Heart: Emerging Treatments - Unstable Angina

IN THIS ARTICLE

Is unstable angina serious?

What can be done?

New drugs

Too much Vitamin A from meat and dairy products can weaken the bones of the elderly. more...

OTHER TOPICS

Diet and heart disease

Current treatment for heart attacks

Emerging Treatments: Unstable Angina

Brian M. Go, M.D., and H. Vernon Anderson, M.D.

Drs. Brian Go and Dr. Vernon Anderson are cardiologists at the Hermann Heart Center in Houston. Dr. Anderson, an Associate Professor, University of Texas Medical School, is a world renowned expert on unstable angina and interventional cardiology.

When the heart muscle is deprived of sufficient blood flow or oxygen, intense chest pain, called angina, occurs. In unstable angina (UA), the angina happens more often and with increasing severity, sometimes even at rest. UA is one of the most frequently cited diagnoses for hospital admissions in the United States¹^,² and is, unfortunately, associated with significant short-term disability and death.³ Until recently, the condition was easily missed because the electrocardiogram, the doctor's standard technique for detecting heart problems, is, usually, completely normal in the presence of UA.⁴ Today, however, equipped with new blood tests measuring levels of specific enzymes (CK-MB, troponin-T, troponin-I, CK-MB isoforms and myoglobin) that rise with heart tissue damage, doctors are able to identify unstable angina earlier.⁶

What Causes the Symptoms?
In certain people, who have high levels of circulating fats (lipids), extra patches (called plaques) of lipid and cells build out from the walls of their arteries. If a plaque erodes or tears, platelets and other elements of the blood clotting system are activated and, eventually, a clot (thrombus) forms. More platelets continue to enter the area and the thrombus continues to grow until blood flow past the plaque is reduced. The artery wall, damaged by years of contact with the fat-laden plaques, can't expand wide enough to allow more blood flow. Tissues dependent on the oxygen-rich blood are deprived of oxygen. Oxygen deprivation of the heart muscle produces the pain of angina. Increasing evidence suggests that inflammation from an infectious agent may play a key role in UA and it is possible that, one day, angina patients may benefit from treatment with an antibiotic which should help prevent the initial deposit of fat into the arterial walls.¹³

With our current diagnostic tools, we do not know which blockage will cause unstable, as opposed to stable and more easily treatable, angina. The degree of artery obstruction does not differ between stable and unstable angina. In fact, how much blockage there is in a coronary artery does not even predict whether medical therapy will be beneficial.¹²^,¹⁴^,¹⁵^,¹⁶^,¹⁷ X-ray pictures, taken with special contrast, that demonstrate the blood-containing lining of the artery suggests that the type of coronary lesion might determine the clinical course.¹⁸ Patients with UA often have plaques that have hazy and irregular borders (which suggests that the artery lining may have a blood clot sticking to a broken plaque). Because unstable plaques seem to possess elevated temperatures, doctors may, one day, be able to identify them with a thermal sensor.¹⁹

Is Unstable Angina Serious?
Unless there is evidence of a heart attack, patients are treated with observation, monitoring and an intensive medical regimen, including blood thinners, artery dilator drugs to lower the heart rate and blood pressure, and platelet inhibitors. Although more than 80% of patients with UA stabilize comfortably on intensive medical therapy,²⁰ there is no standard way to predict which of these patients are at increased risk for a heart attack or cardiac death. The electrocardiogram (ECG), a snapshot in time, isn't of much help in following this dynamic, ever changing condition. As a result, continuous ECG monitoring has been proposed as a better way to identify patients at increased risk for heart problems.²¹

New Markers for Heart Damage
There are, however, several indicators of heart tissue damage. Within the first 24 hours following an attack of unstable angina, blood levels of specific enzymes, CK-MB, the troponins (troponin-T and troponin-I), rise and may remain elevated for up to 11 days. These enzyme markers are very sensitive and can detect even minor heart tissue damage.^22,23,24 Elevation in troponin levels in UA patients carries a worse prognosis.⁷^,⁸^,⁹^,¹⁰^,¹¹

If You Have UA, What Can Be Done?
The twin goals of therapy are to improve blood flow to the heart tissue and to stabilize the plaque so that it doesn't continue to promote clot build-up. Many drugs are now available.⁴

Aspirin is useful because it slows down platelet clumping and deposition on the plaque inside the artery²⁵ and greatly decreases the incidence of heart attack and death.²⁶^,²⁷^,²⁸^,²⁹ Intravenous heparin inhibits further blood clot formation and, in combination with aspirin, is especially effective.³⁰^,³¹ Nitroglycerin dilates coronary arteries and improves blood flow. It is given IV to high-risk patients and to those with recurrent chest pain. Patients can be changed to an oral or topical form, once chest pain episodes subside and stabilization is achieved.^4,⁵ Beta-blockers lower the heart rate and blood pressure which decreases the workload of the heart and have been found to help prevent progression of UA to heart attack and death. For patients in whom beta-blockers are not a good idea, calcium antagonists have helped prevent the UA to heart attack progression.

New Drugs

Antiplatelet Agents
An emerging new class of drugs, IIb/IIIa receptor inhibitors, prevent clot formation by blocking receptors on platelets.³² These drugs are all given intravenously and include eptifibatide (Integrilin^®), tirofiban (Aggrastat^®), and abciximab (ReoPro^®).³³ Taken together with heparin, they greatly reduce the occurrence of heart attacks among UA patients.³⁴^,³⁵^,³⁶ One note of caution -- because heparin can also cause bleeding, the doctor must carefully adjust the dosage to the patient's weight. An oral form of these receptor inhibitors is now being evaluated and may offer the possibility of long-term administration and extended effects.

Two other new drugs, ticlopidine (Ticlid^®) and clopidogrel (Plavix^®), both taken orally, also inhibit the activity of platelets, but by a different pathway. Like the receptor-inhibitors, they have been shown to decrease the incidence of heart attack and death in patients with UA.³⁷ Unlike aspirin, however, beneficial effects of ticlopidine may not be apparent for at least a week because it takes a while for it to build up in the body.^25,26 Both clopidogrel and ticlopidine can be used in patients who have an intolerance to aspirin.⁴ Combination therapy that includes aspirin and either ticlopidine or clopidogrel has not been fully evaluated but, theoretically, may offer significant advantages.

Antithrombins (Low-Molecular-Weight Heparin)
Low-molecular-weight heparin (LMWH) offers benefits over standard heparin. It can be especially effective when added to aspirin³⁸ and will not, unlike standard heparin, cause an increase in major bleeding.³⁹ Existing LMWHs include dalteparin (Fragmin^®), nadroparin (Fraxiparin^®) and enoxaparin (Lovenox^®).

Surgical Treatments
For UA patients, the central therapeutic question is when to perform coronary angiography(X-ray pictures with special contrast that demonstrate the blood containing lining of the artery), coronary angioplasty ("balloon surgery" to stretch open the partially blocked artery) or bypass surgery (surgical insertion of a segment of vein between the main artery or aorta and the coronary or heart artery which routes the blood flow around the blockage). UA management ultimately centers on individualization of therapy and the concept of plaque stabilization. If sufficient blood flow through the coronary arteries cannot be guaranteed with medical therapy, then coronary angiography with an eye to proceeding with coronary angioplasty or bypass surgery is warranted.

October 1999

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References
1. Braunwald E et al. Diagnosing and managing unstable angina. Agency for Health Care Policy and Research. Circulation 1994;90:613-622. return

2. Braunwald E et al. Unstable angina: diagnosis and management. In: Clinical Practice Guideline, Number 10. Rockville, Md: US Dept of Health and Human Services publication 94-0602. Agency for Health Care Policy and Research; 1994. return

3. Anderson HV et al. One year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 1995;26:1643-1650. return

4. Theroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation 1998;97:1195-1206. return

5. Gersh BJ, Braunwald E, Rutherford JD. Chronic coronary artery disease. In: Braunwald EB, Ed. Heart Disease: A Textbook of Cardiovascular Medicine, 5th Edition, 1997, Philadelphia, Pennsylvania; W.B. Saunders Company. return

6. Califf RM. Editorial: good news for the treatment of thrombotic disorders. In: Presentations in Focus. Acute Coronary Syndromes: Current Perspectives and Directions (from data presented at the American Heart Association 70th Scientific Sessions), 1997, New York, New York; Medical Education Network. return

7. Galvani M et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation 1997;95:2053-2059. return

8. Luscher MS, Thygesen K, Ravkilde J, Heickendorff L, for the TRIM Study Group. Applicability of cardiac troponin T and I for early risk stratification in unstable coronary artery disease. Circulation. 1997;96:2578-2585. return

9. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335;1342-1349. return

10. Wu AHB et al. Prognostic value of cardiac troponin T in unstable angina pectoris. Am J Cardiol 1995;76:970-972. return

11. Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996;93:1651-1657. return

12. Crea F et al. Role of Inflammation in the pathogenesis of unstable coronary artery disease. Am J Cardiol 1997;80(5A):10E-16E. return

13. Gurfinkel E et al. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350(9075):404-407. return

14. Ambrose JA et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609-616. return

15. Forrester JS et al. A perspective of coronary disease seen through the arteries of living man. Circulation 1987;75:505-513. return

16. Moise A et al. Unstable angina and progression of coronary atherosclerosis. N Engl J Med 1983;309:685-689. return

17. Vejar M et al. Comparison of low-dose aspirin and coronary vasodilators in acute unstable angina. Circulation 1990;81(suppl I):4-11. return

18. Dangas G et al. Correlation of angiographic morphology and clinical presentation in unstable angina. J Am Coll Cardiol 1997;29:519-525. return

19. Casscells W et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447-1451. return

20. Brown CA et al. Prospective study of medical and urgent surgical therapy in randomizable patients with unstable angina pectoris: results of in-hospital chronic mortality and morbidity. Am Heart J 1981;102:959-964. return

21. Dellborg M, Anderson K. Key factors in the identification of the high-risk patient with unstable coronary disease: clinical findings, resting 12-lead electrocardiogram, and continuous electrocardiographic monitoring. Am J Cardiol 1997;80(5A):35E-39E. return

22. Hamm CW. New serum markers for acute myocardial infarction. N Engl J Med 1994;331(9):607-608. return

23. Hamm CW et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327(3):146-150. return

24. Mair J. Progress in myocardial damage detection: new biochemical markers for clinicians. Crit Rev Clin Lab Sci 1997;34:1-66. return

25. Patrono C, Renda G. Platelet activation and inhibition in unstable coronary syndromes. Am J Cardiol 1997;80(5A):17E-20E. return

26. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990;336:827-830. return

27. Cairns JA, Gent M, Singer J. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985;313:1369-75. return

28. Theroux P et al. Aspirin, heparin or both to treat acute unstable angina. N Engl J Med 1988;319:1105-1111. return

29. Lewis HD et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983;313:1369-75. return

30. Oler S, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996;276:811-815. return

31. Cohen M et al., and the Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Circulation 1994;89:81-88. return

32. Coller BS. Blockade of platelet GP IIb/IIIa receptors as an antithrombotic strategy. Circulation 1995;92:2373-2380. return

33. Cannon CP. The glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. In: The New Era of Reperfusion, Physician Edition, December 1997 Vol. 1, No. 4, Belle Mead, New Jersey; Excerpta Medica, Inc. return

34. The CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE trial. Lancet 1997;349;1429-1435. return

35. Theroux P, for the PRISM-PLUS Investigators. Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms. Presented at the American College of Cardiology Scientific Sessions, Anaheim, California, March 17, 1997. return

36. Califf R, for the PURSUIT Investigators. Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Trial (PURSUIT). Presented at the European Meeting of Cardiology, Stockholm, August 25, 1997. return

37. Balsano F, et al. And the Studio della Ticlopidina nell�Angina Instabile Group. Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter trial. Circulation 1990;82:17-26. return

38. The FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347:561-568. return

39. Klein W, et al. for the FRIC Investigators. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997;96:61-68. return

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