Angiotensin-converting inhibitors in patients with congestive heart failure: a class effect?
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Biomedical subjects
Publications and source records attributed to B Pitt.
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Sudden cardiac death is a common cause of mortality in patients with congestive heart failure. To determine if low-dose amiodarone could reduce sudden death among these patients, a prospective, placebo-controlled, double-blind pilot trial was conducted. One hundred one patients with ejection fractions less than 30%, New York Heart Association class III or IV symptoms, and frequent but asymptomatic spontaneous ventricular ectopy (Lown class II to V) were randomly assigned to treatment with low-dose amiodarone (400 mg/day for 4 weeks and then 200 mg/day) or placebo. Mean follow-up was 357 days (range 4 to 1009 days). Side effects were infrequent and there was no difference in the incidence of side effects between the treatment groups. The frequency of spontaneous ventricular ectopy in the group receiving amiodarone fell from 4992 +/- 1240 beats/24 hours at baseline to 1135 +/- 494 beats/24 hours after 1 month of treatment (p = 0.02) and remained low after 6 months, while there was no change in ventricular ectopy among the patients receiving placebo. Despite the reduction in ectopy, there was no improvement in mortality or decrease in the incidence of sudden death. One-year mortality by Kaplan-Meier analysis was 28% in the group receiving amiodarone and 19% in the group receiving placebo (p = NS). One-year mortality in patients with greater than 75% reduction in ventricular ectopy after 1 month of treatment was 31% versus 17% in patients with less than or equal to 75% ectopic suppression (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Despite many advances since its inception in humans in 1977, coronary angioplasty continues to be limited by the problems of abrupt arterial closure and late restenosis. Excessive platelet deposition at the site of angioplasty undoubtedly plays an important role in the pathophysiology of both of these problems. Monoclonal antibodies and snake venom-derived or synthetic peptides directed against a common protein recognition sequence on the platelet glycoprotein IIb/IIIa receptor are currently in the early stages of preclinical and clinical testing and hold promise of preventing abrupt closure and restenosis by inhibiting platelet function. Whether any of these agents will eventually be commonly used in clinical practice will depend on their effects on the complex pathophysiology of these problems and on their safety profile when administered to patients who are likely to receive other antithrombotic medications and who are instrumented for coronary angioplasty.
The adjunctive use of intravenous captopril with tissue plasminogen activator early during acute myocardial infarction offers theoretic advantages of diminishing left ventricular volume, preventing ventricular dilation and improving patient survival. To test the safety and efficacy of combined early administration of intravenous captopril and recombinant tissue-type plasminogen activator (rt-PA), 38 patients treated with rt-PA 3 +/- 0.3 h (mean +/- SE) after the onset of myocardial infarction were randomized to intravenous followed by oral captopril or placebo therapy. They underwent cardiac catheterization with measurement of hemodynamic variables and left ventricular function and determination of serum renin, angiotensin and aldosterone levels on days 1 and 7. Oral administration of the selected agent was continued for 3 months along with other antianginal medications, including nonangiotensin-converting enzyme inhibitor vasodilators. Repeat measurements of left ventricular function were obtained before hospital discharge and at 3 months. There were no significant differences in baseline clinical characteristics between groups. One patient in the captopril-treated group became hypotensive during intravenous therapy, requiring discontinuation of treatment. Compared with the placebo-treated group, the captopril-treated group had significant reductions at day 7 in left ventricular end-diastolic pressure (22.5 +/- 1.5 versus 16.3 +/- 1.6 mm Hg, p less than 0.01) and mean systemic arterial pressure (93.6 +/- 3.3 versus 86.2 +/- 2.7 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: The comparative effects of aspirin and F(ab')2 fragments of monoclonal antibody 7E3 against the platelet glycoprotein IIb/IIIa receptor on ex vivo platelet aggregation and in vivo thrombosis were studied in a canine coronary balloon angioplasty model. METHODS AND RESULTS: Three groups were studied. Group 1 (n = 8) was pretreated with saline placebo, group 2 (n = 8) was pretreated with 325 mg aspirin, and group 3 (n = 8) was pretreated with 0.8 mg/kg 7E3 F(ab')2. Coronary angioplasty was performed in the left anterior descending coronary artery of open-chest dogs under fluoroscopic control; serial measurements of basal and hyperemic coronary blood flows were then made for 2 hours after application of an external stenosis that decreased hyperemic flow by 50%. There were no significant differences in platelet counts or hemodynamic measurements during the experiments. Platelet aggregation was decreased by treatment: group 1, 64 +/- 13% versus 50 +/- 13% (p = NS); group 2, 57 +/- 4% versus 25 +/- 4% (p less than 0.001); and group 3, 77 +/- 5% versus 10 +/- 6% (p less than 0.0002). Compared with initial measurements, the 7E3 antibody was superior to aspirin in maintaining hyperemic coronary blood flow after release of the external stenosis: group 1, 177 +/- 14 versus 21 +/- 14 ml/min (p less than 0.0003); group 2, 189 +/- 9 versus 110 +/- 28 ml/min (p less than 0.008); and group 3, 194 +/- 12 versus 181 +/- 15 ml/min (p less than 0.02). In group 1, arterial occlusion developed in five dogs, and nonocclusive thrombus was seen in three dogs. In group 2, arterial occlusion developed in one dog, and nonocclusive thrombus was seen in five dogs. No thrombotic material was visualized in group 3 dogs treated with 7E3 F(ab')2. CONCLUSIONS: In this animal model, the 7E3 antiplatelet antibody is superior to aspirin in inhibiting platelet aggregation, thrombosis, and acute closure after deep arterial injury caused by coronary balloon angioplasty.
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Controversy exists as to whether and how long heparin treatment is necessary after infarct vessel recanalization. To determine the role of heparin, patients with suitable angiographic features after reperfusion therapy were randomly allocated to receive a brief infusion of intravenous heparin for less than or equal to 24 hours (group 1), adjusted to a partial thromboplastin time of 2 times control or a prolonged infusion for greater than or equal to 72 hours (group 2), using the same titration mechanism. Patients were excluded for complex intimal dissections, large residual filling defects, less than Thrombolysis in Myocardial Infarction grade 3 flow pattern or greater than 50% residual stenosis. Heparin was sustained except for discontinuation 2 to 4 hours before periaccess sheath removal, or if significant bleeding (greater than or equal to 2 units blood transfusion) occurred. The primary endpoints were 1-week patency determined by repeat catheterization or recurrent ischemia, or both, and the incidence of bleeding complications. Fifty patients were randomized, 25 in both groups. Baseline variables were similar; 14 group 1 and 15 group 2 patients received thrombolytic treatment; 20 patients in each group had coronary angioplasty. Two documented reocclusions occurred in both groups. Significant bleeding complications occurred in 0 of 25 (0%) group 1 versus 6 of 25 (24%) group 2 patients (p less than 0.05). Thus, in low-risk patients after successful reperfusion, prolonged heparin therapy does not protect against rethrombosis and is associated with a significantly higher rate of bleeding complications. Therefore, prolonged heparin therapy for greater than 24 hours does not appear to be justified in low-risk patients with successful reperfusion.
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The evidence that retirement is an important cause of mental illness is largely lacking, though it may contribute a little to depression, neurosis, subjective anxiety and marital tension. The situation is complex but possibly denial is one of the worst ways of adjusting to it. Physical and mental activity, good health, adequate means, well considered accommodation, an absorbing interest, congenial company and a philosophy which encompasses mortality are among the assets and attitudes which may promote successful retirement.
The results of several major trials of i.v. thrombolysis in patients with acute myocardial infarction have demonstrated the efficacy of the treatment in reducing mortality. Streptokinase and rt-PA have been shown to be effective (APSAC = anisoylated plasminogen streptokinase activator complex; GISSI = Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto miocardico, ASSET = Anglo Scandinavian study of early thrombolysis, rt-PA). This treatment is associated with the potential for cerebral and major bleeding, especially in elderly patients. The benefit of this treatment in patients with cardiogenic shock or hypotension (ISIS-2) is discussed. There is no convincing evidence that patients with ST-segment depression or those with an equivocal electrocardiogram had been benefited from i.v. thrombolysis. Further studies with i.v. thrombolysis and/or other strategies need to be explored. Overall the use of i.v. thrombolytic agents in combination with PTCA in patients with acute myocardial infarction have resulted in improvement in ventricular function and survival in patients eligible for this therapy. However, new techniques and therapeutic approaches to prevent reocclusion, to prevent reperfusion injury, to prevent restenosis after PTCA, to prevent atherosclerosis in the infarct and non-infarct related arteries, and to reduce the potential for ventricular arrhythmias and sudden death as well as the potential for mural thrombi and embolization after infarction are needed. The 1990's will see attempts to determine the optimum adjunctive therapy or "cocktail" of agents to be used with i.v. thrombolysis.
Thirty-five patients greater than 70 years of age with acute myocardial infarction (AMI) were treated with emergency percutaneous transluminal coronary angioplasty (PTCA). Seventeen (49%) patients received previous thrombolytic therapy: streptokinase (10 patients), tissue plasminogen activator (6) and combined tissue plasminogen activator and urokinase (1). Infarct-related artery patency was achieved in 26 patients (74%) after PTCA. Total in-hospital mortality was 34%. Univariate analysis showed a higher in-hospital mortality in patients with an occluded vessel after PTCA (78%) than in those patients with a patient infarct-related artery (19%) (p = 0.003). Symptomatic coronary reocclusion occurred in 3 patients (15%) during the hospital stay. Compared with emergency PTCA in 200 consecutively treated patients less than 70 years of age, the in-hospital mortality was increased (34 vs 6%, p less than 0.001), and the primary success rate was reduced (66 vs 90%, p less than 0.001). At a mean follow-up of 28 months, there has been a 13% out-of-hospital mortality rate in the elderly patients (3 patients died). Of the 20 surviving patients, 14 are asymptomatic and 6 have class II angina. In conclusion, emergency PTCA for AMI in elderly patients is associated with a decreased success rate and a higher mortality rate. However, the in-hospital mortality rate is not dissimilar to that in elderly AMI patients treated with conventional therapy or thrombolytic therapy alone, and the postdischarge mortality rates are low.
Management of the patient with acute myocardial infarction is in flux. In the current "reperfusion era," many patients receive intravenous thrombolytic therapy and aspirin before admission to the coronary care unit. Appropriate use of drugs limits expansion of the infarct and reduces mortality rates in patients with uncomplicated myocardial infarction. Percutaneous transluminal coronary angioplasty may be necessary in those who are not candidates for drug treatment or who show recurrent ischemia after thrombolysis, while cardiac transplantation may be the only hope for patients with multivessel disease who are in cardiogenic shock. The "cocktail era," in which polypharmacy is both acceptable and effective, will likely be the next stage in management of acute myocardial infarction.
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The relation between baseline clinical variables and subsequent mortality was examined in 295 patients with mild to moderate heart failure who participated in a multicenter trial comparing the effect on treadmill exercise tolerance of captopril, digoxin and placebo given in addition to a diuretic drug. At baseline study, all patients had a left ventricular ejection fraction less than or equal to 40%; 81% were in New York Heart Association functional class II. The etiology of heart failure was ischemic in 62% and nonischemic in 38%. During an average follow-up period of 16 months, 47 patients (16%) died and 24 deaths were classified as sudden. By univariate analysis, left ventricular ejection fraction, ventricular premature beat frequency, couplet frequency, ventricular tachycardia frequency, functional class, treadmill exercise time and nonischemic heart disease were statistically associated with mortality. With multiple logistic regression analysis, left ventricular ejection fraction was identified as the variable most closely associated with total mortality (p = 0.006). Twenty-seven percent of patients with an ejection fraction less than or equal to 20% died compared with 7% with an ejection fraction greater than or equal to 30%. Ventricular tachycardia frequency on Holter monitoring was independently associated with both total mortality (p = 0.008) and sudden death (p = 0.003). Patients with a ventricular tachycardia frequency of greater than 0.088 events/h had a mortality rate of 34% compared with 12% in those without ventricular tachycardia. In the multivariate model, functional class (p = 0.02) and etiology of nonischemic heart disease (p = 0.04) remained as independent predictors of mortality, whereas treadmill exercise duration did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiographic, angioscopic and pathologic reports have recently demonstrated a high incidence of intracoronary thrombus in patients with unstable angina. To determine if thrombolysis could be beneficial when combined with maximal medical therapy, 40 patients with rest angina, angiographically documented coronary artery disease and pacing-induced ischemia were randomly assigned to intravenous recombinant tissue-type plasminogen activator (rt-PA, 150 mg/8 h) or placebo in a prospective double-blind trial. All patients received nitrates, a beta-adrenergic blocking agent, a calcium channel blocker, aspirin and heparin. Pacing thresholds for ischemia and quantitative coronary stenosis were measured before and after infusion of the study medication. Intracoronary thrombus was identified angiographically before infusion of the study medication in 16 patients; 7 received rt-PA and 9 received placebo. The ischemic pacing threshold in patients treated with rt-PA increased from 112 +/- 4 beats/min at baseline to 127 +/- 5 beats/min (p = 0.007) by the end of the infusion versus an insignificant change in patients who received placebo (from 116 +/- 4 to 119 +/- 4 beats/min, p = NS). In patients with intracoronary thrombus, the ischemic pacing threshold increased 26 +/- 7 beats/min with rt-PA treatment versus 0 +/- 3 beats/min with placebo (p = 0.004). In contrast, in patients without thrombus, there was no difference in ischemic pacing threshold increments between treatment groups (7 +/- 11 beats/min for rt-PA versus 6 +/- 5 beats/min for placebo, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)