EXPEDITED REVIEW: EDITORIAL COMMENT
Ranolazine: Augmenting the Antianginal Armamentarium*
John A. Cairns, MD, FRCPC, FACC*
University of British Columbia, Vancouver, Canada.
* Reprint requests and correspondence: Dr. John A. Cairns, Jim Pattison Pavilion North, Room 3150, Vancouver General Hospital, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 4E3. (Email: jacairns{at}medd.med.ubc.ca).
In January 2006, the Food and Drug Administration (FDA) approved ranolazine for use in chronic stable angina following the completion of a study mandated under the FDA’s special protocol assessment (SPA) process and reported in this issue of the Journal (1). This is the first agent from a new class of antianginal agents to be approved in almost 25 years, and its potential widespread use warrants careful review of the evidence for benefit and harm.
Pharmacologic prophylaxis against angina symptoms currently involves the use of beta-blockers, calcium antagonists, and long-acting nitrates (2,3). The evidence for efficacy is derived from randomized placebo-controlled trials assessing reductions of anginal frequency and nitroglycerin consumption, improved exercise test performance, and side effects. Change in quality of life has not been systematically evaluated for any of these agents (2). Long-term studies among survivors of myocardial infarction (MI) and unstable angina/non–ST-segment elevation MI have shown a reduction of subsequent coronary events with beta-blockers but not with calcium antagonists or long-acting nitrates (2). A meta-analysis of comparative studies (the majority of them before the release of amlodipine and felodipine) found that beta-blockers compared with calcium antagonists were associated with significantly fewer episodes of angina per week, but there was no significant difference in exercise time (4). Adverse events were significantly less frequent with beta-blockers, but this difference was confined to nifedipine. In the relatively few trials comparing beta-blockers or calcium antagonists to long-acting nitrates, no significant differences were found, although there were trends in nitroglycerin use favoring beta-blockers and in angina episodes favoring calcium antagonists.
It is generally recommended, based on reasonable evidence, that combinations of agents from 2 or even all 3 of these drug classes be used in persistently symptomatic patients (2). Nevertheless, as many as 5% to 15% of the estimated 6,500,000 Americans with stable angina may be refractory to even triple therapy and yet not considered suitable for revascularization (5,6). It is likely that many more experience undesirable side effects on currently available therapies, particularly in combination, and might benefit from an alternative agent. Accordingly, great interest attends the evaluations of novel antianginal agents.
Ranolazine is an orally active piperazine derivative, which, compared with placebo, reduces angina frequency and nitroglycerin consumption and improves exercise test performance (7,8). Its efficacy is similar to that of atenolol (9), and is modestly incremental when added to standard monotherapy with atenolol, diltiazem, or amlodipine (10). Ranolazine is well tolerated; the principal side effects include dizziness, nausea, asthenia, constipation, and headache (7,11). Of concern is its propensity to dose-related prolongation of the QTc, the net effect of its inhibition of IKr, late INa, and late ICa (7). However, there has been no evidence of increased dispersion of repolarization nor any documented cases of torsades de pointes. Ranolazine is metabolized in the liver and excreted in the urine and is contraindicated with hepatic impairment. It is metabolized primarily by CYP3A, which is potently inhibited by diltiazem and verapamil, neither of which should be used concurrently. Ranolazine inhibits metabolic pathways for simvastatin and digoxin, and dose reductions of these agents may be required (11).
The antianginal effects of ranolazine are not dependent on reduction of heart rate or blood pressure or on increases of coronary blood flow. During exercise testing, patients are able to achieve an increased rate-pressure product at maximal exercise compared with placebo or beta-blocker (9). The mechanism of action of ranolazine is not understood, but the agent is a known inhibitor of myocardial fatty acid oxidation, resulting in preferential glucose oxidation (7). The glucose pathway requires less oxygen for a given level of myocardial work, and this increased "oxygen efficiency" may be an important component of the anti-ischemic action.
The ERICA (Efficacy of Ranolazine in Chronic Angina) trial (1) was well designed, assembling a group of 565 patients (97% from centers in Eastern Europe) who satisfied appropriate exclusion criteria, and who continued to have at least 3 episodes of angina per week while under observation for a 2-week qualifying phase despite taking 10 mg/day amlodipine (8). Amlodipine was maintained throughout the subsequent trial, as were long-acting nitrates in 45% of subjects. There were 564 patients randomized double-blind to 500 mg ranolazine twice daily for 1 week followed by 1,000 mg twice a day for 6 weeks or to placebo. In each group, 98% of patients completed the trial. Ranolazine significantly reduced the frequency of angina episodes (primary efficacy variable) and improved the secondary efficacy variables of nitroglycerin consumption and the anginal frequency component of the Seattle Angina Questionnaire (SAQ). (12). There were no important hemodynamic changes or other side effects. In conjunction with previous data on the antianginal efficacy of ranolazine compared with placebo or atenolol and when added to atenolol, diltiazem, or amlodipine, the results satisfied the FDA that ranolazine offers incremental benefit over current standard therapies.
What is the clinical importance of the statistically significant reductions of angina frequency and nitroglycerin consumption by ranolazine? Issues to consider include: 1) the modest reductions in angina frequency and nitroglycerin consumption; 2) the absence of statistically significant differences in quality of life measures beyond angina frequency; and 3) the lack of comparison to combination therapy with beta-blockers and amlodipine.
Exercise test parameters have been extensively used in the evaluation of antianginal agents, because they are objective and continuous and allow relatively small sample sizes. Quite modest increases in exercise duration in the range of 30 s to 60 s, have been sufficient to claim efficacy of new agents alone and in combinations with established therapies (13,14). Reduced angina frequency and nitroglycerin consumption may be more relevant to patients and were chosen as the outcome measures in the ERICA trial. Ranolazine decreased angina frequency by only 0.43 episodes per week compared with placebo and reduced nitroglycerin consumption by 0.65 tablets per week. However, these differences are not out of line with the modest (13,15) improvements or no change (14) observed in previous studies of new antianginal agents in combination regimens. The changes on placebo alone between baseline and 6 weeks of angina frequency (2.47 fewer episodes per week) and nitroglycerin consumption (2.34 fewer tablets per week) were several times greater than the differences between placebo and ranolazine, a reminder of the importance of placebo controls. Similar observations of placebo effect have been made in earlier trials of antianginal drugs (10,13).
In short-term trials of low-risk patients, major clinical outcomes will not differ, and therefore improvements of practical importance to patient function should be sought. Therefore, the use of the SAQ (12), a disease-specific measurement of quality of life, is an appealing design feature of the ERICA trial. Although the SAQ domain of anginal frequency showed a statistically significantly greater reduction by ranolazine consistent with the major outcome of the study, the differences in the other 4 domains were not significant. Accordingly the clinical importance of the improvement in the study’s primary efficacy variable remains uncertain.
Current guidelines recommend combinations of beta-blockers, calcium antagonists, and long-acting nitrates in appropriate patients (2,3). Ranolazine’s absence of hemodynamic effects suggests theoretically attractive alternative combinations. Studies should be done to compare the addition of ranolazine versus beta-blocker in patients already taking amlodipine and the addition of ranolazine versus amlodipine in patients already receiving a beta-blocker. In patients receiving a beta-blocker and amlodipine, the addition of ranolazine versus placebo should be evaluated. Quality of life measures would be ideal components of such studies.
Because ranolazine prolongs the QTc, the FDA approval is limited to patients who have not responded to other antianginal drugs, and its use in combination with amlodipine, beta-blockers, or long-acting nitrates is recommended. The daily dose should be limited to 1,000 mg and precautions are advised regarding QTc prolongation. Post-release surveillance and additional studies with larger sample sizes and longer durations are essential to assist in determining whether ranolazine’s side effects, including prolongation of QTc, are sufficiently rare and minor to eventually warrant its use as a primary therapy. Additional studies should be done to determine whether the addition of ranolazine to standard monotherapies and combinations is equivalent or superior to the addition of current agents. Quality of life measures allowing comparisons of greater clinical relevance to individual patients have led to clinically relevant conclusions in studies of invasive therapies (16–18), but have been woefully lacking in drug evaluations. The use of a disease-specific measure of quality of life, as in the ERICA trial, should be seriously considered in the design of new trials of antianginal drugs.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Stone PH, Gratsiansky NA, Blokhin A, Huang I-H, Meng L, ERICA Investigators Antianginal efficacy of ranolazine when added to treatment with amlodipinethe ERICA (Efficacy of Ranolazine In Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-575.[Abstract/Free Full Text]2. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary articlea report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003;107:149-158.[Free Full Text] 3. Abrams J. Chronic stable angina N Engl J Med 2005;352:2524-2533.[Free Full Text] 4. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, Hlatky MA. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina JAMA 1999;281:1927-1936.[Abstract/Free Full Text] 5. Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina Eur Heart J 2002;23:355-370.[Free Full Text] 6. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—2006 updatea report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006;113:85-151. 7. Anderson JR, Nawarskas JJ. Ranolazine. A metabolic modulator for the treatment of chronic stable angina Cardiol Rev 2005;13:202-210.[CrossRef][Medline] 8. Chaitman BR, Skettino SL, Parker JO, et al. MARISA Investigators Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina J Am Coll Cardiol 2004;43:1375-1382.[Abstract/Free Full Text] 9. Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris Am J Cardiol 2005;95:311-316.[CrossRef][Web of Science][Medline] 10. Chaitman BR, Pepine CJ, Parker JO, et al. Combination Assessment of Ranolazine in Stable Angina (CARISA) Investigators Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic anginaa randomized controlled trial. JAMA 2004;291:309-316.[Abstract/Free Full Text] 11. FDA Label Document. Available at: http://www.fda.gov/cder/foi/label/2006/021526s000lbl.pdf. Accessed April 17, 2005.. 12. Spertus JA, Nerella R, Kettlekamp R, House J, Marso S, Borkon AM, Rumsfeld JS. Risk of restenosis and health status outcomes for patients undergoing percutaneous coronary intervention versus coronary artery bypass graft surgery Circulation 2005;111:768-773.[Abstract/Free Full Text] 13. Boden WE, Bough EW, Reichman MJ, Rich VB, Young PM, Korr KS, Shulman RS. Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitratesa randomized, double-blind, placebo-controlled cross-over study. Circulation 1985;71:1197-1205.[Abstract/Free Full Text] 14. Ronnevik PK, Silke B, Ostergaard O. Felodipine in addition to beta-adrenergic blockade for angina pectoris. A multicentre, randomized, placebo-controlled trial Eur Heart J 1995;16:1535-1541.[Abstract/Free Full Text] 15. Lehmann G, Reiniger G, Beyerle A, Rudolph W. Pharmacokinetics and additional antiischaemic effectiveness of amlodipine, a once-daily calcium antagonist, during acute and long-term therapy of stable angina pectoris in patients pre-treated with a beta-blocker Eur Heart J 1993;14:1531-1535.[Abstract/Free Full Text] 16. Kim J, Henderson RA, Pocock SJ, Clayton T, Sculpher MJ, Fox KA, RITA-3 Trial Investigators Health-related quality of life after interventional or conservative strategy in patients with unstable angina or non–ST-segment elevation myocardial infarctionone-year results of the Third Randomized Intervention Trial of Unstable Angina (RITA-3). J Am Coll Cardiol 2005;45:221-228.[Abstract/Free Full Text] 17. Mortensen OS, Madsen JK, Haghfelt T, et al. DANAMI Study Group Health related quality of life after conservative or invasive treatment of inducible postinfarction ischaemia Heart 2000;84:535-540.[Abstract/Free Full Text] 18. Strauss WE, Fortin T, Hartigan P, Folland ED, Parisi AF, Veterans Affairs Study of Angioplasty Compared to Medical Therapy Investigators A comparison of quality of life scores in patients with angina pectoris after angioplasty compared with after medical therapy. Outcomes of a randomized clinical trial Circulation 1995;92:1710-1719.[Abstract/Free Full Text]
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