergoing a one-off – likely curative – ablation procedure. Similarly, some patients may prefer the option of a slower-acting oral tablet over the discomfort of intranasal administration of etripamil.

5.4. Arrhythmic uncertainties

We have discussed etripamil in the setting of PSVT throughout this review. However, patients with manifest ventricular pre-excitation were excluded from the studies described here. A small number of patients (e.g., 10% in NODE-1) had orthodromic AVRT. Although these patients represent the minority of PVST cases, this is a limitation of the existing evidence base. Patients with orthodromic AVRT may still be prone to developing pre-excited AF, a setting in which AV nodal-blocking drugs may be harmful. A patient may not be able to distinguish AVRT from pre-excited AF symptomatically, and administration of etripamil in the latter could potentially be disastrous. It will therefore be important to capture electrocardiographic evidence of the patient's arrhythmia to understand the underlying mechanism prior to etripamil prescription, although this limitation also applies to oral therapies. Similarly, excluding manifest pre-excitation and significant ventricular impairment will be important.

5.5. Long-term considerations

Several intranasal drugs have been shown to cause potential damage to the nasal mucosa [28]. It is possible, although not proven, that repeated administration of etripamil could result in similar effects. Long-term studies will be required to prove safety in this regard. In general, given most patients are unlikely to use it regularly, it is hoped that this will not prove to be a significant issue.

A related consideration for long-term use is that patients may develop intermittent nasal congestion (e.g., due to seasonal colds), and this may result in the inability to administer etripamil. This is less of an issue with oral therapy and irrelevant with ablation.

5.6. Other real-world issues

Tightly controlled clinical trials provide an optimal setting for studying a new therapy. Unfortunately, there are always difficulties in extrapolating this to the real world. First, how etripamil combines with other drug therapies is not well known. The existing studies provide some information; for example, combining non-dihydropyridine CCBs with beta-blockers can be dangerous. However, approximately one-third of etripamil patients were taking beta-blockers during both NODE-301 and RAPID, and safety concerns were minimal [21]. The short half-life of etripamil undoubtedly helps here. Interactions with other, non-studied drugs remain possible.

Second, safety in elderly people may be an issue. The risk of adverse effects of such medications is well known to be higher in older patients. The mean age in NODE-301 was ~60 years and closer to 50 years in RAPID. A subgroup analysis of etripamil in the over-70 age group, with and without concomitant cardiovascular medications, was performed in RAPID; however, this only included 20 patients, of whom only 15 were taking relevant concurrent medications. Only efficacy outcomes were reported for these groups, and with such low numbers, powering for uncommon safety outcomes would be inadequate. In people of advanced age, potentially with multiple comorbidities and polypharmacy, the role of etripamil is less clear. Additionally, in this complex patient group, PSVT may not be as ‘benign’ as it is in younger patients, given the higher risk of syncope. In such a setting, ablation may be the preferred option.

Similar issues apply to patients with heart failure. Nondihydropyridine CCBs are negatively inotropic and could potentially be harmful to those with impaired cardiac output. Although etripamil is short-acting, its safety in heart failure is uncertain and, as described earlier, ablation may be preferable given the potentially less ‘benign’ status of PSVT in heart failure patients.

This raises the question: for whom will etripamil be suitable? As discussed, we do not have adequate evidence for its use in patients with antidromic AVRT, heart failure, or in the elderly. Equally, patients unable to take intranasal medications (e.g., due to unusual anatomy, intolerance, or inability to perform the technique) also would not be suitable. This leaves a relatively homogenous group, consisting of younger patients with mostly AVNRT and structurally normal hearts who are able and willing to use an intranasal medication and prefer this over tablets or ablation. It may be telling that several other intranasal therapies for cardiac conditions have been tested, such as nifedipine, nitroglycerine, and propranolol [13], and none of these are in routine use today.

These aspects are speculative and perhaps overly pessimistic. We remain hopeful that etripamil can fill the aforementioned gap in the market for suitable patients.

6. Conclusion

Intranasal etripamil is capable of rapid termination of PSVT with minimal safety risk and a short half-life. It may be suitable for patients with AVNRT or orthodromic AVRT and structurally normal hearts who are not candidates for or prefer to avoid catheter ablation. Etripamil acts faster than oral therapy and is more effective than vagal maneuvers.

Ongoing studies will provide more information on the efficacy and safety of etripamil before consideration of real-world use. Subsequently, data on real-world patient uptake and cost–effectiveness will be critical in determining whether etripamil finds a role in clinical practice.

7. Future perspective

In the future, assuming regulatory approval is achieved, we hope to see real-world observational studies demonstrating the benefits of etripamil. These should include aspects described in our review – for example, cost–effectiveness analyses; safety, particularly in the elderly; and patient satisfaction. We speculate that etripamil will play a beneficial role, particularly for those patients for whom catheter ablation is not feasible.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Competing interests disclosure

P Calvert reports no conflicts of interest. D Gupta reports institutional research grants from Boston Scientific and Medtronic and speaker fees from Boston Scientific. As part of the peer review process, the manufacturer (Milestone Pharmaceuticals) reviewed the article for factual accuracy. Their comments were reviewed, and the manuscript was updated accordingly; however, the authors vouch for their opinions to remain independent. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.