Re-thinking angina.

William Heberden in 1772 published "some account of the disorder of the breast" which contains the essential elements of angina pectoris as we understand it today. The number of existing cases in the U.S. population today is 6.4 million. Myocardial ischemia manifested by angina pectoris can be either acute or chronic. Patients with chronic stable angina will be the focus of this supplement. The majority of patients are symptomatic but approximately 25% can be asymptomatic. The clinical manifestations of myocardial ischemia generally are chest discomfort, arrhythmias, and LV dysfunction. Myocardial ischemia is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. High grade coronary stenosis are the usual cause of decreased oxygen supply. The classic hemodynamic factors increasing myocardial oxygen demand include hypertension and increased heart rate due to tachyarrhythmias of any etiology. Exertion is the usual precipitating cause of chronic myocardial ischemia. New information has come forward indicating that myocardial ischemia is associated with disruption of cellular sodium and calcium homeostasis. Ischemia results in a rise of intracellular sodium concentration and thus sodium overload which then activates the sodium calcium exchanger and leads to increased intracellular calcium. When this occurs there is electrical instability and mechanical dysfunction which increases oxygen demand and decreases oxygen supply. The compound Ranolazine is thought to selectively inhibit the late sodium current and attenuates the abnormalities of ventricular repolarization and contractility associated with myocardial ischemia. This compound is the first new class of anti-anginal medication approved in 25 years which may provide physicians with additional therapy for chronic stable angina along with the other anti-angina agents, beta blockers, calcium antagonists and nitrates.

Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization.

BACKGROUND: Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization. METHODS AND RESULTS: The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia-guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (P<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison. CONCLUSIONS: A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.

Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study).

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001).

Isosorbide dinitrate and nifedipine in variant angina pectoris.

The efficacy of isosorbide dinitrate (ISDN) in variant angina is enhanced by the addition of a calcium antagonist. A prospective double-blind, crossover trial of ISDN, 40 to 120 mg/day, and nifedipine, 40 to 120 mg/day, in 19 patients with variant angina and various degrees of coronary atherosclerosis showed that although both agents were equally effective in controlling angina of vasospastic origin, some patients responded better to one or the other drug. Such response could not be predicted by demographic factors, ECG changes, or degree of coronary atherosclerosis. Since quantitative angiography done in a similar group of patients showed that intracoronary nitroglycerin, 200 micrograms, was a more potent vasodilator than sublingual nifedipine, 10 mg (p less than 0.01), the calcium antagonists may have a different mechanism of preventing variant angina attacks and may act in an additive or synergistic fashion when administered in combination with long-acting nitrates. Such a combination will increase coronary blood flow, reduce ventricular volume and end-diastolic pressure, and reduce systemic arterial resistance. Coronary vasospasm may be directly prevented by a general inhibition of smooth muscle contraction by the calcium antagonist. Clinical studies suggest that combination therapy significantly improves the long-term prognosis of patients with variant angina and reduces the need for bypass surgery. Thus combining ISDN with a calcium antagonist is a rational and effective treatment for variant angina.

Calcium antagonists.

At present nitrates remain the initial treatment for relief or prevention of angina in patients with coronary artery disease. In cases where nitrates and beta blockers have been used and are ineffective for managing effort angina, calcium antagonists may be substituted or added to the beta-blocking treatment. When the predominant symptom is rest angina, and there is evidence suggesting coronary artery spasm, nitrates and a calcium antagonist can be effective therapy. In patients with heart block, bradyarrhythmias, heart failure, or hypertension nifedipine may be the drug of choice. In contrast verapamil merits choice when supraventricular tachycardia is present. Diltiazem appears intermediate between nifedipine and verapamil and may be particularly useful when hypotension or other side effects must be avoided.

Large vessel coronary vasospasm: diagnosis, natural history and treatment.

The diagnosis of coronary artery spasm is confirmed by angiography, for example, change in caliber of the coronary arteries plus evidence of ischemia. The prevalence and contribution of coronary artery spasm in the individual patient with symptoms of ischemic heart disease is not known and depends on how the condition is defined. The prognosis of patients with coronary artery spasm appears to depend on the presence or absence of severe coronary atherosclerosis, that is, those with severe disease have a worse prognosis. Nitrates should be used to initiate therapy in all patients with this problem. Intravenous nitrates have proven useful in patients whose symptoms are difficult to control and who require hospitalization. beta blockers used alone may be detrimental in patients with coronary artery spasm, but studies supporting the detrimental effects are few. The combination of nitrates, beta blockers and nifedipine has proved effective therapy for many patients with recurrent angina at rest, possibly related to coronary artery spasm. Several open-label and double-blind placebo control trials have shown that all of the calcium antagonists are effective short-term agents for patients with proven coronary artery spasm. When nifedipine was compared with isosorbide dinitrate in a randomized crossover, double-blind trial in patients with coronary artery spasm, both drugs were shown to be efficacious and neither was superior. The traditional alpha-blocking agents have not been shown to be an effective therapy, but a recent study of prazosin, a selective alpha blocker, revealed excellent results in patients whose conditions were resistant to therapy with traditional calcium blockers, beta blockers and, in 1 case, phenoxybenzamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil.

The clinical outcome after the initial year of therapy with either diltiazem (D), nifedipine (N), or verapamil (V) was examined in 45 patients with rest angina. Age, frequency of angina, duration of symptoms, and ejection fraction were similar in all three treatment groups. Coronary artery disease was present in 60% of patients (5 of 13 given D, 8 of 16 given N, and 14 of 16 given V). Coronary spasm was suspected (ST elevation with angina) or documented (angiographically) in 35 (78%) patients. Twenty-nine (64%) patients had greater than 50% decrease in angina without a coronary event (9 taking D, 11 taking N, and 9 taking V). Coronary events (sudden death, infarction, and hospitalization for unacceptable angina control or bypass surgery) occurred in 13 (29%) patients (two taking D, four taking N, and seven taking V). To achieve these responses, 20 (44%) patients required additional antianginal drugs (long-acting nitrates, beta blockers, or other calcium blockers). Four of these 20 patients were taking D, nine were taking N, and seven were taking V. Seventeen (38%) patients experienced a side effect (none taking D, 6 taking N, and 11 taking V). Although rest angina can be controlled in the majority of patients during the initial year of treatment with calcium blockers, additional therapy is often required. Furthermore, the clinical course of patients presenting with rest angina remains unpredictable, even during calcium blocker treatment. Morbid events continue to occur, related in part to the extent of coronary artery disease.

Long-term responses to nifedipine in patients with coronary spasm who have an initial favorable response.

Twenty-six patients with angina and coronary spasm participated in a randomized crossover trial comparing nifedipine with isosorbide dinitrate. Eighteen patients had a short-term beneficial response to nifedipine, and 14 of these were followed up for an average period of 9.4 months. During follow-up study, nifedipine was the primary therapy in these 14 patients, but other drugs were added when clinically necessary to control angina. There was an overall 86% beneficial response rate (greater than 50% decrease in angina frequency). However, 2 patients had a large increase (greater than 10 times) and 4 patients had a slight increase (transient) in angina frequency over the long term compared with the short-term response. The other 8 patients had a similar angina frequency compared with the short-term response. Of the 12 patients with a good response (transient slight increase or no change), 8 (67%) required additional drug therapy to maintain angina control. Nifedipine was discontinued in 2, and the dose was decreased in 3 of the 14 patients because of adverse effects. Three patients had a marked increase in angina at 9, 14, and 3 months, requiring hospitalization; 1 patient had coronary bypass for symptom control. Thus, patients with coronary spasm selected because of a favorable short-term response to nifedipine were effectively treated over the long term with nifedipine; however, additional therapy was often needed to control symptoms. Adverse effects were common, but simple reduction of nifedipine dose usually diminished the unwanted effects of the drug.

Verapamil therapy for unstable angina pectoris: review of double-blind placebo-controlled randomized clinical trials.

The effectiveness of verapamil in the management of patients with unstable angina pectoris associated with obstructive coronary artery disease was evaluated in 2 double-blind placebo-controlled randomized clinical trials. In the 1st study, verapamil was compared with placebo using alternating 48 hour treatment periods in a multiple cross-over protocol. Verapamil was superior to placebo in abolishing symptomatic and asymptomatic ischemic episodes; there were 127 ischemic events during treatment with placebo but only 27 episodes during therapy with verapamil (p less than 0.006). In the 2nd study, verapamil and placebo were compared using a double-blind randomized parallel design in which the choice of drug was altered and the doses administered were increased according to the individual responses. Verapamil reduced anginal attacks in 12 of 13 patients, but placebo was effective in only 1 of 6 (p less than 0.025); verapamil reduced daily anginal attacks from 3.2 to 0.6/day (p less than 0.01). Thus, verapamil is highly effective in the short-term management of patients with unstable angina secondary to coronary artery disease.

Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm.

The effects of nifedinpine and isosorbide dinitrate on the frequency of angina and consumption of nitroglycerin were studied in 19 patients with coronary arterial spasm. After a lead-in phase, the patients were randomized to treatment with either nifedipine or isosorbide dinitrate. After dose titration (40 to 120 mg/day) and evaluation, they were given the alternate therapy. During the initial segment of the double-blind phase, one patient died suddenly (nifedipine phase), one dropped out of the study (nifedipine phase) and another was unable to tolerate therapy (isosorbide dinitrate phase). In the other 16 patients, the mean frequency of angina was less during therapy with both nifedipine (0.69 episode/day, p less than 0.05) and isosorbide dinitrate (0.77 episode/day, p less than 0.05) phases than during the lead-in phase (1.71 episodes/day). The mean frequency of angina was similar in the nifedipine and isosorbide dinitrate phases. A 50 percent or greater decrease in frequency of angina compared with lead-in phase values occurred in 13 of 18 patients during treatment with nifedipine and in 10 of 16 during treatment with isosorbide dinitrate. Of the 16 patients who completed both double-blind phases, 7 showed greater improvement (that is, a 50 percent or greater decrease in frequency of angina) with nifedipine than with isosorbide dinitrate); 6 others showed greater improvement with isosorbide dinitrate, and the other 3 had a less than 50 percent difference in frequency of angina with the two drugs. These findings in a limited number of patients suggest that both nifedipine and isosorbide dinitrate are effective in certain patients with coronary spasm but that neither drug is clearly superior.