Clinical and Health Affairs
Emerging Therapies for Refractory Angina
By Daniel Satran, M.D., Jay H. Traverse, M.D., Gregory W. Barsness, M.D., Amir Lerman, M.D., Robert D. Simari, M.D., Anil K. Poulose, M.D., Randall K. Johnson, M.D., and Timothy D. Henry, M.D.
Abstract
In recent years, improvements in both pharmacologic and revascularization therapies have greatly increased life expectancy for patients with coronary artery disease (CAD). As patients with more extensive CAD live longer, many develop myocardial ischemia and clinical angina that is not amenable to traditional revascularization therapy. Patients with severe, symptomatic, chronic CAD have been described as having refractory angina; they have also been termed “no-option” patients. This article discusses clinical management of this unique and growing group of patients and emerging therapeutic options including pharmacologic agents, enhanced external counterpulsation therapy, therapeutic angiogenesis, neurostimulation, and transmyocardial revascularization.
Case Study
The following case illustrates the dilemma of managing a young patient with severe, premature coronary artery disease, life-limiting angina, and no good option for improvement through traditional revacularization or pharmacologic means.
A 50-year-old man presented in 2002 with an anterior ST-segment elevation myocardial infarction and underwent stent placement to the left anterior descending coronary artery. Over the next 5 years, he had multiple percutaneous interventions (6 total) to all 3 coronary arteries for recurrent angina. In early 2007, he continued to experience angina and underwent 4-vessel coronary artery bypass surgery (internal mammary artery to left anterior descending, vein grafts to the first and second obtuse marginal and right coronary). Three months after bypass, his angina returned. He was referred to the OPTIMIST program at Abbott Northwestern Hospital.
Coronary angiography showed the internal mammary graft was patent, but all 3 vein grafts were occluded. Left ventricular function was normal. Adenosine MRI stress test showed severe ischemia in the inferior and lateral myocardial walls. In clinic his blood pressure was 100/70 on maximally tolerated anti-anginal therapy. He continued to experience angina at rest.
The patient could not tolerate increased doses of nitrates, beta-blockers, and calcium-channel blockers because of hypotension and lightheadedness. Percutaneous revascularization was not possible because of diffuse chronic atherosclerosis. The patient was reluctant to consider another coronary artery bypass surgery because of previous early vein graft failure, although this remains a future consideration with the availability of arterial (radial) conduits and/or a minimally invasive approach (lateral thoracotomy). Enhanced external counterpulsation therapy was considered, but logistics were a problem for this patient. Ultimately, he was enrolled in a placebo-controlled stem-cell angiogenesis trial.
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As many as 900,000 individuals in the United States are believed to have severe, symptomatic, chronic coronary artery disease (CAD)—or refractory angina—that is not amenable to traditional revascularization. Between 25,000 and 75,000 new cases are diagnosed each year.
1,2 A recent study of Olmsted County patients who had had coronary bypass surgery and were undergoing repeat coronary angiography estimated approximately 50,000 new cases of refractory angina per year in the United States.
3 The European Society of Cardiology estimates that 15% of patients who experience angina can be characterized as having refractory angina.
4 As the population ages and CAD mortality decreases, the number of patients with the condition is likely to increase.
Of 500 consecutive patients presenting for coronary angiography at the Cleveland Clinic in 1998, 59 (12%) had evidence of ischemia and were not candidates for traditional revascularization.5 A recent review of 600 consecutive angiography patients at the Minneapolis Heart Institute/Abbott Northwestern Hospital showed similar results. Some of the reasons for poor revascularization candidacy include unsuitable anatomy, diffuse atherosclerosis, 1 or more previous coronary artery bypass surgeries, lack of available graft conduits, degenerated saphenous vein grafts, chronic total coronary artery occlusions, microvascular dysfunction, advanced age, and co-morbid conditions that preclude further procedures or prohibitively increase morbidity and mortality associated with such procedures.4
Researchers disagree about the long-term outcome of patients with refractory angina. One-year follow-up from the small Cleveland Clinic study showed high rates of rehospitalization
(1.3 per patient per year), myocardial infarction (26%), and mortality (17%) for such patients.6 However, a larger series of 1,135 patients followed at the Minneapolis Heart Institute for a median of 4.7 years showed a much lower annual mortality rate (3%).7 Recent data from 196 patients who were treated at Mayo Clinic confirm a similarly low mortality rate (5.5% at 1 year).8 Both the Minneapolis Heart Institute and Mayo Clinic cohorts also have low cardiac mortality (approximately 2% per year). Similarly, patients with refractory ischemia enrolled in clinical trials have low rates of mortality in follow-up. Therefore, the major challenges for patients with refractory angina are persistent angina and poor quality of life.
Therapy Options
The American Heart Association/American College of Cardiology clinical practice guidelines provide little information regarding therapy for refractory angina.9,10 Patients with the condition remain underdiagnosed and undertreated, and the European Society of Cardiology has promoted increased recognition and a more structured approach to evaluation and treatment.4 An aggressive percutaneous revascularization approach may be adopted—for example, with chronic total coronary artery occlusions—but this carries an elevated risk to the patient in terms of morbidity associated with the procedure, as well as exposure to intravenous contrast dye and ionizing radiation. Additional therapeutic options include novel pharmacologic agents, enhanced external counterpulsation (EECP) therapy, therapeutic angiogenesis, neurostimulation, and transmyocardial revascularization (Table 1).
♦ Pharmacologic Therapy
Pharmacologic therapy for patients with refractory angina involves both standard and novel medications. Standard therapy includes anti-platelet and lipid-lowering agents for all patients, with the understanding that it can potentially slow the progression of CAD.9-11 Newly revised American Heart Association/American College of Cardiology guidelines describe the rationale for use and titration of traditional antianginal drug therapy (nitrates, beta-blockers, and calcium-channel blockers).9,10
Novel drug therapy has been reviewed recently.12 Ranolazine, which inhibits the slowly inactivating component of the cardiac sodium current (INa), was recently approved by the Food and Drug Administration (FDA) based on results of the Efficacy of Ranolazine in Chronic Angina (ERICA) trial, a placebo-controlled study of 564 patients showing that ranolazine in addition to amlodipine significantly reduced the frequency of angina episodes without lowering blood pressure.13 Prolongation of the QT interval on electrocardiogram is an important side effect of this medication. However, recently published results of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST–elevation acute coronary syndromes (MERLIN) trial, comparing ranolazine to placebo in 6,560 patients with non-ST–elevation acute coronary syndromes, showed no increased incidence of arrhythmias at a median follow-up of 348 days.14 It should also be noted that ranolazine has not been studied in patients with refractory angina. Another novel pharmacologic therapy, the amino acid L-arginine, theoretically enhances nitric oxide synthesis and endothelial vasodilation and has been studied in 1 small randomized placebo-controlled clinical trial of 22 patients.15 Unfortunately, larger studies of patients with refractory angina are unavailable, and 1 randomized, placebo-controlled trial in patients following acute ST-elevation myocardial infarction showed an association with increased mortality.16 Nicorandil, an adenosine triphosphate-potassium channel activator, and trimetazidine, an inhibitor of fatty acid metabolism, are available in Europe and Asia but not in the United States. Ivabradine, a specific If ion channel inhibitor, also awaits FDA approval.
♦ Enhanced External Counterpulsation
Enhanced external counterpulsation therapy is a noninvasive compression technique that simulates the action of an intra-aortic balloon pump.17 Three pairs of pneumatic blood pressure cuffs are placed on the calves, and upper and lower thighs (Figure). An electrocardiogram trigger sequentially inflates the cuffs (distal to proximal) during diastole, increasing diastolic blood flow and venous return, then deflates the cuffs during systole. A typical course of EECP therapy consists of 35 1-hour sessions over 7 weeks. The course can be shortened by increasing the frequency of therapy to twice daily. Potential mechanisms for EECP’s ability to relieve angina include improved endothelial function, improved hemodynamics, reduced aortic impedence, and enhanced collateral coronary artery blood flow.18 Based on available data, 75% of patients can expect an improvement of greater than or equal to 1 Canadian Cardiovascular Society Angina Class (Table 2) as a result of treatment with EECP.18 The Multicenter Study of Enhanced External Counter Pulsation (MUST-EECP), a double-blind, sham-controlled trial of active EECP therapy or sham treatment in 139 patients, was the pivotal EECP trial. It demonstrated a significant increase in time to ST-depression on treadmill as well as a significant reduction in angina episodes.19 An international registry has confirmed a lasting anti-anginal effect of EECP therapy as well as improved quality of life on a subjective 5-point scale (poor, fair, good, very good, excellent).20 Those benefits also extend to patients with significant left ventricular dysfunction.21 Side effects of EECP therapy including leg pain and bruising are minimal. Few contraindications exist, but significant aortic insufficiency, abdominal aortic aneurysm, and arrhythmias that could interfere with electrocardiogram gating should be ruled out before starting therapy. From a patient perspective, the main limitation of EECP therapy is distance to the treatment center: Many individuals cannot afford or coordinate extensive travel for daily sessions.
♦ Angiogenesis
The potential to grow new blood vessels has been a tantalizing and elusive goal for decades.22,23 Clinical experience with protein growth factors and genes encoding for those growth factors to enhance myocardial angiogenesis primarily involves vascular endothelial growth factor and fibroblast growth factor. Multiple delivery methods (protein alone, plasmid, and adenoviral vectors) and routes (intravenous, intracoronary, intramyocardial) have been used in clinical trials. Although the promise of angiogenesis is great, randomized placebo-controlled trials demonstrate excellent safety but only modest efficacy based on secondary angina and quality-of-life endpoints.24 Therefore, there has been tremendous interest in stem-cell therapy for cardiovascular disease including chronic refractory angina. Although the exact mechanisms underlying how stem cells contribute to angiogenesis are unknown, clinical investigation has forged ahead.25 A preliminary double-blind, randomized, placebo-controlled trial of intramyocardial injection of autologous CD34 stem cells in 24 patients with intractable angina demonstrated safety and preliminary efficacy in terms of improved angina class and quality of life.26 A large multicenter trial of 150 patients is underway, with 1-year follow-up results expected in 2009. Ultimately, angiogenesis therapy may need to “embrace diversity” and combine gene, protein, and/or cell therapy to demonstrate efficacy and fulfill lofty expectations.27
♦ Neurostimulation
Neurostimulation therapy for pain relief has been used in medicine for decades and is the therapy of choice in Europe for refractory angina.4 Transcutaneous electrical nerve stimulation, used for many chronic pain disorders, is seldom used for refractory angina because of skin irritation and breakdown with chronic use. Spinal cord stimulation (SCS) using an indwelling device is FDA-approved for chronic pain but not specifically for refractory angina. The device has an epidural lead, extension wire, and pulse generator. Patients typically receive scheduled stimulation and can induce additional stimulation with a handheld magnet if they experience breakthrough pain. There is no sham-controlled data available for SCS. One trial comparing coronary bypass surgery with SCS in 104 patients showed the device to be effective for improving angina, with a lower incidence of morbidity (stroke) and mortality.28
♦ Transmyocardial Revascularization
Initially, laser transmyocardial revascularization (TMR) was thought to improve oxygenation of cardiac myocytes by creating new channels for blood flow. However, these channels eventually close, and it is more likely that any benefit to the patient comes from myocardial injury from the laser, which stimulates angiogenesis and/or causes denervation. Exactly how this benefits patients remains unclear, and well-designed sham-controlled trials are lacking. Although the procedure is FDA-approved for refractory angina, TMR is now seldom used other than as an adjunct to coronary artery bypass surgery because it is invasive and associated with increased morbidity and mortality. Once promising, percutaneous TMR has been shown to be ineffective.29
Models of Care
Patients with refractory angina receive care from multiple medical providers including family physicians, internists, and cardiologists. Almost all patients have received cardiology consultation but may not be under the continuous care of a cardiologist. Both the Minneapolis Heart Institute/Abbott Northwestern Hospital and Mayo Clinic have developed specialized clinics to care for this unique population of patients. At Abbott Northwestern, the OPTIMIST program offers both subspecialty referral and primary cardiology services for patients with refractory angina. Similarly, the Mayo Clinic Chest Pain and Coronary Physiology Clinic serves as a primary cardiology and referral clinic for patients with refractory angina, small vessel disease, premature atherosclerosis, and coronary endothelial dysfunction.
Both clinics assess a patient’s angina symptoms, anti-anginal regimen, and secondary risk-factor modification for CAD. The patient’s coronary angiogram is also reviewed to determine whether standard approaches to revascularization are possible. If they are not, and if the patient is taking the maximum amount of traditional medical therapy, he or she may receive additional novel pharmacologic therapy, EECP, or neurostimulation, or be enrolled in an angiogenesis clinical trial (see Case Study).
Conclusion
As the population ages and mortality from CAD decreases, an increasing number of patients will be diagnosed with angina pectoris that is refractory to traditional therapy. Novel approaches to treating these patients include pharmacologic therapy, EECP, neurostimulation, and angiogenesis. In addition to clinical trials using the above-mentioned therapies, ongoing clinical research projects are actively investigating the natural history of refractory angina, its economic impact, and novel approaches to imaging ischemia and collateral blood flow. Research initiatives in addition to a multidisciplinary clinical approach to care should improve these patients’ prospects for angina relief while enhancing their quality of life. MM
Daniel Satran, Jay Traverse, Anil Poulose, Randall Johnson, and Timothy Henry are in the divisions of cardiovascular disease and internal medicine at the Minneapolis Heart Institute Foundation/Abbott Northwestern Hospital and the University of Minnesota. Gregory Barsness, Amir Lerman, and Robert D. Simari are at Mayo Clinic.
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