Paul E. Fenster

Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: The Promise Study

OBJECTIVES The aim of this study was to determine the prognostic significance of alterations in serum magnesium in patients with moderate to severe congestive heart failure. BACKGROUND Reductions in serum magnesium have been postulated to play a role in promoting arrhythmias and to have an adverse impact on survival in congestive heart failure, although support for this postulate is lacking. METHODS Serum magnesium levels were measured in 1,068 patients enrolled in a survival study of class III or IV heart failure at the time of double-blind randomization to milrinone, a phosphodiesterase inhibitor, or placebo. All patients received conventional therapy with digoxin, diuretic drugs and a converting enzyme inhibitor throughout the trial. The median follow-up period was 6.1 months (range 1 day to 20 months). RESULTS Patients with high serum magnesium (defined as > or = 1.9 mEq/liter, n = 242) were less likely to survive than were patients with a normal magnesium level (n = 627) (p < 0.05, risk ratio = 1.41). Patients with a low magnesium level (defined as < or = 1.5 mEq/liter, n = 199) had no difference in survival compared with the group with a normal magnesium level (p = NS, risk ratio = 0.89). At baseline, the patients in the high magnesium group were older and had more severe functional and renal impairment. An analysis after adjustment for these variables demonstrated no difference in survival comparing the low, normal and high magnesium groups. Although the three groups had no difference in frequency of ventricular tachycardia, length of longest run or frequency of ventricular premature beats on baseline Holter monitoring, the group with hypomagnesemia had more frequent ventricular couplets. CONCLUSIONS Serum magnesium does not appear to be an independent risk factor for either sudden death or death due to all causes in patients with moderate to severe heart failure. Hypomagnesemia is associated with an increase in the frequency of certain forms of ventricular ectopic activity, but this is not associated with an increase in clinical events. The higher mortality rate among the patients with hypermagnesemia is attributable to older age, more advanced heart failure and renal insufficiency.

Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation

Patients with atrial fibrillation and with documented aortic plaque who were assigned to adjusted-dose warfarin therapy (international normalized ratio 2.0 to 3.0) had an annual rate of cholesterol embolization of 0.7% (95% confidence interval [CI] 0.1% to 5.3%/patient-year). Warfarin-assigned patients with plaque had a lower rate of embolic events (5.9%/year; 95% CI 3.0 to 12) than those on combination low-dose warfarin (international normalized ratio <1.5) plus aspirin (17.3%/year; 95% CI 11 to 27; p = 0.01).

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.

Efficacy, Plasma Concentrations and Adverse Effects of A New Sustained Release Procainamide Preparation

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Effect of quinine on digoxin kinetics

Six subjects were evaluated for the effect of quinine, the 1‐isomer of quinidine, on digoxin pharmacokinetics. A 1.0‐mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half‐life (t½) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x̄ = 628.29 μg to x̄ = 772.52 μg (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quantitatively different, from quinidine.

Digitoxin-quinidine interaction: pharmacokinetic evaluation.

The effect of quinidine on digitoxin single-dose pharmacokinetics was evaluated in five healthy adults. Blood was collected for 3 weeks, and a complete urine collection was obtained for 4 days, after a single intravenous dose of digitoxin. The protocol was conducted once while each subject was taking oral quinidine, for 3 weeks, and then repeated 10 days after discontinuing quinidine treatment. Quinidine induced the following changes in digitoxin pharmacokinetics: Elimination half-life was prolonged from 174 +/- 25 to 261 +/- 58 hours (p less than 0.02); total body clearance decreased from 1.54 +/- 0.40 to 1.09 +/- 0.31 mL/h . kg (p less than 0.05); renal clearance decreased from 0.65 +/- 0.07 to 0.46 +/- 0.17 mL/h . kg (p less than 0.05). Digitoxin volume of distribution and protein binding were unaltered by quinidine. Quinidine caused a rise in serum digitoxin levels. Digitoxin total body clearance was decreased by quinidine to an extent comparable to that reported for digoxin; however, the mechanism of the interaction with the two digitalis glycosides may, in part, be different.

Digoxin-quinidine-spironolactone interaction

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0‐mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t½. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.

Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Pretreated With a Beta Blocker for Chronic Stable Angina Pectoris

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Mexiletine and quinidine in ventricular ectopy

The antidysrhythmic efficacy and tolerance of mexiletine and quinidine were compared in 26 ambulatory patients with chronic ventricular ectopy. Thirteen patients were treated with mexiletine and 13 with quinidine. The treatment groups were comparable in age and cardiac diagnoses, in frequency of untreated ventricular ectopy, in the presence of complex forms, and in previous drug failures. After two 24‐hr ambulatory ECG recordings, the patients were treated according to a double‐blind, dose‐ranging protocol. Efficacy was defined as reduction in ventricular ectopic frequency by at least 70% in a comparison of two 24‐hr ambulatory ECG recordings after drug with the two pretreatment recordings. Suppression of ventricular ectopic frequency by at least 70% was achieved in seven mexiletine‐treated patients and eight quinidine‐treated patients. Neither drug consistently abolished complex forms of ectopy. The incidence of adverse effects was of the same order in the two groups. We conclude that mexiletine is as effective as quinidine in the suppression of ventricular ectopy. Use of both drugs is limited by adverse effects.

Clinical Implications of the Blood Pressure Response to Exercise

The blood pressure response during exercise testing is useful in evaluating cardiac status. Failure of the systolic pressure to rise with increases in work load, or a hypotensive response, are signs of significant heart disease. In the patient with coronary artery disease, the maximal systolic pressure achieved during exercise correlates with survival. Exertional hypotension in coronary artery disease is an insensitive, but highly specific, indicator of three-vessel disease or significant left ventricular dysfunction.