Faculty Peer Reviewed
Case: A 75- year-old non-smoking male with a history of type II diabetes, hypertension and hyperlipidemia comes to clinic with several months of stable anginal chest pain provoked by ten blocks of exercise with no change in exercise tolerance. He has seen you several times over the past year and has been placed on aspirin, beta blockers, calcium channel blockers and long acting nitrates with some relief of symptoms. In addition, he is on atorvastatin with an LDL of 77. His blood pressure is well controlled at 122/78 and his heart rate is 62. His BMI is 25. An EKG shows a normal sinus rhythm at 62 with no evidence of prior myocardial infarction. A transthoracic echo shows a normal ejection fraction with no wall motion abnormalities. An adenosine nuclear stress test was performed that showed a small reversible perfusion defect in the territory of the distal circumflex with a normal ejection fraction. The patient asks if there are any further medical options or if it isnecessary for him to have a percutaneous intervention.
Coronary artery disease continues to be a leading cause of death among both women and men. Angina pectoris is one of several syndromes that results from coronary artery disease. The symptoms of angina manifest as chest discomfort resulting from insufficient supply of oxygen to the heart with increasing demand. In the United States, 16 million adults suffer from coronary artery disease and of those 9.1 million have angina. The total cost of coronary artery disease is 475.3 billion dollars . Moreover, the number of patients suffering from and the health care cost of angina will continue to rise with a growing aging population.
The traditional medical management of chronic stable angina attempts to balance oxygen supply and demand and prevent thrombosis while minimizing cardiovascular risk factors through smoking cessation, weight loss, blood pressure, cholesterol and diabetic management. Medical management includes the use of beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy including aspirin or clopidogrel in patients intolerant of aspirin [2-3]. Beta-blockers should be titrated to reduce the resting heart rate to 55-60 beats per minute. In more severe cases of angina, beta-blockers can be titrated to a heart rate less than 50 if no adverse symptoms or heart block occur. Sublingual nitroglycerin or spray nitroglycerin can be used for immediate relief of angina or prophylaxis prior to anginal causing activities. Long acting nitrates, such as isosorbide dinitrate, mononitrates, transdermal nitroglycerin patches, and nitroglycerin ointment can be used to prevent angina. Patients must have a nitrate free period of 8 to 12 hours in order to prevent nitrate tolerance . Long acting nitrates can be titrated for prevention of symptoms as long as no hypotension or side effects such as headaches develop.
There is little data to suggest that dual antiplatlet therepy is beneficial in patients with stable coronary disease. Data from the CHARSIMA trial has shown that dual antiplatelet therapy with aspirin and plavix does not reduce the rate of cardiovascular events but does increase the rate of bleeding when compared to aspirin alone . However, in post hoc analysis the CHARISMA trial did show a significant reduction in cardiovascular events in patients with stable chronic angina with prior history of MI, stroke or symptomatic peripheral arterial disease [6-7]. As a result, dual antiplatelet therapy may be useful for patients at the highest risk for adverse events or who have recently undergone percutaneous coronary intervention (PCI).
Revascularization continues to be the routine treatment for refractory angina. According to the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Interventions patients continuing to have angina despite medical optimization (beta-blockers, calcium channel blockers, nitrates and antiplatelets therapy) should undergo PCI if there is a low likelihood of mortality and morbidity and high likelihood of success . However, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) sought to compare clinical endpoints in patients receiving medical management alone verse medical management plus PCI.
The COURAGE trial compared cardiovascular outcomes of PCI as an initial management for chronic stable angina to optimal medical therapy alone. In the COURAGE trial, 2287 patients with evidence of ischemia or significant coronary artery disease where randomized to receive PCI plus medical optimization therapy or medical optimization alone. All patients received ischemic therapy with beta-blockers, calcium channel blockers, long and short acting nitrates, as well as antiplatelet therapy with either aspirin or clopidogrel and aggressive lipid-lowering therapy, including administration of a statin with or without ezitimibe. In the initial follow up period, there was a statistically significant reduction in the number of anginal free patients in the PCI group, at one and three years (respectively 66% vs 58%, P< 0.001 and 72% vs 67%, P=0.02). The benefit of PCI persisted at five years. However, at five years, the number of patients that were free of angina, between the two groups, was not statistically significant (74% in the PCI group and 72% in the medical therapy group, P=0.35). It is important to note that 36.6% of all patients in the medical therapy group crossed over to the PCI group by five years. The study did not find any statistical difference between the PCI and medical therapy group in composite death, myocardial infarction and stroke (respectively 20% and 19.5%, P=0.62). . This study supports the idea that PCI is not superior to optimal medical management in terms of death, myocardial infarction and stroke in patients with stable coronary artery disease. However, PCI continues to be beneficial for anginal symptom relief, but can be safely deferred in patients with stable coronary artery disease who are optimally medically managed.
How should you treat patients that continue to have anginal symptoms despite lifestyle and dietary modifications and the addition of anginal medications such as beta-blockers, calcium channel blockers, nitrates and antiplatelet therapy? Or how do you treat patients that have undergone catheterization with no known lesion or are not candidates for catheterization? Is there any medical therapy beyond the current guidelines?
Ranolazine (Ranexa) was approved by the Food and Drug Administration for chronic stable angina in 2006. The use of ranolazine has been shown to be effective to improve anginal symptoms in several studies [9-10]. Ranolazine is a piperazine derivative that works through the inhibition of the late inward sodium current in cardiac cells. Inhibition of late inward sodium current in cardiac cells leads to a decrease in intracellular calcium, increased myocardial relaxation during diastole and inhibits the rapidly activating component of the delayed rectifier potassium current (IKr). Although ranolazine inhibits the delayed rectifier potassium current and causes a modest increase in QTc, it is not associated with proarrhythmic activity . However, given the possibility of prolongation of the QTc, a baseline EKG and EKG after initiation should be obtained. In clinical study, ranolazine does not statistically affect heart rate or blood pressure .
The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, a multi-national, randomized, double-blind, placebo-controlled study, was the first trial of ranolazine SR 500, 1000 and 1500 mg BID monotherapy in patients with chronic angina. The study population consisted of patients older than 21 years of age with well-documented coronary artery disease, angina pain for at least three months that responded to beta-blockers, calcium channel blockers and/or long acting nitrates. During the study, all patients discontinued their anti-anginal treatment. Comparison of exercise stress testing before and after treatment showed that exercise duration increased with ranolazine 500, 1,000, and 1,500 mg twice daily by, respectively, 94, 103, and 116 seconds (P< 0.005). The increase in exercise performance from monotherapy ranolazine is similar to those reported for maximal doses of nitrates, beta-blockers and calcium channel blockers. 
The Combination Assessment of Ranolazine In Stable Angina (CARISA) trial examined the exercise tolerance, angina attacks and nitroglycerin use of 823 patients with symptomatic chronic angina taking standard doses of atenolol (50 mg), amlodipine (5 mg), or diltiazem (180 mg once daily) before and 12 weeks after being randomized to receive 750 mg or 1000 mg twice daily of ranolazine or placebo. Ranolazine reduced the mean number of angina attacks per week from 3.3 ± 0.3 for placebo to 2.5 ± 0.2 for 750 mg (p = 0.006) to 2.1 ± 0.2 for 1000 mg (p < 0.001) ranolazine. It also significantly reduced nitroglycerin consumption (p < 0.02). Exercise duration increased significantly with ranolazine by 115.6 seconds from baseline in both ranolazine groups vs 91.7 seconds in the placebo group (P = .01). The time to onset of anginal symptoms increased significantly in both the 750 mg and 1000 mg group (respectively 144 seconds, P=0.01 and 140.3 seconds, P=0.03). There were no clinically significant changes in blood pressure or heart rate. These finding were independent of background therapy, and persisted for 12 weeks . Similar reduction in angina symptoms were reported in the Efficacy of Ranolazine In Chronic Angina (ERICA) trial that examined the use of amlodipine (10 mg) and ranolazine (1000 mg twice daily) . Post hoc analysis of diabetics in the CARISA trial showed a significant reduction in HbA1C levels .
Chronic angina is a debilitating disease that impacts millions of Americans. The mainstay of treatment involves dietary and lifestyle modifications along with beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy. Current guidelines reflect these mainstays of treatment. Ranolazine should be used as second line treatment when beta-blockers, nitrates and calcium channel blockers have failed to relieve symptoms. Unlike other anti-anginal medications ranolazine does not affect hemodynamics. As a result, ranolazine should be used in addition or alone when the titration or use of beta-blockers, calcium channel blockers or nitrates is limited by blood pressure or heart rate. The most common side effects of ranolazine include dizziness (11.8%) and constipation (10.9 %). These symptoms led to discontinuation of ranolazine in 0.9% and 0.5% of patients, respectively . Syncope and orthostatic hypotension has been seen in a minority of patients receiving 1000 mg twice daily. This may be due to alpha blockade with higher doses of ranolazine and possible drug interaction between higher doses of ranolazine and diltiazem . As a result, it is recommended that clinicians start at the lowest possible dose of ranolazine and titrate up to effectiveness and tolerability. Ranolazine is contraindicated in patients with preexisting long QT prolongation intervals and should be used with caution with other medications that prolong QT intervals. It is also contraindicated in clinically significant liver disease. It should be used with caution in patients with Childs-Pugh class A or B liver impairment. Ranolazine is a potent inhibitor of CYP3A4, thus it should be used with caution in combination with other drugs that utilize CYP3A4 such as diltiazem and verpamil. When used with medications that use CYP3A4 the dose of ranolazine should not exceed 500 mg twice daily. Ranolazine also interferes with the metabolism of digoxin and simvastatin, thus dose reduction of these drugs may be necessary.
In conclusion, the addition of ranolazine to current guidelines may defer the decision for patients with chronic angina to go for PCI. It is likely that ranolazine may be part of future chronic angina management guidelines and should be considered in patients with chronic stable angina.
Commentary by Sohah Iqbal, MD, Division of Cardiology
As the above thoughtful review has highlighted, medical therapy for coronary disease and chronic stable angina continues to evolve. Ranolazine, anecdotally and in clinical trials, has been shown to improve exercise capacity in those with activity limiting angina. There are 2 key criteria that need to be met before adding ranolazine: (1) Identifying patients with chronic stable angina and (2) Ensuring that these patients are on optimal medical management.
Angina that progressively limits patient in their basic activities of daily living or angina changing in character and pattern need to be identified as unstable in nature and should be treated via a different algorithm. Also, before adding ranolazine, patients with coronary artery disease and chronic stable angina must be on medications that have been shown to reduce clinical end points such as aspirin, beta blockers, statins, and in certain subgroups, ace-inhibitors. Once these two criteria have been met, ranolazine is an excellent additional agent to manage chronic stable angina.
Dr. Pfeffer is Chief Resident at NYU Langone Medical Center
Peer reviewed by Sohah Iqbal, MD, Division of Cardiology, NYU Langone Medical Center
1. Rosamond, W., et al., Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008. 117(4): p. e25-146.
2. Trujillo, T.C. and P.P. Dobesh, Traditional management of chronic stable angina. Pharmacotherapy, 2007. 27(12): p. 1677-92.
3. Fraker, T.D., Jr., et al., 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation, 2007. 116(23): p. 2762-72.
4. Gibbons, R., Abrams, J, Chatterjee, K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina. [cited 2009 September 13]; Available from: http://www.acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
5. Bhatt, D.L., et al., Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med, 2006. 354(16): p. 1706-17.
6. Bhatt, D.L., et al., Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol, 2007. 49(19): p. 1982-8.
7. Bakhru, M.R. and D.L. Bhatt, Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin? Cleve Clin J Med, 2008. 75(4): p. 289-95.
8. Smith, S.C., Jr., et al., ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation, 2006. 113(7): p. e166-286.
9. Wilson, S.R., et al., Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol, 2009. 53(17): p. 1510-6.
10. Chaitman, B.R., et al., Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 2004. 291(3): p. 309-16.
11. Keating, G.M., Ranolazine: a review of its use in chronic stable angina pectoris. Drugs, 2008. 68(17): p. 2483-503.
12. Chaitman, B.R., et al., Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004. 43(8): p. 1375-82.
13. Stone, P.H., et al., Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol, 2006. 48(3): p. 566-75.
14. Timmis, A.D., B.R. Chaitman, and M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J, 2006. 27(1): p. 42-8.
15. Koren, M.J., M.R. Crager, and M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol, 2007. 49(10): p. 1027-34.