Effect of angiotensin-converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function.

Mitral regurgitation (MR) is a common, frequently asymptomatic valvulopathy that can ultimately lead to left ventricular failure. With the objective of forestalling MR progression, a prospective, placebo controlled, double-blind study was conducted. It measured the effectiveness of lisinopril, an angiotensin-converting enzyme inhibitor, in reducing the echocardiographic signs of MR severity over a one-year period. Severe coronary disease was excluded by stress echocardiography. Treatment effectiveness was estimated to be proportional to the reduction in MR fraction and cardiac chamber dimensions, compared with baseline, according to intention-to-treat analysis. A final patient population of 23 asymptomatic adults aged 53.3 +/- 2.4 years (mean +/- SEM), with moderate, organic MR and normal left ventricular function was selected from the echocardiographic database. All baseline patient characteristics were comparable in the two treatment groups, including the MR fraction (55 +/- 3%). Twelve patients received lisinopril (18 +/- 1 mg) and 11 received placebo. After one year of treatment, a statistically significant difference in the MR fraction was observed between the two groups. For the lisinopril group the MR fraction dropped by 6.4 +/- 3.5% and for the placebo group it increased by 3.7 +/- 3.2% versus baseline (P < 0.05). No differences in left atrial or ventricular dimensions were observed. The study drug was stopped in four patients after one patient presented with rapid atrial fibrillation and angina while three patients were intolerant to lisinopril. Only one patient receiving placebo was taken off therapy. In conclusion, treatment with lisinopril indicates some reduction in the severity of chronic moderate MR in asymptomatic patients with normal left ventricular function. This approach appears to be safe, but side effects are not uncommon, warranting regular follow-up.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 1: Clinical data.

There is an increasing body of clinical trial evidence to support the use of angiotensin-converting enzyme (ACE) inhibitors in the management of patients following myocardial infarction (MI). Enthusiasm for the use of ACE inhibitors in the acute phase of MI had previously been tempered by the adverse results of an early trial. However, exciting new information is available from several large, randomized studies that has not only quelled those initial concerns but also attests to the efficacy of using this class of medication in the first 24 h after an acute MI. A Canadian National Opinion Leader Symposium was held in November 1995 to review the results of the major ACE inhibitor clinical trials and to discuss key issues and controversies surrounding their use in acute MI. The focus of this paper, the first of two parts, is on the results of the major ACE inhibitor clinical trials.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 2: Clinical issues and controversies.

Over the past 10 years, several clinical studies have concluded that, in patients already receiving conventional therapies, angiotensin-converting enzyme (ACE) inhibitors further reduce the risk of death following myocardial infarction (MI). Post-MI ACE inhibitors have proven to be effective as long term therapy in high risk patients as well as when used for much shorter periods in a broad patient population. However, while considerable mortality data have been collected, the effects of ACE inhibitors post-MI on other cardiovascular outcomes have not been as well documented. In addition, a number of issues regarding the most effective use of these agents remain unresolved. This paper, the second of two parts, focuses on the clinical issues and controversies surrounding the use of ACE inhibitors following acute MI. The effects of ACE inhibitors on the outcomes of sudden death, nonsudden death, recurrent angina, mitral regurgitation and left ventricular dysfunction are reviewed and potential mechanisms of action are proposed. In addition, ACE inhibitor therapy is discussed in terms of patient selection criteria, choice of agent, optimal dosing regimen, concomitant use of other therapies and relative costs of treatment. Finally, potential mechanisms of action of ACE inhibitors are proposed for each of the outcomes examined.

PROTECT (Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial): a randomized, double-blind clinical trial of diltiazem versus atenolol in secondary prophylaxis post non-Q wave myocardial infarction.

OBJECTIVE: To describe the rationale and design of the Prospective Reinfarction Outcomes in the Thrombolytic Era Cardizem CD Trial (PROTECT). DESIGN: A multicentre, randomized, double-blind, parallel-group comparison of once daily beta-therapy versus heart rate lowering calcium channel blocker therapy, in the reduction of one-year nonfatal reinfarction and cardiovascular death (combined primary end-point) initiated 24 to 96 h post non-Q wave myocardial infarction. SETTING: One hundred and twenty hospitals across Canada. PATIENTS: Over 7500 women and men aged 21 years or older with enzyme-confirmed non-Q wave infarction and without significant left ventricular systolic dysfunction will be recruited over two years. INTERVENTIONS: Once daily beta-blocker therapy (oral atenolol, 50 to 200 mg) versus once daily calcium channel blocker therapy (oral diltiazem 120 to 360 mg) with follow-up for up to three years. CONCLUSIONS: The PROTECT will be the largest all-Canadian cardiovascular trial to date and will compare two commonly prescribed agents for secondary prophylaxis following non-Q wave infarction. The scientific question addressed by the PROTECT is of major public health importance and the results of the study will directly affect current clinical practice.

Out-of-hospital rapid-sequence induction for intubation of the pediatric patient.

OBJECTIVE: To determine the effectiveness and morbidity of out-of-hospital rapid-sequence induction (RSI) for endotracheal intubation (ETI) in the pediatric population. METHODS: The medical records were retrospectively reviewed for a consecutive series of pediatric patients undergoing out-of-hospital RSI by flight paramedics from July 1990 through July 1994. Patient demographics, pharmacologic agents, ED arterial blood gas data, pulmonary complications, and RSI-related complications were abstracted. RESULTS: Forty patients (31 injured, 9 medical) with a mean age of 8.1 years (range 0.5-17 years) underwent out-of-hospital RSI. Indications for intubation included hyperventilation (n = 20), combativeness (n = 16), apnea (n = 5), and unknown (n = 5). Intubation mishaps occurred in 13 patients (33%); these included multiple attempts (n = 9), aspiration (n = 8), and esophageal intubation (n = 1). The success rate of ETI was 97.5% (one failed attempt). Hemodynamic side effects occurred in three patients (8%); all three had bradycardia, with one developing hypotension. Bradycardia was associated with failure to pretreat with atropine (p < 0.05). Sixteen pulmonary complications, seven pneumonia (18%) and nine atelectasis (22.5%), occurred in 13 patients within the first ten hospital days. Intubation mishaps were not associated with pulmonary complications. There were six deaths, none associated with RSI. CONCLUSIONS: 1) Rapid-sequence induction is an effective method for obtaining airway control in the critically ill pediatric patient. 2) Intubation mishaps did not influence the rate of pulmonary complications. 3) Omission of atropine was associated with bradycardia during RSI in pediatric patients.

Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina.

BACKGROUND: Antiplatelet therapy with aspirin and antithrombotic therapy with heparin both prevent the complications of unstable angina; however, no definitive data exist on the relative clinical efficacy of the two drugs. METHODS AND RESULTS: Aspirin (325 mg bid) or heparin (5000-U intravenous bolus followed by a perfusion titrated to the APTT) were compared in a double-blind randomized trial of 484 patients in two cohorts enrolled sequentially. The study was initiated at admission to hospital at a mean of 8.3 +/- 7.8 hours after the last episode of pain. End points were assessed 5.7 +/- 3.3 days later, when the decision for long-term management was made. Myocardial infarction occurred in 2 (0.8%) of the 240 patients randomized to heparin and in 9 (3.7%) of the 244 randomized to aspirin (P = .035), an odds ratio of 0.22 and a risk difference of 2.9% (95% confidence limits, 0.3% to 5.6%) with heparin. The only death resulted from a myocardial infarction in an aspirin patient. Survival curves with Cox logistic regression analysis showed that the improvement in survival without myocardial infarction with heparin (P = .035) was independent of other baseline characteristics. CONCLUSIONS: This study documents that heparin prevents myocardial infarction better than aspirin during the acute phase of unstable angina.

Reactivation of unstable angina after the discontinuation of heparin.

BACKGROUND: Heparin is an effective, widely used treatment for unstable angina. Among patients enrolled in a double-blind, randomized, placebo-controlled trial comparing intravenous heparin, aspirin, both treatments, and neither during the acute phase of unstable angina, we encountered patients in whom unstable angina was reactivated after heparin was discontinued. METHODS: The study population included 403 of the original 479 patients in the trial who had completed six days of blinded therapy without refractory angina or myocardial infarction. After the discontinuation of therapy, clinical events, including reactivation of unstable angina and myocardial infarction occurring within 96 hours after hospitalization, were closely monitored. RESULTS: Early reactivation occurred in 14 of the 107 patients who received heparin alone, as compared with only 5 patients in each of the other three study groups (P less than 0.01). These reactivations required urgent intervention (thrombolysis, angioplasty, or coronary-bypass surgery) in 11 patients treated with heparin alone, but in only 2 patients in the other groups combined (P less than 0.01). Four of the six patients who had a myocardial infarction during a reactivation of their disease were in the heparin group. Reactivations in this group occurred in a cluster a mean (+/- SD) of 9.5 +/- 5 hours after the discontinuation of the study drug but were randomly distributed over the initial 96 hours in the other three groups. CONCLUSIONS: Although heparin is beneficial in treating unstable angina, the disease process may be reactivated within hours of the discontinuation of this drug. Concomitant therapy with aspirin may prevent this withdrawal phenomenon.

Predictors of survival of in-hospital cardiac arrest.

A prospective study was conducted of all cases of attempted resuscitation following cardiac arrest occurring over a period of one year in a tertiary care teaching hospital. Analysis was made of the effects on survival of preselected variables of patients and circumstances of arrest. In 125 cases for which resuscitation was attempted, 49 attempts (39%) were initially successful. Twenty-three patients were discharged from hospital (18% overall survival). The most potent predictors of successful resuscitation were early successful resuscitation (less than 20 mins), age less than 75 years, and cardiac arrest in proximity to an acute ischemic cardiac event (less than 48 h). Survival to discharge was extremely poor when the arrest was unwitnessed (zero of 20 cases) or when the arrest occurred on medical or surgical wards (two of 62 cases). Such low efficacy indicates that reassessment of policy regarding the administration of cardiac resuscitation to patients in hospital is warranted.

Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group.

A total of 1,975 plasma diltiazem concentrations were obtained from 1,067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population, we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose, (2) drug dose taken, (3) patient height (an index of lean body weight), and (4) patient age were important determinants of plasma concentration. For an equivalent dose, plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure, they were not altered by renal dysfunction, hepatic disease or beta blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p less than 10(-9), but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations, but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration greater than 150 ng/ml (7.4 and 1.9%, respectively) than among patients with lower concentrations (2.6% for atrioventricular block, 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related, and that the consideration of patient size, age, and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.

Assay of glyceryl trinitrate, isosorbide dinitrate, and their metabolites in plasma by large-bore capillary column gas-liquid chromatography.

Two large-bore capillary columns, one with dimethyl polysiloxane (HP-1) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB-17), were used to develop gas-liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide-2-mononitrate (2-ISMN), and isosorbide-5-mononitrate (5-ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0.75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl-methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large-bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary-column assays. The chromatographic resolution of analytes and column efficiency of the large-bore capillary columns were comparable to the results previously found using capillary-column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP-1 column is appropriate for the analysis of GTN and metabolites, and the DB-17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large-bore capillary columns provides rapid and reliable GLC assays for organic nitrates.

Age-related prognosis after acute myocardial infarction (the Multicenter Diltiazem Postinfarction Trial).

The basis for the excess mortality with age after acute myocardial infarction (AMI) is not clear, nor is it known whether the mode of death is altered with age. Age-related factors predictive of mortality and age-related mechanisms of the 333 deaths were examined in 2,466 patients who were enrolled in a placebo-controlled trial to determine the effect of diltiazem on mortality and reinfarction after AMI. There were 3 age groups with increasing mortality rates: ages 25 to 49 (n = 499), 50 to 64 (n = 1,228) and 65 to 75 years (n = 739). There was a significant age-related increase in the proportion of patients with baseline risk factors. These baseline characteristics did not differ by treatment (placebo vs diltiazem). However, multivariate survivorship analysis still identified age as an independent risk factor for cardiac death. The proportion of arrhythmic and myocardial failure deaths did not differ by treatment or age group.

Attenuation of class 3 and sinus node effects of amiodarone by experimental hypothyroidism.

Amiodarone's class III effects may be due to inhibition of the cardiac effects of thyroid hormone. If so, amiodarone would not be expected to cause QT prolongation in hypothyroid subjects. The electrocardiographic (ECG) changes induced after treatment with amiodarone were compared in euthyroid and hypothyroid guinea pigs. Hypothyroidism was induced with intraperitoneal (i.p.) administration of 1 mCi I131 (eight animals). Three of these animals also received oral methimazole to block any residual thyroid hormone production. Significant increases in body weight (28 +/- 9%), RR (14 +/- 8%), QT (14 +/- 5%), and QTc (7 +/- 2%) intervals occurred after induced hypothyroidism. Pilot studies with amiodarone treatment for 4 weeks in euthyroid guinea pigs demonstrated that maximal effects on ECG intervals were achieved after 1 week of drug therapy. Therefore, both euthyroid and hypothyroid groups were treated with daily i.p. amiodarone (80 mg/kg) for 7 days. Euthyroid guinea pigs treated with amiodarone had significant increases in RR (33 +/- 10%), QT (31 +/- 15%), and corrected QT (13 +/- 11%) intervals. In contrast, when hypothyroid animals were treated with amiodarone, no statistically significant changes occurred in ECG intervals. Plasma concentrations of amiodarone did not differ between the two groups (0.7 +/- 0.6 vs. 0.7 +/- 0.4 mg/L in hypothyroid and euthyroid groups, respectively). We conclude that intact thyroid function is a prerequisite for class III and sinus node effects of amiodarone in the guinea pig. This implies that at least some of amiodarone's effects are mediated through antagonism of thyroid action.

Aspirin, heparin, or both to treat acute unstable angina.

We tested the usefulness of aspirin (325 mg twice daily), heparin (1000 units per hour by intravenous infusion), and a combination of the two in the early management of acute unstable angina pectoris in a double-blind, randomized, placebo-controlled trial involving 479 patients. The patients entered the study as soon as possible after hospital admission (at a mean [+/- SD] of 7.9 +/- 8.0 hours after the last episode of pain), and the study was ended after 6 +/- 3 days, when definitive therapy had been selected. Major end points--refractory angina, myocardial infarction, and death--occurred in 23, 12, and 1.7 percent of the 118 patients receiving placebo, respectively. Heparin was associated with a decrease in the occurrence of refractory angina (P = 0.002). The incidence of myocardial infarction was significantly reduced in the groups receiving aspirin (3 percent; P = 0.01), heparin (0.8 percent; P less than 0.001), and aspirin plus heparin (1.6 percent, P = 0.003), and no deaths occurred in these groups. There were too few deaths overall to permit evaluation of the effect of treatment on this end point. The combination of aspirin and heparin had no greater protective effect than heparin alone but was associated with slightly more serious bleeding (3.3 vs. 1.7 percent). We conclude that in the acute phase of unstable angina, either aspirin or heparin treatment is associated with a reduced incidence of myocardial infarction, and there is a trend favoring heparin over aspirin. Heparin treatment is also associated with a reduced incidence of refractory angina.

Bevantolol disposition in patients with hepatic cirrhosis.

Bevantolol is a new, cardioselective beta-receptor antagonist that undergoes extensive hepatic biotransformation. To evaluate changes in the disposition of bevantolol produced by liver disease, a single 200-mg oral dose of bevantolol was administered in ten patients who had hepatic cirrhosis and to ten age-matched controls. Cirrhotic patients had a greater plasma bevantolol half-life (6.9 +/- 4.0 hr, mean +/- SD) then did patients with normal liver function (2.8 +/- 1.1 hr, P less than .01), and they also had a longer duration of significant bevantolol-induced heart rate slowing (for 12 hours after oral dose in cirrhotics versus three hours for controls). On the other hand, the peak concentration after the oral dose and the magnitude of bradycardiac effect were similar for both groups. Plasma bevantolol half-life was more variable in cirrhotic patients than in controls. Some of this variability among cirrhotics was attributable to age, which was a significant determinant of bevantolol half-life in the cirrhotic (but not in the control) patient sample. These results indicate that hepatic cirrhosis alters the disposition of bevantolol and suggest that modifications in bevantolol dose should be considered when using this drug to treat patients with liver disease.

Diltiazem dose responses in sustained therapy for stable angina pectoris.

Fifteen patients with stable effort angina were treated for 2 weeks with each of diltiazem 120 mg, 240 mg, 360 mg or placebo in a double-blind crossover protocol. The frequency of angina was decreased from 7.2 +/- 1.1 (mean +/- S.D.) episodes per 2 weeks with placebo to 5.9 +/- 5.2 (N.S.), 4.1 +/- 1.1 (p less than 0.01) and 1.5 +/- 0.8 (p less than 0.005) with 120 mg, 240 mg and 360 mg diltiazem respectively. Similar decreases occurred in nitroglycerin consumption. Ten hours after the last dose of each treatment period, each patient was challenged with 120 mg diltiazem. Treadmill exercise testing was carried out at 0, 1, 2, 4 and 8 hours. Time to onset of angina and 0.1m V ST depression increased at 1 hour, was maximal at 2 and 4 hours, and remained elevated at 8 hours. Two weeks of sustained treatment with diltiazem did not alter the responses in treadmill performance to 120 mg diltiazem. Hemodynamic changes were consistent with decreased myocardial oxygen demand and increased myocardial oxygen supply by diltiazem. There was no significant attenuation of hemodynamic response with sustained therapy. Trough plasma levels of diltiazem at 10 hours following the last dose of sustained therapy varied in a dose-dependent manner. However, corresponding exercise tolerances were identical regardless of the plasma level. Peak drug levels at 4 hours following 120 mg aldo did not correlate with exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial exercise testing in patients with effort angina: variable tolerance, fixed threshold.

To investigate the frequency and mechanism of variable threshold angina, seven treadmill exercise tests were performed in each of 28 patients with stable effort angina and exercise-induced ST segment depression. Each patient had tests at 8 AM on 4 days within a 2 week period and on 1 of these days had three additional tests at 9 AM, 11 AM and 4 PM. Time to 1 mm ST depression increased from 277 +/- 172 seconds on day 1 to 319 +/- 186 seconds on day 2, 352 +/- 213 seconds on day 3 and 356 +/- 207 seconds on day 4 (p less than 0.05). Rate-pressure product at 1 mm ST depression remained constant. Similarly, time to 1 mm ST depression increased from 333 +/- 197 seconds at 8 AM to 371 +/- 201 seconds at 9 AM and to 401 +/- 207 seconds at 11 AM and decreased to 371 +/- 189 seconds at 4 PM (p less than 0.01). Again, rate-pressure product at 1 mm ST depression remained constant. The standard deviation for time to 1 mm ST depression, calculated as a percent of the mean for each patient's seven tests and then averaged for the entire group, was 22 +/- 11%. The standard deviation for rate-pressure product at 1 mm ST depression, calculated in the same way, was significantly less at 8.4 +/- 2.8% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A double blind placebo controlled crossover randomized trial of diltiazem in Raynaud's phenomenon.

We report the results of a double blind placebo controlled crossover randomized study of the calcium channel blocking agent diltiazem in the treatment of Raynaud's phenomenon. Our results showed a significant reduction in both frequency and duration of attacks of vasospasm in the hands. There was no detectable difference in response between patients with primary and those with secondary Raynaud's phenomenon. Our study supports the use of calcium channel blocking agents in the treatment of intermittent digital vasospasm.

Dose response effects of diltiazem on treadmill tolerance in chronic stable angina: a randomized double-blind, placebo-controlled crossover trial.

Sixteen patients with stable angina underwent treadmill exercise on 4 separate days prior to and at 1, 2, 4 and 8 hours following a single dose of 30 mg, 60 mg or 90 mg of diltiazem or identical placebo. Prolongation of exercise time to the onset of angina, 0.1 mV ST depression and to maximal exercise developed within 2 hours, peaked at 4 hours and persisted for 8 hours. Time to angina at control with placebo and 90 mg of diltiazem was 399 +/- 176 and 368 +/- 193 seconds respectively (X +/- SD) and 4 hours post drug was 474 +/- 216 and 635 +/- 209 seconds respectively (p less than 0.001). The pressure-rate product at angina 4 hours following 90 mg of drug was higher than after placebo (189 +/- 48 and 168 +/- 44 mmHg-1 X 10(-2) respectively). Heart rate increased (127 +/- 24 vs. 117 +/- 19 bpm) while systolic pressure was unchanged (147 +/- 17 and 142 +/- 21 mmHg). During submaximal exercise at a fixed work load, diltiazem, 90 mg, decreased heart rate from 114 +/- 14 to 97 +/- 18 bpm (p less than 0.005), systolic blood pressure from 148 +/- 19 to 135 +/- 18 mmHg (p less than 0.005) and rate-pressure product from 169 +/- 37 to 131 +/- 36 mmHg-1 X 10(-2) (p less than 0.005). Peak diltiazem plasma levels occurred at 4 hours, being 37 +/- 34, 74 +/- 67 and 106 +/- 68 ng/ml for 30, 60 and 90 mg respectively. Drug levels paralleled increased exercise tolerance when mean data were considered; however, correlation on an individual basis was poor.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerin-induced coronary vasoconstriction.

Nitroglycerin is routinely used during coronary angiography for its vasodilating effects. An unusual case is described in which nitroglycerin induced severe coronary artery spasm. Interpretation of coronary angiograms after nitroglycerin should be made with caution.