Ranolazine Unveiled: Rediscovering an Old Solution in a New Light
Abstract
:1. Introduction
2. Side Effects
3. Ranolazine and APD
4. Atrial Fibrillation
- (1)
- INa blockers, like ranolazine, also have a non-negligible effect on other channels, such as IKur, which are exclusively expressed in atrial cells. The blockage of Ikur current prolongs APD and atrial refractoriness.
- (2)
- Ranolazine’s inhibitory effect on rapid Na current becomes more relevant at higher frequencies (i.e., with shorter CL). In canine-model experiments reported by Antzelevitch, ranolazine reduces sodium current Vmax by 60% with a cycle length of 300 ms. This is a common characteristic of drugs that inhibit Na channels with rapid unbinding kinetics, such as amiodarone and vernakalant.
Author Year | Setting | Comparison | Other AADs | Result [p Value] | Side Effects |
---|---|---|---|---|---|
Fragakis 2012 [29] | Conv. in recent-onset AF | R (1500 mg) + A (loading dose + maintenance) vs. A alone (loading dose + maintenance) | Beta-Blocker (55%) CCBs (20%) Digoxin (14%) | Same conv. rate [0.06] Shorter time to conv. with R [<0.01] | Not reported |
Koskinas 2014 [25] | Conv. in recent-onset AF | R (1500 mg) + A (loading dose + maintenance) vs. A alone (loading dose + maintenance) | Beta-Blocker (75%) CCBs (21%) Digoxin (21%) | Higher conv. rate with R [0.02] | Dizziness and nausea (2%) |
Scirica 2015 [30] | AF in NSTE-ACS | I.V. R (bolus + maintenance up to 96 h) followed by R 1000 mg p.o. BID vs. Placebo | Beta-Blocker (89%) | Reduction in AF burden in the year following ACS in R group [0.01] | Not reported |
De Ferrari 2015 [31] | AF recurrences after SR restoration in perAF | Placebo vs. R (375 mg) vs. R (500 mg) vs. R (750 mg) | Beta-Blocker (41%) Digoxin (13%) Previous Class I/III AAD (18%) | Same AF recurrence rate with R 500 mg and 750 mg vs. placebo [0.053] | Not reported |
Reiffel 2015 [28] | pAF | Placebo vs. R (750 mg) + D placebo vs. R placebo + D (225 mg) vs. R (750 mg) + D (150 mg) vs. R (750 mg) + D (225 mg) | - | Lower AF recurrence rate with R + D 225 mg [<0.01] | Dizziness, constipation, Nausea |
Tsanaxidi 2017 [25] | Conv. of recent-onset (<48 h duration) AF | R (1000 mg) + A (loading dose + maintenance) vs. A alone (loading dose + maintenance) | - | Faster SR restoration [<0.01] and higher conv rate [0.02] in R group | Not observed |
Simopoulos 2018 [32] | Post-CS AF | R (750 mg p.o. in 12 h) + A (500 mg po) vs. A alone (loading dose + maintenance) | Beta-Blocker (98%) Digoxin (0.2%) | Faster SR restoration with A + R [<0.01] | Not reported |
5. Ventricular Arrhythmias
Author | Setting | Comparison (Numerosity) | Other AADs | Ranolazine Dose | Result [p Value] | Side Effects |
---|---|---|---|---|---|---|
Scirica 2007 [49] | VT in NSTE- ACS | R (3162) vs. Placebo (3189) | Beta-Blocker (89%) | I.V. R (bolus + manteinence) and subsequent po BID administration | Lower incidence of VT in R group | Not reported |
Bunch 2011 [41] | AADs refractory VT with recurrent ICD shocks | (12) | A (92%) Lidocaine/Mexiletine (50%) Sotalolo (8%) | 500 mg daily | Reduction in both VT burden ICD shocks | GI problems (17%) Severe hypoglycemia (8%) |
Pelliccia 2015 [40] | Palpitations in stable CAD | R (53) vs. Placebo (52) | Beta-Blocker (100%) | 750 mg BID | R more effective in reducing both VA and symptoms in R group | Not observed |
Curnis 2017 [42] | ICD carriers with increased VA burden/ at least one appropriate ICD intervention in the previous 6 months | (17) | Beta-Blocker (94%) A (71%) | 500 mg BID (dose reduction to 350 mg BID allowed) | Reduction in both VA/ICD interventions [0.045] and symptoms [<0.01] | Not observed |
Zareba 2018 [38] | High-risk ICD carriers | R (510) vs. Placebo (502) | Beta-Blocker (93%) Digitalis (17%) A (10%) Other antiarrhythmic (17%) | 500 mg BID (7 days) followed by uptritation to 1000 mg BID | R more effective in reducing recurrent VT/VF requiring ICD therapy [0.03] | Dizziness (8%) Nausea (6%) Costipation (4%) vomiting (2%) headaches, and fatigue (2%) Indigestion, cough, chest pain, shortness of breath, and dry mouth (1%) |
Younis 2022 [39] | High-risk ICD carriers | R (510) vs. Placebo (502) | Beta-Blocker (93%) Digitalis (17%) Amiodarone (10%) Other antiarrhythmic (17%) | 500 mg BID (7 days) followed by uptritation to 1000 mg BID | Ranolazine more effective in reducing VA burden, especially in CRT-treated patients, in patients without AF and AADs naïve [<0.01] | Not observed |
5.1. LQTS
Author | Setting | N° | Dose Ranolazine | Result [p Value] | Side Effects |
---|---|---|---|---|---|
Moss 2008 [52] | LQTS3 (ΔKPQ mutation) | 5 | IV R (bolus + maintenance) | QTc interval reduction and improvement in diastolic relaxation [<0.01] | Not reported |
Chorin 2016 [51] | LQTS3 | 8 | 500 mg BID (up-titration to 1000 mg BID after 3 days) | QTc interval reduction [0.01] | Constipation (13%) |
Olivotto 2018 [53] | Symptomatic non-obstructive HCM | 40 (R) vs. 40 (Placebo) | 500 mg BID (up-tritation up to 1000 mg BID) | Reduction in PVCs/24 h burden [0.04] | Not reported |
Argirò 2023 [54] | HCM | 119 | 375 mg BID (up-titration to 500 mg BID) | Reduction in CCS class [symptomatic relief in 73%] | GI problems, dizziness, and headache (2%) Augmented transaminase and skin rash (1%) |
5.2. HCM
6. Conclusions
Funding
Conflicts of Interest
References
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Side Effects [9] | Frequency |
---|---|
Dizziness | 5–7% |
Constipation | 4–8% |
Headache | 6% |
Nausea | 2–4% |
Abdominal pain | 1% |
Dry mouth | 1% |
Peripheral edema | 1% |
Pancytopenia | Extremely rare (<0.1%) |
Neurological symptoms (including myopathy) | Anectodical |
Side effects are observed more frequently in patients with eGFR between 80 and 30 mL/min/1.73 m2 and when a higher dosage of 1000–1500 mg twice daily is administered [5,7] | |
Principal Contraindications | |
Pre-existing QT prolongation [5] | |
Hepatic impairment [5] | Child–Pugh C |
Renal Failure [5] | eGFR < 30 mL/min/1.73 m2 |
Pediatrics | |
Strong CYP3A inhibitors [4] | Ketoconazole, itraconazole, macrolides, clarithromycin, erythromycin, non-dihydropyridine calcium blockers, and ritonavir |
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De Santis, G.A.; De Ferrari, T.; Parisi, F.; Franzino, M.; Molinero, A.E.; Di Carlo, A.; Pistelli, L.; Vetta, G.; Parlavecchio, A.; Torre, M.; et al. Ranolazine Unveiled: Rediscovering an Old Solution in a New Light. J. Clin. Med. 2024, 13, 4985. https://doi.org/10.3390/jcm13174985
De Santis GA, De Ferrari T, Parisi F, Franzino M, Molinero AE, Di Carlo A, Pistelli L, Vetta G, Parlavecchio A, Torre M, et al. Ranolazine Unveiled: Rediscovering an Old Solution in a New Light. Journal of Clinical Medicine. 2024; 13(17):4985. https://doi.org/10.3390/jcm13174985
Chicago/Turabian StyleDe Santis, Giulia Azzurra, Tommaso De Ferrari, Francesca Parisi, Marco Franzino, Agustin Ezequiel Molinero, Alessandro Di Carlo, Lorenzo Pistelli, Giampaolo Vetta, Antonio Parlavecchio, Marco Torre, and et al. 2024. "Ranolazine Unveiled: Rediscovering an Old Solution in a New Light" Journal of Clinical Medicine 13, no. 17: 4985. https://doi.org/10.3390/jcm13174985