Ranolazine-Angiotensin Inhibitor Interactions: Reality or Fantasy?

Ranolazine is approved as an antianginal and is used as a second-line therapy in stable ischemic heart disease.¹ The agent blocks the late sodium channels (I_Na) preventing a downstream rise in cytosolic Ca²⁺ concentrations.²  This translates into a decrease in left ventricular wall tension and an increase in coronary blood flow.³  This pharmacologic effects leads to angina relief.  In addition, I_Na blocking activity stabilizes the myocardial cell membrane and the late rectifier K⁺ current inhibition both contribute to its anti-arrhythmic property.³  Finally, ranolazine blocks Na+ channels in islet alpha-cells to inhibit glucagon release and may have properties that preserve β-cells contributing to its beneficial effects in diabetes. ^4-5 Ranolazine is a commonly prescribed drug in cardiovascular disease. 

Drugs that inhibit the renin-angiotensin-aldosterone system are mission critical to cardiovascular prevention and treatment. Therefore, when a recent manuscript researching the Metabolic Efficiency with Ranolazine for Less Ischemia in non-ST Elevation Acute Coronary Syndromes (MERLIN)⁶ finds that an association that ranolazine increases the adverse effect profile of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) there is concern for patient safety.⁷ Patients in the MERLIN trial were randomized to receive ranolazine or placebo and were monitored for a median of 348 days (78% received ACEi and 22% received an ARB). 

Rates of ACEi- or ARB-beneficial effects were lower and ACEi- and ARB-induced adverse events were higher in patients who received ranolazine.⁷ The major three ACEi or ARB-induced beneficial effects including raising serum potassium levels and lowering blood pressure were with ranolazine. Rates of ACEi or ARB-induced adverse effects including angioedema, dry cough, renal impairment, hypotension, anemia, and serum potassium > 5.5 mmol/L were higher in patients on receiving concomitant ranolazine. The authors suggest a hypothetical mechanism for this interaction maybe inhibition of the influx organic cation transporter OCT2 (transporter from extracellular to intracellular), which is widely distributed in human tissue, by ranolazine.⁷ Ranolazine undergoes substantial metabolism with several metabolites that are not well characterized, but maybe OCT2 inhibitors.^7-8 This hypothesis needs to be proven.

This interaction may have serious patient efficacy and safety concerns and therefore should be taken into consideration when initiating either component of this drug-drug interaction.  Obtaining baseline serum potassium, creatinine, and hemoglobin prior to prescribing either ranolazine or an ACEi or ARB together and, after starting the two drugs, close monitoring blood pressure response and patient symptoms of cough and swelling of the eyes, mouth, tongue, hands, genitals and feet  (all related to angioedema) seems prudent. If an apparent lack of efficacy or adverse event is occurring, discontinuation of ranolazine seems the best alternative over discontinuation of the ACEi or ARB-both with established efficacy to reduce cardiovascular events. An important unanswered question is whether the beneficial effects of ACEi and ARBs on cardiovascular events are reversed. This should be evaluated in the near future.   

References:

Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAO/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease ONLINE FIRST J Am Coll Cardiol. 2012;():. doi:10.1016/j.jacc.2012.07.013

Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late Sodium current inhibtion as a new cardioprotective approach. J Mol Cell Cardiol 2008;44:954-67.
Ghosh GC, Gohsh RK, Bandyopadhyay D, Chatterjee K, Aneja A. Ranolazine: multifaceted role beyond coronary artery disease, a recent perspective.Heart Views 2018;19(3):88-98.

Dhalla AK, Yank M, Ning Y, Kahlig KM, Krause M, Rajamani S, et al. Blockade of Na+ channels in pancreatic α-cells has antidiabetic effects. Diabetes 2014;63:3545-56.
Ning Y, Zhen W, Fu Z, Jiang J, Liu D, Belardinelli L, et al. Ranolazine increases B-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther 2011;337:50-8.

Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297(10):1775-83.

Marciniak TA, Serebruany V. Ranolazine, ACE inhibitors, and angiotensin receptor blockers. Am J Medhttps://doi.org/10.1016/j.amjmed.2019.02.032

Marciniak TA. Cross Discipline Team Leader Review NDA 21-526/S004, Ranexa/ranolazine. Published 2008.Accessed 04/2019.