Pharmacotherapy of Vasospastic Angina.

Vasospastic angina is a diagnosis of exclusion that manifests with signs and symptoms, which overlap with obstructive coronary artery disease, most often ST-segment elevation myocardial infarction. The pharmacotherapy that is available to treat vasospastic angina can help ameliorate angina symptoms. However, the etiology of vasospastic angina is ill-defined, making targeted pharmacotherapy difficult. Most patients receive pharmacotherapy that includes calcium channel blockers and/or long-acting nitrates. This article reviews the efficacy and safety of the pharmacotherapy used to treat vasospastic angina. High-dose calcium channel blockers possess the most evidence, with respect to decreasing angina incidence, frequency, and duration. However, not all patients respond to calcium channel blockers. Nitrates and/or alpha1-adrenergic receptor antagonists can be used in patients who respond poorly to calcium channel blockers. Albeit, evidence for use of nitrates and alpha1-adrenergic receptor antagonists in vasospastic angina is not as robust as calcium channel blockers and can exacerbate adverse effects when added to calcium channel blocker therapy. Despite having a clear benefit in patients with obstructive coronary artery disease, the benefit of beta-adrenergic receptor antagonists, statins, and aspirin remains unclear. More data are needed to elucidate whether or not these agents are beneficial or harmful to patients being treated for vasospastic angina. Overall, the use of pharmacotherapy for the treatment of vasospastic angina should be guided by patient-specific factors, such as tolerability, adverse effects, drug-drug, and drug-disease interactions.

ST-T wave changes in a patient complicated with vasospastic angina and Brugada syndrome: differential responses to acetylcholine in right and left coronary artery.

A 49-year-old man with chest pain and syncope presented saddleback or occasionally coved type ST elevation in V1-V3. Coronary spasm in the left anterior descending artery was induced by acetylcholine injection and ST elevation changed from saddleback to coved type in V2-V3 together with ST depression in V4-V5, whereas acetylcholine injection into the right coronary artery did not provoke spasm, but induced augmented and coved type ST elevation in V2 without ST-T changes in V4-V5. These electrocardiographic changes in response to acetylcholine administration into each coronary artery are compatible with pathogenesis of vasospastic angina and Brugada syndrome, respectively.

Multivessel variant angina unresponsive to urapidil.

We present a case of variant angina complicated by recurrent sudden cardiac death. During coronary angiography a diffuse 3-vessel vasoconstriction was observed progressing to a more severe vasoconstriction in the mid LAD. Intracoronary administration of urapidil did not reverse the vasoconstriction of the LAD; instead an occlusive vasospasm occurred accompanied by marked ischaemia.

Circadian variation of basal total vascular tone and chronotherapy in patients with vasospastic angina pectoris.

Vasospastic angina pectoris (VSA) is an anginal attack which occurs characteristically between night and early morning. The aim of this study was to clarify the cause of VSA. The subjects consisted of 16 patients with VSA, 18 patients with effort angina (EAP) and 15 healthy individuals, who were used as the control group. Subjects were attached to an ambulatory blood pressure monitor and a non-invasive continuous cardiac output monitor concurrently, over a 24-hour period. Mean blood pressure (MBP), and cardiac index (CI) were measured. Then basal total vascular tone (TVT) was calculated as follows: basal TVT = (MBP/CI) x 1,332 dyne/sec/cm5. The decrement of CO was greater during sleeping hours as compared with the decrement of the MBP in the VSA group. Nocturnal basal TVT was significantly greater in the VSA group than in the EAP group or the control group. The increased nocturnal basal TVT was significantly suppressed by long acting calcium antagonists to the level of the EAP and the control groups. The treatment also decreased the frequency of ischemic attacks.

Re-evaluation of the mechanism and treatment of angina decubitus.

30 patients with angina decubitus (AD) were studied during hospitalization. These patients were found to have severe coronary artery obstructive lesions and an increase of myocardial oxygen consumption (MOC) before the onset to AD, indicating that AD belongs to the category of effort angina. 18 patients were investigated by continuous hemodynamic monitoring. Three patients had significant increase in pulmonary artery diastolic pressure (PADP) before the onset. In the other 15 patients, PADP increased slightly in 12 and remained unchanged in 3 cases before the onset. Left ventriculography showed ejection fraction (EF) > 45% in 25 of the 27 patients. These results indicate that left ventricular (LV) systolic dysfunction is not a major factor in the pathogenesis of AD. The patients with LVEDP > 12 mmHg constituted 60% of 25 patients with EF > 45%, suggesting that these patients had obvious LV diastolic dysfunction, which may be the major factor in the pathogenesis of AD. According to the results of our treatment, beta blockers may be used as the major form of treatment in the patients with AD.

24 h anti-anginal and anti-ischaemic effects with once daily felodipine. A double-blind comparison with nifedipine, twice daily, and placebo in patients with stable exercise induced angina pectoris.

The effects, as monotherapy, of felodipine ER 10 mg o.m. and nifedipine SR 20 mg b.d. were compared in a double-blind, randomized, placebo-controlled, three-way cross-over trial in 43 patients with stable exercise-induced angina pectoris. The exercise tests were performed at the end of dosage interval (i.e. 24 h after felodipine ER, 12 h after nifedipine SR) and at the expected peak time of 3 h post dose. Felodipine and nifedipine improved exercise duration by 66 and 50 s, respectively, (P < 0.001) compared with placebo at the end of the dosing interval. Time to the end of exercise showed no statistically significant difference between the two calcium antagonists. The onset of anginal pain and time to 1 mm ST depression were significantly more delayed by felodipine ER than nifedipine SR (22 s and 19 s, respectively, P < 0.05). Both felodipine and nifedipine decreased the pain score and rate pressure product at the highest comparable work load. Overall tolerability was good for both drugs.

Felodipine (once daily) versus nifedipine (four times daily) for Prinzmetal's angina pectoris.

In 30 consecutive patients with Prinzmetal's angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the well-established therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Holter monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive 6-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occurred in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 +/- 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinzmetal's angina pectoris, 24-hour antiischemic protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life.

Clinical effects of nitrendipine on variant angina pectoris.

The clinical effects of nitrendipine, a new calcium antagonist, were investigated in a single-blind test on 21 patients with variant angina pectoris. The efficacy of the drug was evaluated on the basis of frequency of anginal attacks and Holter electrocardiographic findings during different treatment periods at doses of 10 mg once a day (period I) and 20 mg once a day (period II). The number of anginal attacks decreased significantly from a pretreatment level of 2.1 +/- 0.3 per day to 0.7 +/- 0.2 per day in treatment period I and 0.3 +/- 0.1 per day in treatment period II (p less than 0.01, p less than 0.001, respectively). The consumption of sublingual nitroglycerin tablets decreased significantly in both treatment periods in comparison with the observation period before treatment (p less than 0.01, p less than 0.001, respectively). In 20 patients with continuous ECG monitoring, the frequency of ST-segment elevation was 4.5 +/- 1.0 per day during the pretreatment period; it decreased significantly to 0.9 +/- 0.6 per day in treatment period I and 0.5 +/- 0.3 per day in treatment period II (p less than 0.01, p less than 0.001, respectively). The duration and the maximum magnitude of ST-segment elevation also improved significantly in both treatment periods. These results demonstrate the efficacy of nitrendipine in the treatment of variant angina at a single daily dose of 10 mg.

[Comparison of isosorbide dinitrate and nifedipine in the treatment of variant angina pectoris. Randomized study]. / Srovnání isosorbid dinitrátu a nifedipinu v lécbe variantní anginy pectoris. Randomizovaná studie.

The effects of isosorbide dinitrate single dose 120 mg daily and nifedipine 20 mg twice daily were studied in 17 patients with variant angina pectoris due to coronary artery spasm. After a placebo phase the patients were randomized to treatment with either isosorbide dinitrate or nifedipine. After six weeks the patients were crossovered for another six weeks period of treatment. There was significant decrease of number of angina attacks during both treatment regimens. Using 24 hours Holter monitoring we also proved significant decrease of number of ST segment elevation or depression, either symptomatic or asymptomatic. There was increase of performed work during exercise tests after both treatment periods. The efficacy of Isoket 120 mg and Adalat Retard 2 x 20 mg daily in the treatment of patients with active variant angina pectoris was comparable in our study. 3 patients suffered untolerable headache during isosorbide dinitrate phase and had to terminate treatment after first day only.

Different coronary vasomotor effects of nifedipine and therapeutic correlates in angina with spontaneous and effort components versus Prinzmetal angina.

Flow impedance, probably of vasomotor origin, superimposed on severe coronary stenosis has been considered a trigger for the spontaneous component of angina occurring both on effort and at rest. To investigate more thoroughly this pathophysiologic aspect we evaluated (by means of quantitative coronary angiography) the acute vasomotor reaction to nifedipine (10 mg sublingually) of significant (greater than 50%) stenotic lesions in 22 patients with double-component angina. We also correlated this reaction with the clinical response (daily number of ischemic episodes evaluated by means of 48-hour Holter ambulatory monitoring) to treatment with nifedipine (20 mg four times a day); calcium channel blockade, in fact, is considered a specific remedy in cases of altered coronary vasomotility. Patients with Prinzmetal angina, who were known to have homogeneous coronary vasodilating reactions and favorable clinical responses to nifedipine, were studied by means of the same methods and served as the control group (14 patients). In double-component angina the residual lumen diameter of significant lesions was unchanged in two patients, enhanced in 10, and reduced in 10 after sublingual nifedipine; lumen variations from baseline values ranged from +1.29 to -1.56 mm. Acute changes in stenosis correlated closely with results obtained with oral treatment. In the group with Prinzmetal angina, coronary stenoses invariably responded with dilatation (the residual coronary lumen increased by an average of 69% of baseline); 100% of the patients in this group responded favorably to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Prompt relief of vasospastic angina by calcium antagonists.

A 57-year-old man had recurrent episodes of angina pectoris at rest. An electrocardiogram (ECG) during attack revealed transient ST elevations in leads V1 to V5. His symptoms were not relieved by sublingual nitroglycerin (TNG), but subsided promptly following sublingual or intravenous calcium antagonists. However, there was no difference between the degree of ST elevation on ECG recorded during the treatment of angina with either TNG or with calcium antagonist. Recurrent angina and painless ST elevation on Holter ECG recordings were prevented by a large dose of diltiazem. Coronary arteriography revealed only mild stenosis at the proximal portion of the left anterior descending coronary artery. It is suggested that coronary artery spasm was the cause of angina in this case and that sublingual or intravenous calcium antagonist was more effective in the treatment of acute attack of vasospastic angina than sublingual TNG.

Vasospastic angina: control of disease activity and efficacy of drug treatment using the prolonged hyperventilation test.

Sixteen consecutive patients with vasospastic angina underwent a control provocation test in the coronary care unit or the cardiac catheterization laboratory in order to evaluate the disease activity and the efficacy of long-term calcium antagonist treatment. In patients without angina at rest, the prolonged hyperventilation test was negative in 10/10 patients on calcium antagonist treatment (group A + B) and in 4/5 patients without medication (group C). The test was positive in 1/1 patient with angina at rest without medication (group D). However, the test provoked vasospastic angina in 1/5 patients who were asymptomatic without medication. In both the latter patients the prolonged hyperventilation test became negative after the restart of calcium antagonist treatment. During a mean follow-up period of 18 months (range 16-19) after the control hyperventilation test, no relapse of angina at rest, arrhythmias, syncopes, deaths or myocardial infarctions were registered. Thus, a negative test is compatible with low disease activity and/or efficacy of calcium antagonist treatment. Further, the test may reveal a subclinical tendency to coronary artery spasm.

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.

Concomitant calcium antagonist plus isosorbide dinitrate therapy for markedly active variant angina.

The present study was performed to assess the efficacy of concomitant calcium antagonist/isosorbide dinitrate therapy in patients with frequent episodes of variant angina and to compare such combination therapy with isosorbide dinitrate alone. We enrolled nine such patients (six men and three women, aged 47 +/- 9 [mean +/- standard deviation] years) in a long-term comparison of (1) oral isosorbide dinitrate (117 +/- 63 mg per day) alone, (2) verapamil (453 +/- 75 mg per day) + isosorbide dinitrate (given in the same dose as stated above), and (3) nifedipine (71 +/- 14 mg per day) + isosorbide dinitrate (also given in the same dose as stated), each administered for 2 months. During isosorbide dinitrate therapy, these nine patients averaged 23.7 +/- 37.3 chest pains per week, consumed 24.4 +/- 47.4 sublingual nitroglycerin tablets per week, and demonstrated 46.5 +/- 43.2 episodes per week of transient ST segment deviations on calibrated two-channel Holter monitoring. During therapy with verapamil/isosorbide dinitrate and nifedipine/isosorbide dinitrate, the frequency of angina and ST segment deviations was dramatically reduced (verapamil/isosorbide dinitrate, 3.9 +/- 3.6 chest pains per week and 3.5 +/- 2.6 ST segment deviations per week, p less than 0.05; nifedipine/isosorbide dinitrate, 3.1 +/- 4.0 chest pains per week and 5.5 +/- 6.6 ST segment deviations per week, p less than 0.05). In all respects, verapamil/isosorbide dinitrate and nifedipine/isosorbide dinitrate were similar to one another.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of therapeutic response to nifedipine to coronary anatomy and motion of S-T segment during unstable angina pectoris.

Of 77 patients hospitalized for unstable angina pectoris and failure of oral, dermal, or intravenous nitrates and/or beta blockade, 81 percent with negligible or single-vessel disease and 55 percent with two- or three-vessel disease showed response (p less than 0.05) to nifedipine therapy. Patients with either S-T elevation or no change during pain responded better (31 of 45) than those with any S-T depression (16 of 32; p less than 0.05). Patients with negligible or single-vessel disease had a higher prevalence of S-T elevation (13 of 16) than patients with two- or three-vessel disease (15 of 31; p = 0.004). S-T motion did not predict response in patients with two- or three-vessel disease, but did predict response in patients with negligible or single-vessel disease. On follow-up study at 9 +/- 8 (range one to 33) months, 39 of 42 who had shown response were free from pain. Three died from infarction without unstable angina. (range one to 33) months, 39 of 42 who had shown response were free from pain. Three died from infarction without unstable angina. Five who showed response had elective bypass surgery. The addition of nifedipine abolished or reduced pain episodes by more than 50 percent in 61 percent of patients with refractory unstable angina pectoris. Patients with negligible or single-vessel disease with S-T elevation benefit most. In patients with two- or three-vessel disease, the type of S-T motion did not predict response. Follow-up of all those with response indicated sustained amelioration by nifedipine therapy. Failure of nifedipine therapy should not be accepted until a dose of 120 mg per day has been achieved, or until intolerable side effects appear.

Verapamil therapy for Prinzmetal's variant angina: comparison with placebo and nifedipine.

This study was performed (1) to assess the efficacy and safety of verapamil in patients with variant angina, and (2) to compare verapamil and nifedipine in patients with this clinical syndrome. In 27 patients, placebo and verapamil were administered in a long-term randomized, and double-blind study of 9 months' duration. In comparison to placebo, verapamil reduced the frequency of angina, nitroglycerin usage, transient episodes of electrocardiographic S-T segment deviation (as assessed by 2-channel Holter monitoring), and hospitalizations required for clinical instability. Subsequently, 23 patients were treated with nifedipine in a nonblind fashion for 2 months, and this agent exerted a beneficial effect similar to that of verapamil. Finally, gated equilibrium blood pool scintigraphy, performed in 10 patients at rest and during exercise during treatment with placebo, verapamil, and nifedipine, demonstrated that neither calcium antagonist caused a deterioration of left ventricular performance. Thus, (1) long-term oral verapamil and nifedipine are each superior to placebo and are of similar efficacy in patients with variant angina, and (2) neither agent adversely influences left ventricular performance in patients with relatively normal left ventricular function.