Ointments and transdermal nitroglycerin patches for stable angina pectoris

Summary Nitroglycerin (NTG) ointment is used for the prophylaxis against angina pectoris, but there are no data to support its effectiveness during long-term therapy. Continuous, once-daily application of isosorbide dinitrate cream produces tolerance with complete loss of efficacy within 1 week. Nitroglycerin patches are very popular and continuous once-daily application is still claimed by some investigators to provide 24 hour antiischemic and antianginal efficacy. This claim is based on data from postmarketing studies in a very large number of patients and placebo-controlled studies in smaller groups of patients from Italy, Yugoslavia, Greece, and Germany. In contrast, studies from the United States, Canada, England, and some centers in Germany have failed to show superiority of patches over placebo during continuous therapy. This controversy was addressed by the NTG cooperative study group, in which a total of 562 patients who were responders to sublingual nitroglycerin were studied. Patients received either placebo or NTG patches delivering low (15–30 mg/24 hr), moderate (45–60 mg/ 24 hr), or large (75 and 105 mg/24 hr) amounts of NTG. Four hours after the initial application, NTG patches increased exercise duration compared to placebo, but this beneficial effect had disappeared by 24 hours. Furthermore, after 8 weeks of continuous therapy, none of the NTG patches were superior to placebo, whether patients were or were not taking concomitant beta-blockers. Therefore, current opinion is that continous therapy with NTG patches produces pharmacologic tolerance and is ineffective. Pharmacologic tolerance can be minimized when patches are applied every morning and removed after 10–12 hours at night. However, patches delivering >15 mg NTG/24 hr are required to maintain an increased exercise duration for up to hour 8 after the patch application. Intermittent therapy with patches, however, may lead to rebound nocturnal angina in some patients. Also, intermittent therapy with patches has been associated with worsening of exercise performance in the morning prior to the patch renewal, compared to therapy with placebo patches. This has been referred to as the zero-hour effect and probably represents a rebound phenomenon following nitrate withdrawal. Patients experiencing either nocturnal or early morning angina during intermittent therapy with patches should either be switched to oral long-acting nitrates or should in addition be treated with a beta-blocker, provided there are no contraindications to beta-blocker treatment.The opinions expressed here are those of the authors and should not be taken as those of FDA.     

Unstable angina pectoris: National cooperative study group to compare surgical and medical therapy: III. Results in patients with S-T segment elevation during pain

A prospective randomized study comparing intensive medical therapy with urgent coronary bypass surgery for the acute management of patients with unstable angina pectoris was carried out by nine cooperating medical centers under the auspices of the National Heart, Lung, and Blood Institute. Between 1972 and 1976, a total of 288 patients were entered into the study; 79 of these (27 percent of the total study group) with 70 percent or more fixed obstruction in one or more coronary arteries had episodes of pain at rest associated with transient S-T segment elevation. Forty-two were randomized to medical and 37 to surgical therapy. The hospital mortality rate was 4.8 percent for the medical and 5.4 percent for the surgical group (difference not significant). The rate Of in-hospital myocardial infarction was 12 percent in the medical and 14 percent in the surgical group (difference not significant).During the 1st and 2nd years of follow-up, 25 percent in the medical and 15 percent in the surgical group complained of New York Heart Association class III or IV angina (difference not significant). During an average follow-up period of 42 months 45 percent of the medically treated patients later underwent surgery to relieve unacceptable angina. In the medical group 65 percent were working full- or part-time at the end of 1 year and 61 percent at the end of 2 years of follow-up; comparable figures for the surgically treated group were 63 and 68 percent.The results indicate that patients with unstable angina pectoris with transient S-T segment elevation during pain at rest with fixed obstruction of 70 percent or more in one or more coronary arteries do not differ significantly from patients with pain at rest associated with transient S-T segment depression or T wave inversion. The condition of such patients can be stabilized, and they can be managed with a maximal medical program including propranolol and long-acting nitrates in pharmacologic doses with good control of pain in most and no increase in rate of early mortality or myocardial infarction. Later, elective surgery can be performed with a lower risk and good clinical results if the patient's angina fails to respond to intensive medical therapy.     

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure

Summary Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhydryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinicla concer. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and anti-ischemic effects of nitrates for 10–14 hours during the day-time can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120–240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10–12 hours each day). Only the patch on an off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients within 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30–40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.     

Effect of maximal medical therapy on refractoriness of unstable angina pectoris.

A group of 125 patients with unstable angina were studied over a 5-year period to define the incidence of refractory unstable angina in the current era of 5-drug medical therapy with intravenous heparin, aspirin, nitrates, calcium antagonists and beta blockers. All patients had greater than 20 minutes of chest pain at rest with reversible electrocardiographic changes occurring in the absence of myocardial infarction. Patients were considered refractory only if chest pain continued despite treatment with maximal 5-drug therapy. At the time of transfer to the center, 65 patients continued to have ischemic chest pain at rest and were considered "medically refractory" by their referring physicians. A more aggressive medical regimen was used, and 54 patients (83%) were rendered chest pain-free. Of the 11 truly refractory patients (8.8%), coronary arteriography revealed an increased likelihood of left main or 3-vessel disease (7 of 11 vs 26 of 114; p = 0.01). In-hospital treatment strategies for the 114 patients stabilized with medical therapy included continued medical therapy (n = 37), coronary angioplasty (n = 46) and bypass grafting (n = 31). The rate of myocardial infarction or death in patients managed medically was 3%. Coronary angioplasty in medically stabilized patients was complicated by an abrupt closure rate of 26%, and a 17% rate of myocardial infarction, death or need for emergency bypass grafting. Medically stabilized patients undergoing bypass grafting had a 9% rate of myocardial infarction or death. Unstable angina truly refractory to current, maximal medical therapy is infrequent (8.8%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of nitrates in unstable angina pectoris.

Unstable angina pectoris is a clinically heterogeneous process with patient symptoms varying between reduced threshold for exertional angina and the occurrence of multiple episodes of rest pain. The major factors in the pathogenesis of unstable angina appear to be intracoronary platelet aggregation and thrombus formation secondary to fissuring or rupture of atheromatous plaques, with associated coronary vasoconstriction due to release of constrictor materials from aggregating platelets and deficiency of endothelium-related vasodilator activity. The latter factor is of particular interest in view of the similar biochemical mechanisms of action of nitroglycerin (NTG) and endothelium-derived relaxing factor (EDRF). The efficacy of NTG in limiting platelet aggregation is also of particular interest in this condition. Medical therapy in patients with unstable angina usually requires use of multiple agents. In the short term, there is a strong case for the use of intravenous heparin both to relieve pain and to reduce the risk of acute myocardial infarction. Aspirin is perhaps less effective in the short term, but very useful in long-term treatment of such patients. Despite their widespread clinical use, beta-adrenoceptor antagonists are probably only marginally beneficial, whereas dihydropyridine calcium antagonists such as nifedipine are potentially harmful as monotherapy and of questionable use in combination with other drugs. Other agents that are effective in relieving ischemic symptoms are the nondihydropyridine calcium antagonists verapamil and diltiazem and the oxygen-sparing agent perhexiline maleate. Despite a paucity of controlled trial data, nitrates are used in the vast majority of patients with unstable angina.     

Treatment of unstable angina pectoris.

Unstable angina pectoris may be manifested as new-onset angina, a change in the anginal pattern, pain at rest with associated electrocardiographic (ECG) changes, or postinfarction angina. Of these, pain at rest with ischemic ECG changes is known to be associated with the poorest prognosis. The pathogenesis of unstable angina pectoris involves a combination of a fixed atherosclerotic obstruction and a dynamic component related to coronary vasoconstriction, thrombus formation, or both. Long-acting nitrates, inhibitors of platelet aggregation, beta blockers, and calcium antagonists are among the agents that have been shown to be effective in the medical management of unstable angina. A study now in progress is evaluating the routine use of thrombolytic therapy for this indication. Although alleviation of symptoms and prevention of death and myocardial infarction are important therapeutic goals, the overall efficacy of a particular medical therapy can best be assessed by objective evaluation of its ability to control ischemia, using such techniques as exercise scintigraphy and ambulatory ECG monitoring. Cardiac catheterization and revascularization are indicated for patients with unstable angina who continue to experience symptoms or who show evidence of silent ischemia despite medical therapy. A study is under way to determine the advisability of routine revascularization of such patients. Revascularization will provide symptomatic relief in most patients with unstable angina and may prolong survival and improve left ventricular function in certain subsets.     

Unstable angina pectoris: the first half century: natural history, pathophysiology, and treatment

Unstable angina pectoris as a distinct syndrome intermediate between chronic stable angina and acute myocardial infarction was first described about a half century ago. The incidence of death or myocardial infarction rises in the first few months after destabilization of angina. Hemodynamic, scintigraphic, and arteriographic studies in the last 15 years have shown that unstable angina is chiefly due to "dynamic" coronary stenoses, transient reversible limitations in coronary blood flow caused by a complex interaction between coronary vasoconstriction, transient platelet plugging, and transient thrombosis. The trigger for the onset of dynamic coronary stenoses is probably acute changes in coronary arterial morphology in or near atherosclerotic plaques making those areas more thrombogenic. A large fraction of patients with unstable angina restabilize initially with medical management. The role of beta blockers is unclear, but they may protect against development of coronary events for patients with unstable angina similar to that reported for patients with myocardial infarction. Nitrates and calcium blockers are probably superior to beta blockers in restabilization of angina, but protection against coronary events has not yet been demonstrated clearly. Further investigation is needed to distinguish the relative benefits of a two-drug (heart rate-limiting calcium blocker plus nitrates) regimen vs. a three-drug regimen including beta blocker. There is no basis for emergency coronary bypass surgery to prevent myocardial infarction or death. Urgent surgery should be limited to patients who do not stabilize readily with medical therapy. One third or more of the patients who initially restabilize with medical therapy will require coronary revascularization in the year after unstable angina because of severe angina. An antithrombotic regimen of aspirin (or possibly heparin) reduces the incidence of progression to death or myocardial infarction. Two important future directions for research should be promising: development of better antithrombotic regimens other than aspirin alone for protection against coronary events; and improved ability to distinguish the patients who initially respond to medical therapy who are at low risk for later severe angina from those at higher risk.     

Role of coronary artery spasm in ischemic heart disease. Therapeutic implications

The term coronary artery spasm should not be used interchangeably with the specific clinical syndrome "variant angina" since it does occur in other acute and chronic ischemic heart disease syndromes. The term coronary artery spasm should not be applied to patients with ischemic heart disease unless there is clinical, angiographic, and physiologic evidence of its presence. The diagnosis of coronary artery spasm is confirmed by angiography, i.e. change in caliber of the coronary arteries plus evidence of ischemia. Probable diagnosis is in patients who have the syndrome of variant angina, i.e. rest angina associated with ST segment elevation on the electrocardiogram. One can be highly suspicious that the spasm is at work in patients who have rest angina, especially those with unstable angina. One can be suspicious of patients who have variable effort angina or walk-through angina. Coronary artery spasm is a possibility in patients with an acute myocardial infarction or acute re-infarction and is also possible that sudden death in patients with normal coronary arteries can be related to coronary artery spasm. Coronary artery spasm is the usual cause of myocardial ischemia in patients with rest angina without effort angina. This has also commonly been documented in patients with rest and effort angina. There are isolated reports suggesting that patients with effort angina pectoris also develop coronary artery spasm. Coronary artery spasm has been documented to occur in association with acute myocardial infarction. Whether coronary artery spasm is the cause or the result of myocardial infarction has not been determined at this time. However, the recent combined use of intracoronary nitroglycerin and intracoronary streptokinase in patients with acute myocardial infarction has shown reversal of totally obstructed arteries and suggests the relationship between coronary artery disease, coronary artery spasm, and in situ coronary thrombosis. The incidence of sudden death in patients with documented coronary artery spasm is unknown. But, since complete heart block and/or ventricular tachycardia occur during episodes of coronary artery spasm, it is not unreasonable to assume that some patients have died as a result of these rhythm disturbances. The prognosis of patients with coronary artery spasm seems to depend on the presence or absence of severe coronary atherosclerosis, i.e. those with severe disease have a worse prognosis. Current therapy of patients with coronary artery spasm involves the use of nitrates and calcium antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)     

Treatment of stable angina.

Severe atherosclerotic narrowing of one or more coronary arteries is responsible for myocardial ischemia and angina pectoris in most patients with stable angina pectoris. The coronary arteries of patients with stable angina also contain many nonobstructive plaques, which are prone to fissures or rupture resulting in presentation of acute coronary syndromes (unstable angina, myocardial infarction, sudden ischemic death). In addition to symptomatic relief of symptoms and an increase in angina-free walking time with antianginal drugs or revascularization procedures, the recent emphasis of treatment has been to reduce adverse clinical outcomes (coronary death and myocardial infarction). The role of smoking cessation, aspirin, treatment of elevated lipids, and treatment of high blood pressure in all patients and of beta-blockers and angiotensin-converting enzyme inhibitors in patients with diminished systolic left ventricular systolic function in reducing adverse outcomes has been well established. What is unknown, however, is whether any anti-anginal drugs (beta-blockers, long-acting nitrates, calcium channel blockers) effect adverse outcomes in patients with stable angina pectoris. Recent trials evaluated the usefulness of suppression of ambulatory ischemia in patients with stable angina pectoris, but it remains to be established whether suppression of ambulatory myocardial ischemia with antianginal agents or revascularization therapy is superior to pharmacologic therapy targeting symptom relief. Patients who have refractory angina despite optimal medical treatment and are not candidates for revascularization procedures may be candidates for newer techniques of transmyocardial revascularization, enhanced external counterpulsation, spinal cord stimulation, or sympathectomy. The usefulness of these techniques, however, needs to be confirmed in large randomized clinical trials.     

Calcium antagonists for Prinzmetal's variant angina, unstable angina and silent myocardial ischemia: therapeutic tool and probe for identification of pathophysiologic mechanisms

The calcium antagonists provide a unique tool to reduce myocardial oxygen demand and prevent increases in coronary vasomotor tone. For patients with Prinzmetal's variant angina, diltiazem, nifedipine and verapamil are extremely effective in preventing episodes of coronary vasospasm and symptoms of ischemia. Unstable angina pectoris is a more complex pathophysiologic syndrome with episodes of ischemia due to increases in coronary vasomotor tone, intermittent platelet aggregation or alterations in the underlying atherosclerotic plaque. Each of the calcium antagonists is effective as monotherapy in decreasing the frequency of angina at rest. Nifedipine is the only calcium antagonist that has been studied in a combination regimen with beta blockers and nitrates for patients with unstable angina, and control of angina is better with the combination regimen than with either form of therapy alone. Although symptoms of myocardial ischemia in unstable angina are reduced by calcium antagonists, these agents do not seem to decrease the incidence of adverse outcomes. Antiplatelet therapy appears to improve morbidity and mortality in patients with unstable angina, suggesting that thrombus formation may play a central role in that disorder. Episodes of silent or asymptomatic myocardial ischemia, identified by ST-segment monitoring, occur in a variety of disorders of coronary disease. Among patients with Prinzmetal's variant angina and unstable angina, episodes of silent ischemia appear to be as frequent as episodes of angina and the calcium antagonists are effective in decreasing episodes of ischemia regardless of the presence or absence of symptoms. Persisting episodes of silent ischemia among patients with unstable angina despite maximal medical therapy identify patients at high risk for an early unfavorable outcome. Among patients with stable exertional angina, episodes of silent ischemia may be up to 5 times as frequent as episodes of angina, and may be due to increases in coronary vasomotor tone, transient platelet aggregation or increases in myocardial oxygen demand. Preliminary experience suggests that calcium antagonists and beta blockers are effective in decreasing episodes of silent ischemia in patients with stable exertional angina and that a combination regimen may be more effective than either form of therapy alone.     

Nifedipine in the treatment of unstable angina,coronary spasm and myocardial ischemia

The effects of nifedipine, a potent calcium antagonist, were studied in patients with unstable angina, coronary spasm and myocardial ischemia. Data from two separate groups of patients studied in the cardiac catheterization laboratory indicate that intracoronary injection of nifedipine promptly reversed coronary spasm—whether provoked or spontaneous—in five of six patients. In other patients, direct intracoronary injection of the drug was compared with intravenous administration. After intracoronary injection, local mechanical cardiac action virtually ceased, and the ventricular wall became thinner during systole. Thus, a specific inhibitory action on contractile energy expenditure could be demonstrated in the presence of increased coronary flow. This “oxygen-sparing” effect was tested in a group of 31 patients with symptomatic unstable angina whose pain at rest, with ST-T changes, had not responded to 8 hours of treatment with maximal beta adrenergic blockade, nitrates and bed rest. The addition of 6 × 10 mg of nifedipine rendered 27 of these patients asymptomatic within 1.5 hours. In the four patients who did not respond, coronary arteriography demonstrated severely stenotic lesions. Two of the four patients subsequently responded to intraaortlc balloon pumping and bypass surgery; one patient had a myocardial infarction and one who had a 90 percent reduction in the diameter of the left main coronary artery, died.It is concluded that nifedipine should be added to beta adrenergic blockade therapy if the latter does not appear to be immediately effective. This combination has not been shown to cause any hemodynamlc deterioration, and only a minority of the patients treated sustained a myocardial infarction during the first 3 months of follow-up. The use of nifedipine in unstable angina deserves further clinical evaluation.     

On the Significance of Magnesium in Extreme Physical Stress

Drug therapy in stable angina has two aims: the prevention of major cardiac events (such as unstable angina, myocardial infarction, or death) and the control of chest pain and transient myocardial ischemia. Given the low incidence of major cardiac events in patients with stable angina, primary preventive studies are scarce because they require a large sample size and long-term follow-up. Thus far, only aspirin and some lipid-lowering agents have been shown to be effective for this purpose. Antiischemic drugs reduce the imbalance between myocardial oxygen demand and supply, either by reducing oxygen consumption or by increasing coronary blood flow. The ideal approach would be to target drug therapy against the ischemia-inducing factor in each patient. The characteristics of anginal symptoms do not seem to help in selecting medical therapy, whereas a standard exercise test and a provocative test of coronary vasoconstriction may provide useful information in order to select patients who will preferentially respond to either a beta-blocker or a calcium antagonist. The combination of two or more anti-ischemic drugs does not seem to be any more effective than an adequately titrated monotherapy in reducing the occurrence of myocardial ischemia in individual patients. Combination therapy in stable coronary artery disease should include an individually selected and optimally titrated anti-ischemic agent and aspirin, with the addition of a lipid-lowering agent in patients with even mild hypercholesterolemia.     

Increased levels of monocyte-related cytokines in patients with unstable angina

Inflammatory cytokines play important roles in coronary artery disease. We investigated the clinical significance of monocyte-related cytokine expression in patients with angina pectoris. We studied 26 patients with stable effort angina and 20 patients with unstable angina in whom stenotic lesions of the coronary arteries were confirmed by selective coronary angiography. Plasma levels of interleukin-6 (IL-6), macrophage colony stimulating factor (MCSF), and monocyte chemoattractant protein-1 (MCP-1) were measured. Plasma levels of IL-6, MCSF, and MCP-1 in patients with unstable angina were significantly higher than those in patients with stable angina or control subjects. Patients with unstable angina were further divided into sub-groups according to their clinical classification; Levels of IL-6, MCSF, and MCP-1 in patients, who had anginal attacks at rest within the 48 h prior to admission (Braunwald class IIIB) were significantly higher than those in patients, who did not have attacks at rest (class IB). Five unstable patients, who were refractory to medical therapy and were referred for emergency coronary revascularization showed marked elevation of plasma MCSF and MCP-1 levels. In conclusion, plasma levels of monocyte-related cytokines were elevated in unstable angina. These increases were marked in patients with unstable angina with recent ischemic attack at rest, suggesting that activation of monocytes is involved in vulnerability of underlying atheromatous plaque.     

Addition of nifedipine to maximal beta-blocker-nitrate therapy: effects on exercise capacity and global left ventricular performance at rest and during exercise

Nifedipine is a potent coronary vasodilator in the resting state and an effective afterload-reducing agent. This study was undertaken because of the concern that the addition of nifedipine to beta-blocker therapy could produce serious untoward hemodynamic consequences. Although this combination is usually well tolerated, occasional reports suggest that the combination of nifedipine and beta-blocking agents may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. Further, there is a need to know if the addition of nifedipine to therapy with maximally tolerated doses of long-acting nitrates and beta blockers would provide further symptomatic relief without excessive adverse effects. Finally, the effect of adjunctive nifedipine on global left ventricular performance at rest and during exercise was examined. Sixteen patients, all of whom had 3 or more episodes per week of angina pectoris despite therapy with long-acting nitrates and beta blockers, were selected. Radionuclide ventriculography was performed at rest and during exercise; global ejection fractions (EFs) were determined by manually tracing the left ventricular end-diastolic perimeter with an electronic cursor. In the first phase, beta blockers and nitrates were used; in the second phase nifedipine, 10 mg every 6 hours, was added and titrated to reduce systolic blood pressure at rest by at least 10 mm Hg or until intolerable adverse effects occurred. When nifedipine was added to therapy, the difference between global EF at rest and during exercise was reduced from - 0.15 to + 0.02 (p less than 0.00001); exercise duration was increased from 431 seconds to 532 (p less than 0.001), with only 8 patients limited by angina, compared with 16 during the initial therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiographic observations and clinical relevance of coronary thrombus in unstable angina pectoris

To assess the mechanisms of unstable angina, the coronary angiographic studies in 69 patients with severe unstable angina (prolonged pain or pain at rest) and in 20 patients with stable angina were blindly reviewed to assess the coronary morphologic changes in these syndromes. Coronary angiography was performed an average of 1.7 days from admission and an average of 24 hours from last symptoms of chest pain in patients with unstable angina. Angiographic studies were analyzed for evidence of coronary thrombus (intraluminal filling defects) at significant stenoses in patent vessels or thrombus at sites of total occlusion) and for coronary lesion morphology suggesting a complex or acute lesion (irregular or ill-defined margins, inhomogeneity, haziness or ulceration). Angiographic evidence of coronary thrombus was present in 40 of 69 patients (58%) with unstable angina: 31 (45%) had intraluminal filling defects and 9 (13%) had thrombotic total occlusion with well-developed collaterals present. Only 1 of 20 patients (5%) with stable angina had evidence of thrombus (p less than 0.001). Complex lesions were present in 18 other unstable patients (26%) and in 2 other patients (10%) with stable angina who did not have angiographic evidence of thrombus. Overall, 58 of 69 patients (84%) with unstable angina had morphologic findings suggesting an acute process (thrombus or complex lesion) compared with 3 of 20 patients (15%) with stable angina, p less than 0.0001. Thus, unstable angina is associated with a high prevalence of angiographic coronary thrombus and complex lesions suggesting an acute process, in contrast to stable angina.(ABSTRACT TRUNCATED AT 250 WORDS)     

Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina

Silent myocardial ischemia as detected on Holter electrocardiographic (ECG) monitoring is present in greater than 50% of patients with unstable angina despite intensive medical therapy. The presence and the extent of silent ischemia have been correlated with an increased risk of early (1 month) unfavorable outcome including myocardial infarction and need for coronary revascularization for persistent symptoms. Seventy patients with unstable angina who had undergone continuous ECG monitoring for silent ischemia were followed up for 2 years; 37 patients (Group I) had Holter ECG evidence of silent ischemia at bed rest in the coronary care unit during medical treatment with nitrates, beta-receptor blockers and calcium channel antagonists; the other 33 patients (Group II) had no ischemic ST segment changes (symptomatic or silent) on Holter monitoring. Over a 2 year follow-up period, myocardial infarction occurred in 10 patients in Group I (in 2 it was fatal) compared with one nonfatal infarction in Group II (p less than 0.01 by Kaplan-Meier analysis); revascularization with either coronary bypass surgery or angioplasty for symptomatic ischemia was performed in 11 Group I and 5 Group II patients (p less than 0.05). Multivariate Cox's hazard analysis demonstrated that the presence of silent ischemia was the best predictor of 2 year outcome. Therefore, persistent silent myocardial ischemia despite medical therapy in patients with unstable angina carries adverse prognostic implications that persist over a 2 year period.     

Selection of optimal therapy for chronic stable angina

Patients with chronic stable angina (CSA) seek a medical opinion for relief of their symptoms and because of fear of having a heart attack. The underlying lesion responsible for CSA is often a severe narrowing of one or more coronary arteries. In addition, the coronary arteries of patients with CSA contain many more nonobstructive lesions, which progress at variable rates, and are prone to rupture and may manifest as acute coronary syndromes (myocardial infarction , unstable angina , or sudden ischemic death). Most patients with CSA can be managed with medical treatment. For angina relief, optimum doses of one of the antianginal drugs (beta blockers , long-acting organic nitrates, or calcium channel blockers ) should be used. If the patient remains symptomatic, combination treatment of BBs plus nitrates or BBs plus dihydropyridine CCBs, or nondihydropyridine CCBs plus nitrates should be tried. Triple therapy has not been shown to be more effective than treatment with two agents. To reduce the incidence of MI, UA, and sudden ischemic death, treatment strategies should include smoking cessation, daily aspirin, daily exercise, and pharmacologic therapy for dyslipidemias, and for elevated blood pressure. Patients who remain symptomatic despite medical therapy and those not willing to take or unable to tolerate antianginal drugs should be considered for percutaneous or surgical coronary revascularization. Patients who do not respond to medical therapy and are not candidates for a revascularization procedure may be considered for additional treatment with trimetazidine or nicorandil (these drugs are not available in the United States or approved by the US Food and Drug Administration, but are available in some other countries). Ranolazine also looks promising but is not yet available for clinical use. As a last resort, enhanced external counterpulsation, spinal cord stimulation, sympathectomy, or direct transmyocardial revascularization should be considered for symptom relief.     

Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitrates in silent ischemia

Summary In recent years it has become clear that episodes of transient myocardial ischemia commonly occur in patients with coronary artery disease in the absence of chest pain or angina equivalent. These episodes of silent myocardial ischemia are particularly well documented during continuous ambulatory electrocardiographic monitoring in daily life. Evidence suggests that these episodes represent true ischemia, and appear to be a marker of unfavorable outcome. While the pathophysiology is not completely understood, it appears as though the mechanisms of angina and silent ischemia are the same. Both forms of ischemia respond to conventional antianginal medication. While long-acting nitrates are effective in reducing or preventing myocardial ischemia, because of their propensity to cause tolerance they should be used intermittently and in association with either beta-blockers or calcium antagonists. Nitrates are safe and comparatively inexpensive, and will continue to play an important role in the treatment and prevention of angina. However, in the light of current knowledge, there is no specific indication for the treatment of silent ischemia by nitrates.     

Akute Koronarsyndrome – ein Update Teil II: Koronare Revaskularisation und Risikostratifizierung

CORONARY REVASCULARIZATION: PTCA in patients with refractory unstable angina is associated with a substantial risk of the following complications: death, myocardial infarction, need for emergency surgery, and restenosis. The introduction of intracoronary stents, however, has improved both short-term and long-term outcomes. The newer adjunctive pharmacologic therapies enhance even further the benefits associated with the use of stents. The decision regarding the specific revascularization procedure to be used (e.g., CABG, PTCA, stent placement, or atherectomy) is based on the coronary anatomy, the left ventricular function, the experience of the medical and surgical personnel, the presence or absence of coexisting illnesses, and the preferences of both the patient and the physician. RISK STRATIFICATION: Among patients with unstable angina or non-Q-wave myocardial infarction, there is an increased risk of death within 6 weeks in those with elevated troponin I levels and the risk of death continues to increase as the troponin level increases. Reversible ST segment depression is associated with an increase by a factor of 3-6 in the likelihood of death, myocardial infarction, ischemia at rest, or provocable ischemia during a test to stratify risk. Exercise or pharmacologic stress testing provides important information about a patient's risk. Although the conditions of the majority of patients with unstable angina will stabilize with effective antiischemic medications, approximately 50-60% of such patients will require coronary angiography and revascularization because of the "failure" of medical therapy. High-risk patients are those who have had angina at rest, prolonged angina, or persistent angina with dynamic ST segment changes or hemodynamic instability, and they urgently require simultaneous invasive evaluation and treatment. Medical therapy should be adjusted rapidly to relieve manifestations of ischemia and should include antiplatelet therapy (aspirin, or ticlopidine or clopidogrel if aspirin is contraindicated), antithrombotic therapy (unfractionated heparin or low-molecular-weight heparin), beta-blockers, nitrates, and possibly calcium-channel blockers. Early administration of glycoprotein IIb/IIIa inhibitors may be particularly important, especially in high-risk patients with positive troponin tests or those in whom implantation of coronary stents is anticipated.