Case 2. Recurrence of myocardial infarction.

A 50-year-old man arrives in the emergency room with signs and symptoms occurring intermittently over a period of 48 h consistent with a myocardial infarction. He has several major risk factors for a recurrent event. A number of management strategies have already been attempted. Two opinions for further management are presented.

Candesartan cilexetil is not associated with cough in hypertensive patients with enalapril-induced cough. Multicentre Cough Study Group.

The aim of this study was to evaluate the occurrence of dry cough during treatment with candesartan cilexetil, enalapril, or placebo in patients with hypertension and a history of angiotensin converting enzyme (ACE)-inhibitor-related cough. Patients with confirmed cough during an enalapril (10 mg) challenge period, followed by no cough during a placebo dechallenge period were randomized to 8 weeks of double-blind treatment with candesartan cilexetil (8 mg) (n = 62), enalapril (10 mg) (n = 66), or placebo (n = 26). Incidence and severity of dry cough was evaluated by the symptom assessment questionnaire, frequency of dry cough by a visual analog scale, and the possible impact on quality of life by the minor symptom evaluation (MSE) profile. The percentage of patients with cough was significantly lower with candesartan cilexetil (35.5%) than with enalapril (68.2%, P < .001), and did not differ between candesartan cilexetil and placebo (26.9%, P > .20). Patients coughed less frequently and with less severe cough with candesartan cilexetil than with enalapril, and similarly with candesartan cilexetil and placebo. Changes in the MSE profile were minor, although candesartan cilexetil had better scores for contentment than placebo (P = .03), and also tended to be associated with better sleep than enalapril (P = .08). In hypertensive patients with ACE-inhibitor-induced cough, the incidence, frequency, and severity of dry cough was significantly lower with candesartan cilexetil than with enalapril, and no different from that found with placebo.

Candesartan Cilexetil is not Associated with Cough in Patients with Enalapril-induced Cough.

Treatment with angiotensin-converting enzyme (ACE) inhibitors is frequently associated with persistent dry cough. This side effect is thought to be due to the non-specific action of ACE inhibitors, which, in addition to suppressing the renin-angiotensin system (RAS), leads to the accumulation of kinins, encephalins and other biologically active peptides. Candesartan cilexetil is a new, long-acting angiotensin II type 1 (AT 1 ) receptor blocker, which offers a more specific means of suppressing the RAS than can be achieved with ACE inhibitors. In this study, we compared the incidence and severity of cough during treatment with candesartan cilexetil, enalapril and placebo in patients with hypertension and enalapril-induced cough. Men and women, aged 20-80 years, with a history of medically treated primary hypertension and ACE-inhibitor-related cough were enrolled. The presence of cough was confirmed during a 4-week challenge period with enalapril, 10 mg, which abated during a subsequent 4-week washout period with placebo. Patients with confirmed ACE-inhibitor-related cough were then randomized to double-blind treatment with candesartan cilexetil, 8 mg once daily ( n = 62), enalapril, 10 mg once daily ( n = 66), or placebo ( n = 26). Baseline blood pressure was similar in all groups. Although blood pressure was recorded during the study, this was for safety monitoring, and the measurements were not standardized in relation to study drug intake or time of day. The frequency of dry cough was recorded on a visual analogue scale (VAS). For each assessment, patients marked a cross on a straight horizontal 100 mm line, rating cough frequency from 'none of the time( at one end of the line to 'all of the time( at the other end. The impact of treatment on quality of life was also studied, using the Symptom Assessment (SA) questionnaire and the Minor Symptom Evaluation (MSE) profile. The SA questionnaire assessed the severity of nine symptoms, including dry cough, by means of a five-graded Likert scale (not at all, a little, moderately, quite a bit, extremely). Changes in the three dimensions of the MSE profile - contentment, vitality and sleep - were recorded using a VAS. Candesartan cilexetil was superior to enalapril regarding the change in frequency ( p = 0.001) and severity ( p < 0.001) of dry cough. After 8 weeks of treatment, the proportions of patients with cough were 26.9% for placebo, 35.5% for candesartan cilexetil and 68.2% for enalapril ( p < 0.001, candesartan cilexetil versus enalapril; p > 0.20, candesartan cilexetil versus placebo). Treatment with candesartan cilexetil did not compromise patients' well-being. Compared with placebo, candesartan cilexetil was superior in terms of its effect on contentment; similar trends were noted for vitality and sleep, although the differences were not significant. When all adverse events were considered, candesartan cilexetil was very well tolerated. No serious adverse events occurred in the candesartan cilexetil or placebo groups, while three patients in the enalapril group reported serious adverse events (chest pain, agranulocytosis, accidental fracture). No treatment-related changes of clinical relevance could be found with regard to laboratory variables, ECG or vital signs/physical findings, except the anticipated blood pressure reduction in the active treatment groups. In conclusion, candesartan cilexetil is not associated with cough in hypertensive patients with previous ACE-inhibitor-induced cough. The incidence of dry cough in patients treated with candesartan cilexetil was similar to that of placebo and lower than that of enalapril.

Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/beta-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic < or =90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

Hypertrophy to failure.

Left ventricular hypertrophy (LVH) is a common consequence of hypertension, and an independent risk factor for cardiovascular morbidity and mortality. The presence and severity of LVH is best determined by echocardiography and expressed as left ventricular mass index or left ventricular wall thickness. Pathological LVH, in response to pressure or volume load on the heart, is characterised by myocyte hypertrophy and hypertrophy/hyperplasia of nonmyocyte cells within the myocardium. Angiotensin II and aldosterone are promoters of increased fibroblast activity and a significant increase in collagen fibres in the myocardium. Early diagnosis and treatment of hypertension has significantly decreased the incidence of LVH and subsequent heart failure in many countries, but the choice of antihypertensive therapy alters the rate of reversal of LVH and the subsequent development of heart failure. Angiotensin converting enzyme (ACE) inhibitors, beta-blockers and calcium channel blockers produce the most rapid reversal of hypertrophy. Meta-analysis of these many small trials suggests an advantage of ACE inhibitors over other groups of antihypertensive agents.

Interdisciplinary treatment of morbidity in benign chest pain.

This study tested the hypothesis that functional morbidity in benign chest pain can be modified independently of symptoms through interdisciplinary medical and cognitive-behavioral intervention. Analyses used data collected in a sixteen-week trial of interdisciplinary treatment for disability in benign chest pain. One hundred four chest pain patients having normal coronary arteriograms (NCA) (n = 14) or mitral valve prolapse (MVP) with no other known cardiac or arterial disease (n = 90) were assigned to individual treatment, group treatment, self-monitoring attention control, or a wait-list control group. Results indicate that interdisciplinary intervention, in group or individualized format, was successful for improving short-term and long-term (follow-up range = six to sixteen months) functional status, in both MVP and NCA patients. Correlation analysis indicated that functional improvements were not dependent on reductions in the frequency of symptoms. In fact, significant reductions in disability were obtained in those treated patients (13 of 43) who reported no reduction, or an actual increase, in the frequency of chest symptoms. These data indicate that disability in benign chest pain may be modified independently of symptoms by an integration of medical and cognitive-behavioral strategies.

A Canadian multicentre study of a 48 h infusion of milrinone in patients with severe heart failure.

Milrinone is a nonglycoside, nonsympathomimetic bipyridine with positive inotropic and systemic vasodilator properties. In order to evaluate the efficacy and safety of a short term infusion of milrinone, 105 patients with stable New York Heart Association (NYHA) class III or IV heart failure received a loading dose (50 micrograms/kg) and a 48 h continuous infusion (0.5 micrograms/kg/min). Administration of the loading dose resulted in a 28% decrease in pulmonary capillary wedge pressure (PCWP) (P less than 0.001), a 38% increase in cardiac index (P less than 0.001), and a 34% increase in stroke volume index (P less than 0.001) within 15 mins. Milrinone infusion maintained an average 27% and 24% reduction in PCWP during the first and second days, respectively (P less than 0.001). Cardiac index was 32% and 34% above baseline during the same intervals (P less than 0.001). There were no clinically significant changes in heart rate or mean arterial blood pressure during the study period. In a subset of 47 patients who underwent Holter monitoring before and during infusion, a significant increase in ventricular arrhythmias (premature ventricular complexes per hour, ventricular couplets per hour and ventricular runs greater than or equal to three) was demonstrated (P less than 0.0001). In general, milrinone was well tolerated. Of the 105 patients entered, one died of an acute myocardial infarction after premature termination of the infusion, and the infusion rate was decreased in two others because of supraventricular arrhythmias. In patients with severe heart failure, intravenous milrinone has significant beneficial hemodynamic effects. ECG monitoring for arrhythmias is recommended during milrinone infusion.

Doxazosin for the treatment of chronic congestive heart failure: results of a randomized double-blind and placebo-controlled study.

In this study we evaluated the effects of once-daily administration of oral doxazosin in patients with chronic congestive heart failure (CHF). After a stabilization period of at least 2 weeks with digitalis and diuretics, 73 patients with chronic CHF were randomized to receive additionally either doxazosin or placebo in double-blind fashion. Patients underwent weekly dose adjustments with increasing doses of doxazosin (1, 2, 4, 8, and 16 mg daily) or placebo for 5 weeks, and 67 were evaluated for 12 additional weeks on maximally tolerated doses of blinded study drugs. Treatment groups were evaluated with respect to symptoms of heart failure, indexes of quality of life and left ventricular function, frequency and type of arrhythmia, adverse events, and mortality rates. Doxazosin (11.9 +/- 0.9 mg) given once daily produced a favorable trend in the investigators' and patients' assessments of symptomatic change. Doxazosin was associated with a significantly higher level of voluntary submaximal exercise and a favorable trend on left ventricular ejection fraction (increase of 9.8% of the baseline value vs 2.7% with placebo; p = NS). During the 3-month steady-dosing period, patients treated with doxazosin had a significant (p less than 0.004) reduction in ventricular arrhythmias and significantly fewer morbid and mortal cardiac events (including episodes of worsening heart failure severe enough to prompt discontinuation of the study, myocardial infarction, and death). Doxazosin was well tolerated, producing no major side effects and only a slightly higher frequency of minor treatment-related side effects compared with placebo (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

One year mortality outcomes of all coronary and intensive care unit patients with acute myocardial infarction, unstable angina or other chest pain in Hamilton, Ontario, a city of 375,000 people.

Over a one year period (1979 to 1980) all cardiac admissions to the coronary care units (CCU) and all intensive care unit (ICU) overflow admissions in Hamilton, Ontario, a city of approximately 375,000 people, were documented. Mortality status was determined one year following admission. There were 2004 individuals with either acute myocardial infarction (810), unstable angina (811) or other chest pain (783) as their first CCU/ICU admitting diagnosis that year. Mortalities in-hospital and by one year were: acute myocardial infarction 17 and 27%, respectively; unstable angina 1.5 and 9.2%, respectively; and other chest pain 1.4 and 3.1%, respectively. Of one year mortality following acute myocardial infarction, 63% occurred during the initial hospitalization, whereas this figure was 16% for unstable angina. For acute myocardial infarction, female mortality was greater than male mortality overall and in all but one age category. Mortality following acute myocardial infarction and unstable angina was strongly related to age. Repeat CCU/ICU admission occurred in 24% of acute myocardial infarction, 28% of unstable angina and 15% of other chest pain, while a total of death or nonfatal CCU/ICU readmission occurred in 31% of acute myocardial infarction, 32% of unstable angina and 17% of other chest pain.

Nonbacterial thrombotic endocarditis complicating mitral valve prolapse presenting as Parinaud's syndrome--a case report.

Nonbacterial thrombotic endocarditis is the most common form of endocarditis found at autopsy. Systemic embolization may complicate this condition in patients with mitral valve prolapse. The authors report a case of mitral valve prolapse and nonbacterial thrombotic endocarditis in which the presenting feature was Parinaud's syndrome.

Primary pulmonary artery sarcoma mimicking pulmonary thromboembolism.

A 69-year-old woman presenting with dyspnea had a pericardial window created for fibrinous pericarditis. The patient subsequently developed pulmonary hypertension and a ventilation perfusion scan was compatible with pulmonary thromboembolism. A primary tumour of the pulmonary artery was suggested by angiography, computerized axial tomography and magnetic resonance imaging. Pathology confirmed a spindle cell pulmonary artery sarcoma.

Coronary care unit utilization in Hamilton, Ontario, a city of 375,000 people.

All cardiac admissions to coronary care unit (CCU) beds and all intensive care unit (ICU) overflow admissions in Hamilton, Ontario, a city of 375,000 people, were documented over a one-year period, 1979-80. There were 4180 such admissions, 89% of them to CCUs. In the CCUs, 22% of patients had acute myocardial infarction, 24% unstable angina and 21% other chest pain. For myocardial infarction, hospitalization rate was 224 per 100,000, hospital mortality 42 per 100,000 and 48% of all myocardial infarction deaths in the community occurred in hospital. Of all myocardial infarction patients admitted to the CCU, 69% were correctly diagnosed on admission (sensitivity) and of all the admission diagnoses of myocardial infarction, 72% were eventually found to be correct (positive predictive value). Mean values for CCU patients overall were age 62.5 years, CCU stay 2.88 days and hospital stay 9.7 days; and for acute myocardial infarction patients in CCUs, age 63.4 years, CCU stay 3.98 days and hospital stay 13.28 days. For myocardial infarction, CCU mortality was 10.9%, hospital mortality 15.2% and, with the inclusion of ICU overflow patients, hospital mortality was 17.6%. Age-specific mortality for myocardial infarction was 9.7% age 45 to 64 years, and 32.8% over 70 years.

Anasarca due to pulmonic valve regurgitation with low pulmonary vascular resistance.

A 57-year-old woman underwent pulmonic valvotomy for congenital pulmonic stenosis. She developed severe pulmonic insufficiency, secondary tricuspid regurgitation, and anasarca in spite of a normal pulmonary artery pressure. Insertion of a pulmonary valve prosthesis and tricuspid valve plication reversed all clinical symptoms and signs of this rare complication of pulmonary valvotomy.

Life-threatening ventricular arrhythmias provoked by amiodarone treatment.

We report two patients who developed symptomatic life-threatening ventricular tachyarrhythmias with changing QRS axes (resembling torsades de pointes), during treatment of their supraventricular tachycardias with oral amiodarone. Like other effects of amiodarone on the body, the arrhythmias became evident several days after initiating therapy, at which time electrocardiographic QT prolongation was present. The arrhythmias subsided after amiodarone treatment was withdrawn. No other drugs or electrolyte disturbances could be incriminated as a cause.

Use of calcium ion entry blockers in family practice.

Verapamil, nifedipine, and diltiazem are drugs which decrease intracellular calcium in cardiac muscle, smooth muscle, and nodal cardiac cells. Unlike B-blockers, each drug acts at a different site on the cell membrane and has an important difference in overall action. Verapamil is used to treat angina, systemic hypertension, hypertrophic cardiomyopathy, and supraventricular and junctional tachyarrhythmias. Nifedipine is useful in angina, vasospastic disorders, and hypertension. A specific role for diltiazem is now being defined.

A placebo-controlled study to determine the efficacy of oral disopyramide phosphate for the prophylaxis of ventricular dysrhythmias after acute myocardial infarction.

1 To evaluate oral disopyramide phosphate in the prophylaxis of dysrhythmias occurring in acute myocardial infarction (MI) patients (presenting within 12 h of symptoms, age 21-70 years), a placebo-controlled, randomized double-blind, in hospital trial was conducted. After prognostic stratification (anterior and non-anterior MI at each of 4 regional hospitals) patients were randomly assigned to receive oral disopyramide phosphate (loading dose 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh less than 55, 55-85, or greater than 85 kg, respectively or matching placebo. The primary exclusion criteria were overt heart failure, systolic BP less than 100 mmHg, significant heart block or history of urinary retention. Active drug or placebo was continued for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 premature ventricular contractions (PVCs)/min, R on T PVCs, multifocal PVCs, bigeminal PVCs, ventricular tachycardia or ventricular fibrillation) or (b) onset of exclusion criteria. In addition, plasma drug concentrations were determined and 24 h electrocardiographic tapes were obtained on day 1, and on one of days 4-7 but these results are not presented here. 2 Out of 121 patients entering the trial, 101 had confirmatory ECG and enzyme changes. Of these, 9 of 47 patients receiving disopyramide phosphate required lignocaine compared to 20 of 54 receiving placebo (19% v 37%; P = 0.047). Corresponding numbers for patients discontinuing trial medication for other non-fatal complications of MI were 5 and 3, and for those dying, were 3 (2 infarct extensions and 1 massive infarction), and 0, respectively. Respective numbers discontinuing trial medication for possible drug side effects (viz. urinary retention requiring catheterization) were 6 and 1 (P = 0.031). 3 In circumstances where i.v. therapy is deemed impractical, use of oral disopyramide phosphate given prophylactically in patients with acute MI may reduce the incidence of "warning arrhythmias' by a clinically significant extent.

Intravenous hyaluronidase therapy for myocardial infarction in man: double-blind trial to assess infarct size limitation.

Patients with their first myocardial infarction not initially complicated by severe atrioventricular block or power failure were given a skin test and then randomized to receive either hyaluronidase or placebo in double-blind fashion. Hyaluronidase, 500 IU/kg i.v., was given every 6 hours for 42 hours. Of the 48 eligible patients, 26 received hyaluronidase and 22 received placebo. The mean CK serum entry was 3140 +/- 2111 mIU/ml (mean +/- SD) in hyaluronidase patients and 3574 +/- 1476 mIU/ml in placebo patients (p less than 0.21). The mean infarct size was 54.6 +/- 35.8 CK gram-equivalents in the hyaluronidase patients and 64.0 +/- 31.1 CK gram-equivalents in the placebo patients (p less than 0.20). Among the 21 patients treated within 6 hours of the onset of infarction, the difference in infarct size was greater (p less than 0.15). There was no significant difference in the incidence of power failure, ventricular arrhythmias, recurrence of ischemic pain, infarct extension or mortality. No benefit of hyaluronidase was demonstrated in this study, which was designed to detect a 50% reduction of infarct size. However, to detect a 20% reduction in infarct size would require a much larger study population.