Treatment of ischaemic heart disease

Transcription

1 European Heart Journal (1997) 18 {Supplement B), B11-B15 Treatment of ischaemic heart disease Role of drugs, surgery and angioplasty in unstable angina patients C. R. Conti Department of Medicine and Cardiology, University of Florida, College of Medicine, Gainesville, Florida, U.S.A. The term unstable angina should only be used to describe patients whose immediate prognosis is uncertain and the nature of the unstable disease may vary on a patient to patient basis, making broad categorization of such patients inappropriate. Unstable angina may be caused by extracardiac factors, such as uncontrolled hypertension and tachycardia, disruption of an atheromatous plaque, dynamic or intermittent coronary artery thrombosis, haemorrhagic dissection into an atheromatous plaque, epicardial coronary spasm or progression of atherosclerosis as a result of plaque healing. Control of symptoms using medical therapy with a combination of nitrates, /?-blockers and calcium antagonists is usually quite successful. In the absence of contra-indications, intravenous heparin, and possibly anti-platelet agents, should also be used in the What is meant by the term 'unstable angina'? Many have grappled with the definition of unstable angina. Years ago Paul Wood used the term 'acute coronary insufficiency' to describe these patients' 11. He defined the condition as a 'state in which the coronary circulation is insufficient to meet the full metabolic demands of the myocardium at rest, yet sufficient to prevent myocardial infarction' (MI). The term 'unstable angina' is used to describe complex clinical conditions and was first introduced by Noble Fowler, who made a plea for an objective definition and for a controlled clinical trial of its management' 21. A few years later a classification was proposed to characterize those patients who were considered to be unstable 131. These were identified as those who experienced: (1) recent onset angina on effort; (2) angina on effort with a changing pattern, e.g. increased frequency, severity or duration of chest discomfort; (3) angina at rest. This simple classification has been used by many to define entry criteria for studies of unstable angina Correspondence: Dr C. Richard Conti, Department of Medicine and Cardiology, P.O. Box , University of Florida, College of Medicine, Gainesville, Florida , U.S.A. acute phase of treatment. In addition, one aspirin a day is indicated unless there are definite contra-indications. If symptoms are relieved, evaluation and management should proceed as with chronic stable angina. Identification of patients with a poor prognosis should be the main indication for urgent revascularization. One of the best predictors of a poor prognosis in unstable disease is persistent pain despite optimum therapy. Urgent surgery should be considered in any patient with multivessel coronary artery stenosis who has evidence of persistent myocardial ischaemia, despite adequate medical therapy. (Enr Heart J 1997; 18 (Suppl B): B11-B15) Key Words: Unstable angina, ischaemic heart disease, nitrates, /?-blockers, calcium channel blockers. patients. However, in clinical practice, these broad subclassifications may not be specific enough to identify the cause or predict the outcome of the unstable patient being evaluated. It may be more useful to be more descriptive about the particular patient labelled as having unstable angina. For example, patients who present with an acute ischaemic syndrome in the absence of a recent MI may have a different aetiology for their unstable state as well as a different prognosis than patients who have recurrent angina following an acute myocardial infarction. In addition, it is highly likely that patients with unstable angina who have not been treated will have a different prognosis than those who have been treated and yet are refractory to optimum therapy. The term 'unstable angina' should be used only when the immediate prognosis is uncertain. Examples of patients whose prognoses are uncertain are: (1) patients with new onset or 'crescendo' angina; (2) patients with uncontrolled recurrent angina despite optimum medical therapy; (3) patients whose symptoms and electrocardiograms suggest impending myocardial ischaemia; (4) patients with recurrent angina following a recent MI. If a patient's condition stabilizes, by definition the patient is no longer unstable X/97/0B0O11+05 $18.00/ The European Society of Cardiology

2 B12 C. R Conti What causes unstable angina? Potential causes for the development of unstable angina include: (1) extra-cardiac factors in the patient with severe coronary atherosclerosis, e.g. poorly controlled hypertension and tachycardia; (2) plaque disruption, resulting in transient platelet aggregation and release of vasoactive substances in diseased vessels; (3) dynamic or intermittent coronary artery thrombosis; (4) haemorrhagic dissection into an atheromatous plaque; (5) epicardial coronary artery spasm; (6) progression of atherosclerosis as a result of plaque healing. These variable causes of the unstable state suggest a variable prognosis. Thus it is not logical to think that unstable angina can be treated in the same way for all patients. Some will need urgent revascularization procedures. Factors influencing prognosis in unstable angina Persistent pain When reading the literature relating to prognosis of unstable angina patients, it is noticeable that one of the best predictors of a poor prognosis is the persistence of ischaemic cardiac pain despite optimum medical therapy. This is most strikingly illustrated by three reports. Gazes et al. reported on 54 patients with persistent pain beyond 48 h [4]. Twenty per cent died within 1 month and 43% within 1 year. In contrast, there were no deaths within 1 month, and only one death within 1 year, amongst the 86 patients who had no persistent pain. Neill reported on 24 patients with recurrent pain associated with transient ST-segment shifts in the anterior leads and severe left anterior descending (LAD) coronary stenosis' 51. This combination resulted in a poor prognosis. Sixteen patients were treated medically and 10 of these 16 developed a MI. In contrast, 50 patients were reported without recurrent chest pain and only three of these developed a myocardial infarction. The authors thought that the patients with the poor prognosis were having 'staccato' LAD coronary artery occlusion. Holdright et al. reported on 285 patients who underwent ambulatory ECG monitoring for the first 48 h of treatment' 61. The incidence of inhospital infarction or death was significantly higher in those patients with transient myocardial ischaemia (53% vs 22%, P<00001). These observations suggest that, when identified, such patients should undergo some sort of revascularization procedure on an urgent basis. ST-segment shifts When patients are admitted to a coronary care unit with chest pain, the electrocardiogram, in many instances, will reveal an ST-segment depression or ST-segment elevation during chest pain. This is merely a marker indicating that the chest pain is very likely due to myocardial ischaemia. It may have some prognostic significance, particularly if there is ST-segment elevation, since ST-segment elevation has been associated with more life-threatening arrhythmias than ST-segment depression 171. When ST-segment deviation occurs in combination with chest pain in patients who are refractory to medical therapy, there is clear indication for cardiac revascularization on an urgent basis' 81. Left main coronary artery stenosis When left main coronary artery stenosis is identified, the best long-term strategy for therapy is coronary bypass surgery 1 ' 1. Of course, the only way to identify left main coronary artery stenosis with precision is by coronary angiography. Some have used this as an argument for performing angiography in all patients admitted to hospital with unstable angina. Survival data in patients with left main coronary artery stenosis, however, are based on long-term mortality not acute mortality. Thus, if ischaemia is controlled, emergency surgery does not seem to be necessary. However, all agree that surgery is the eventual treatment of choice in this group of patients. Asymptomatic cardiac ischaemia Several investigators have reported studies using ambulatory ECG monitoring of patients who initially presented with unstable angina' 10 '" 1. Their findings support the concept that patients with continuing ischaemia on an ambulatory ECG have a poorer prognosis than patients who have no ischaemia. At the moment, however, there are no data to indicate that urgent revascularization in these patients alters this prognosis. In addition, studies like this require 48 h of ambulatory ECG and are not very helpful in making rapid decisions in a patient who might require urgent surgery. Results of early medical therapy Analysis of the majority of results published in the literature and consideration of personal experience leads to the conclusion that control of symptoms with the initial pharmacological therapy for unstable angina is usually quite successful. In our own experience with 111 patients, 100 had excellent control of symptoms in the early stages' 121. Of those who had poor control despite medical therapy, seven of the 11 (63%) evolved an acute MI. The overall MI rate was 6-6%. There were four hospital deaths, all in patients who evolved an MI and the overall death rate was 3-6%.

3 Treatment of unstable angina B13 Management strategy One has to develop a strategy to evaluate and manage patients with unstable angina. It is common practice to hospitalize patients in the coronary care unit to identify and treat any precipitating factors. Initial management If extra-cardiac (aggravating) factors are present, these must be controlled or removed. Intravenous nitroglycerin is used frequently to treat patients with unstable angina and clinical experience indicates that, as a result, such patients have reduced symptoms. Unfortunately, there are no long-term clinical trials to indicate that nitrate therapy used alone alters prognosis. If abnormal constriction of a conductive coronary artery is identified as the mechanism for producing myocardial ischaemia, then the use of vasodilators in the early phases of unstable angina seems appropriate. If severe coronary artery disease is found (with or without thrombosis), one can make a strong argument for therapy with i.v. heparin (in the absence of contra-indications) during the acute phase of the illness. A similar argument could be made for the use of anti-platelet agents during the acute and convalescent phase. Several trials have been performed using combination drug therapy, principally calcium antagonists, C/?-blockers and nitrates. In patients already treated with nitrates and /?-blockers, the addition of a calcium antagonist seems beneficial. In contrast, in patients who have not received any drugs, nitrates and /?-blockers seem to be the preferred treatment. How does one select the drugs of first choice, i.e. nitrates, ^-blockers or calcium antagonists? Several factors must be considered: (1) the presumed mechanism or mechanisms of ischaemia; (2) unwanted side effects of the drug and drug interactions; (3) drug tolerance (as seen with nitrates); (4) convenience of drug administration; (5) prevention of infarction and/or sudden death; (6) cost to the patient. Additionally, the choice of specific drug(s) depends on specific indications and contra-indications and will vary depending on whether the patient with unstable angina has heart failure, peripheral vascular disease, obstructive airway disease, is a smoker, has diabetes, bradyarrhythmias, tachyarrhythmias, hypertension or recent myocardial infarction. One also has to consider the interaction of drugs (such as that seen between digoxin and verapamil). If thrombosis is identified, then thrombolytic therapy in the early stages seems reasonable. Management if symptoms are relieved If symptoms are relieved, evaluation and management should proceed as if the patient has chronic angina. It is common practice to perform coronary angiography in most patients during the initial hospitalization to assess severity of disease and prognosis. If no significant coronary artery disease (CAD) is found, a provocative test for spasm using intravenous or intracoronary ergonovine is warranted. If significant CAD is found, angioplasty or coronary bypass surgery should be considered at a convenient time, depending on the stenosis location, degree of stenosis, number of stenotic vessels and degree of ventricular dysfunction. In patients who respond favourably to initial medical therapy, prognosis can also be assessed by exercise testing and ambulatory ECG monitoring. Those with a positive exercise test have a higher incidence of unfavourable events than those with a negative exercise test, and patients with silent ischaemia have a higher incidence of MI within 30 days than those without silent ischaemia. Silent ischaemia occurring for 60 min or longer for 24 h is associated with the worst prognosis' 101. Management if symptoms persist If symptoms persist, despite drug therapy, patients should undergo angioplasty or bypass surgery during the initial hospitalization. Patients whose symptoms are controlled initially on medical therapy, and who then have persistent chronic angina and multiple-vessel disease, should also undergo either PTCA or bypass surgery. Long-term therapy of these patients should include treatment with the usual drugs, i.e. nitrates, yj-blockers and calcium antagonists, if symptoms persist. In addition, one aspirin a day is recommended unless contra-indicated. In my view, weight control, blood pressure control, cessation of smoking and lowering of cholesterol are mandatory. Need for early intervention Identifying patients with a poor prognosis on medical therapy should be the main indication for urgent revascularization. According to published information, there is wide variation in the apparent need for revascularization. For example, the Montreal Heart Group reported a 49% need for intervention during the first year of follow-up 1131, while the Research on Instability in Coronary Artery Disease Group (RISC) reported that 2-5% of the placebo and 5% of the aspirin groups required early intervention' 141. When the U.K. is compared with the U.S.A., 7-7% were revascularized in the U.K. vs 29% in the U.S.A. over a 3-month period' 151. There was no difference in primary endpoints at 3 months. In contrast, the Thrombolysis in Myocardial Infarction 3 (TIMI3) patients in Canada and the U.S.A. had the same revascularization rate' 161.

4 B14 C. R Conti Results of percutaneous transluminal coronary angioplasty In all published studies, symptoms are clearly relieved in the majority of patients undergoing angioplasty. However, all admit that complication rates are higher in patients undergoing angioplasty and directional coronary atherectomy acutely rather than in stable patients' 171, with the main complications being vessel occlusion and MI. Perhaps the use of platelet receptor blockers will decrease this risk of occlusion and MI. Recently, Simoons et al. published a pilot study using a glycoprotein Ilb/IIIa platelet receptor blocker in patients with refractory angina 118 '. They measured the total number of events, including death, MI, urgent CABG or PTCA and placing of stents, in 60 patients undergoing PTCA, randomized either to placebo or receptor blocker. In the placebo group there were 12 events in seven patients (23%) and in the receptor blocker patients one patient had an event (3%). Why it is more hazardous to perform angioplasty in the acute unstable state is not totally clear but, in my opinion, one must consider that the patient's myocardium may be stunned If that is the case, coronary blood flow run-off into the microcirculation might not be as good as it could be after 5-10 days of aggressive medical therapy. This may lead to stasis, platelet aggregation and a propensity towards thrombosis. Results of surgery National Heart Lung and Blood Institute (NHLBI) unstable angina clinical trial In the NHLBI National Cooperative Randomized Study of Unstable Angina, patients were not identified as medical failures when they were entered into the trial' 201. All had evidence of myocardial ischaemia (ST-segment shifts during pain) and all had CAD with left ventricular function that was suitable for surgery. However, patients with left main coronary artery stenosis were excluded, silent ischaemia was not looked for, some received heparin, none received aspirin and none of these patients received calcium antagonists, since they were not available at the time of this study. The study revealed that emergency surgery was not necessary in the population of patients defined by the entry criteria. Early mortality was equal between medically- and surgically-assigned groups but the MI rate was greater in the patients randomized to surgery. Even in 1995, clinical experience indicates that emergent PTCA or surgery is rarely indicated in patients treated with a combination of drugs such as aspirin, heparin, nitrates, /?-blockers and calcium antagonists. It is important to point out that, currently, the 'unstable angina patient' includes patients with postinfarction angina, left main coronary stenosis, previous coronary bypass surgery and often patients with persistent angina on appropriate medical therapy, as well as including intra-aortic balloon counter pulsation. This group of patients has a surgical mortality of approximately 4% compared with <1% in the stable angina patients. It is important to emphasize again that all of the patients indicated above were excluded from previous clinical trials, including the Coronary Artery Surgery Study (CASS), the Oregon study, NHLBI study and the Veterans Administration (VA) study* 21 " 24 '. Both the NHLBI and VA studies were randomized. There was variability in operative mortality ranging from 1-8% in the Oregon study to 5% in the NHLBI trial. In addition, survival rates were reported for variable periods of time (3-10 years) and in the range 79-85%. All of these reports are historic. It is possible that with the use of more modern surgical techniques, including the internal mammary artery, improved anaesthesia and aggressive medical therapy, one may reduce the.operative mortality and prolong survival. Once again, I would emphasize that the patient who is operated on acutely may have a stunned myocardium, which may partially explain why the operative mortality is higher than in similar patients who are stabilized. Thrombolysis in myocardial infarction 3B (TIMI3B) randomized trial The TIMI 3B trial of 1473 patients was recently reported' 251. Patients were randomized to early invasive therapy, within h, or early conservative therapy. The endpoints were death, MI or a positive exercise test at 6 weeks. Revascularization was accomplished within 42 days. Therefore, this was not a trial of emergency revascularization. It is interesting to note that there were no significant differences in the endpoints reported for the two groups with 16-2% in the early invasive and 18-1% in the early conservative patients. In addition, 97% of the early invasive patients underwent angiography, compared with 64% in the conservative group. Furthermore, 61% of the early invasive group were revascularized, while 49% were revascularized in the early conservative group. Thus, a high percentage of patients underwent angiography and revascularization regardless of their randomization assignment. Summary Most patients who present with unstable angina have their symptoms controlled initially with pharmacological management. In 1995, clinical experience indicates that emergent PTCA or surgery are rarely indicated in patients treated with a combination of drugs. Current medical therapy includes aspirin, heparin, nitrates, /J-blockers and calcium antagonists. In the future, therapy may include the use of hirulogues, hirudins and platelet receptor blockers.

5 Treatment of unstable angina B15 If symptoms persist, coronary angioplasty or bypass surgery can be performed but morbidity and mortality is slightly higher than in patients who are stable. Data indicate that patients will do well with either PTCA or bypass surgery. However, percutaneous transluminal coronary angioplasty data reported in the literature are, for the most part, in patients with singlevessel, and some with double-vessel, disease. Thus, these patients are not comparable with the usual population of patients who currently undergo CABG. Urgent surgery should be considered in any patient with multivessel coronary artery stenosis who has evidence of persistent myocardial ischaemia despite adequate medical therapy. Persistent ischaemia may be defined as either spontaneous angina, spontaneous STsegments shift on the ambulatory ECG, a positive exercise test at a low cardiac workload or a markedly positive radionuclide or cardiac ultrasound imaging stress test. These are individuals who are likely to benefit most by early myocardial revascularization procedures. In my view the indications for angiography and revascularization are quite clearcut and comprise unstable angina patients who have had previous PTCA, coronary bypass surgery or MI, refractory angina, a high-risk exercise tolerance test or other non-invasive test, heart failure or marked left ventricular dysfunction and finally, in some instances, when the patient insists on it. The type of revascularization to be performed depends on the enthusiasm and experience of the cardiologist or surgeon. As a general rule, PTCA should be performed in patients with one- or two-vessel disease or in some patients with three-vessel disease who are at low risk. In general, coronary bypass surgery should be performed in the high-risk patient with either single- or multiple-vessel disease. Finally, revascularization procedures should be delayed if possible, since surgery and angioplasty of patients with stunned myocardium does not seem to offer as low a risk as when the myocardium has recovered after several days of aggressive medical management. References [1] Wood P. Acute and sub-acute coronary insufficiency. Br Med J 1961; 24: [2] Fowler NO. Pre-infarction angina: a need for an objective definition and for a controlled clinical trial of its management. Circulation 1971; 44: [3] Conti CR, Brawley RK, Griffith LSC et al. Unstable angina pectoris: morbidity and mortality in 57 consecutive patients evaluated angiographically. Am J Cardiol 1973; 32: [4] Gazes PC, Mobley GM, Faris HM, Duncan RC, Humphries GB. Preinfarction (unstable) angina a prospective study ten year follow-up. Prognostic significance of electrocardiographic changes. Circulation 1973; 48: [5] Neill A. Staccato left anterior descending artery occlusion: a recognizable subset of unstable angina. 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