Fibrinolytic agents for the management of ST-segment elevation myocardial infarction.

Rapid reperfusion is the key treatment goal in patients with ST-segment elevation myocardial infarction (STEMI). The American College of Cardiology-American Heart Association (ACC-AHA) 2004 guidelines for the management of STEMI include recommendations for pharmacologic reperfusion with use of fibrinolytic agents. Fibrinolytic agents are the preferred pharmacologic class for the management of STEMI because of their ability to achieve reperfusion and to restore blood flow when administered within 12 hours of symptom onset. Four fibrinolytic agents are approved for the treatment of STEMI in the United States-streptokinase, alteplase, reteplase, and tenecteplase. Several clinical trials have demonstrated the beneficial effects of these therapies in reducing mortality rates in patients with suspected acute myocardial infarction. Alteplase is administered as an intravenous infusion. However, the relatively long half-lives of reteplase and tenecteplase enable bolus administration, which may be more convenient and less time consuming. Reteplase is administered as a double bolus, and dosing does not depend on the patient's weight; tenecteplase is administered as a single bolus, and dosing is weight based. Adherence to the ACC-AHA guidelines, as well as knowledge about the available fibrinolytic agents, is essential for physicians and pharmacists to make informed decisions regarding appropriate pharmacologic reperfusion strategies.

Pharmacogenomics of renin angiotensin system inhibitors in coronary artery disease.

Renin Angiotensin System (RAS) inhibitors comprise some of the most commonly used medications in coronary artery disease (CAD) and its related syndromes. Unfortunately, significant inter-patient variability seems likely in response to these agents; of which, the influence of genetic determinants is of interest. This review summarizes the available RAS inhibitor pharmacogenomic studies which have evaluated RAS polymorphisms that either elucidate mechanism via surrogate endpoint measurements, or predict efficacy via clinical outcomes in CAD related syndromes.Regardless of the endpoint, none of the RAS genotypes conclusively predicts efficacy of RAS inhibitors. In fact, the results of the pharmacogenomic studies were often in direct conflict with one another. Varied results appear due to methodological limitations (e.g., inadequate study power, genotyping error, methods of endpoint measurement), study conceptualization (e.g., overestimating the contribution of polymorphism to disease, lack of haplotype approach), and differences between studies (e.g., genotype frequency, study subject characteristics, the specific medication and dose used). Thus investigators should consider the various methodological limitations to improve upon the current approach to RAS inhibitor pharmacogenomic research in the vast CAD population.

Evaluation of angiotensin converting enzyme (ACE)-like activity of acellular hemoglobin.

Despite the tremendous progress in research on hemoglobin (Hb) cellular and molecular responses, the current understanding of Hb's overall intrinsic toxicity is still limited. The complete mechanism of Hb-induced vasoconstriction has not yet been established, particularly the involvement of the renin-angiotensin system (RAS). Some studies emphasized that Hb may augment the vascular responsiveness to angiotensin (Ang)-II. It was also reported that Hb, as well as Ang-II, influences the synthesis of 8-iso prostaglandin F2 alpha, which has an impact on renal flow and possibly RAS. Hb in the presence of H(2)O(2) gains enzymatic activity. Thus, it is possible that Hb directly and/or indirectly can activate RAS. In this study, we monitored the effect of ferrous- and ferryl-Hb, and H(2)O(2) alone, on conversion of Ang-I to its active metabolites. The structural and immunological identity of the resulting products were evaluated by reversed phase C-18 HPLC and ELISA, respectively. Additionally, ACE-like activity of Hbs was measured spectrophotometrically by determining their ability to react with the ACE substrate, the synthetic tripeptide N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine. Results indicate that while ferrous-Hb can serve as a receptor for Ang-I, its ferryl form possesses ACE-like activity, being able to convert, within minutes, Ang-I to Ang-II, Ang-III, Ang-IV, Ang (1-7) and other unresolved fragments. H(2)O(2) itself had a very limited hydrolyzing effect on Ang-I. Based on this study, it can be concluded that ACE-like activity of Hb with rapid formation of active angiotensins may be a contributor to the still unexplained vasoconstrictive response observed immediately after Hb administration.

Role of free hemoglobin in 8-iso prostaglandin F2-alpha synthesis in chronic renal failure and its impact on CD163-Hb scavenger receptor and on coronary artery endothelium.

Free hemoglobin (Hb) during autoxidation increases 8-iso-prostaglandin-F2-alpha (8-isoprostane) formation in vitro. Because 8-isoprostane and plasma Hb are elevated in chronic renal failure (CRF), we evaluated the role of Hb in this isoprostane synthesis in vivo. By monitoring correlations between Hb, haptoglobin (Hp), CD163-Hb-scavenger receptor, and 8-isoprostane that is known to induce CD163 shedding, we examined whether 8-isoprostane blocks Hb catabolism in CRF. Additionally, by studying the effect of 8-isoprostane on human coronary artery endothelium (HCAEC) in vitro and its impact on intercellular adhesion molecule-1 (ICAM-1) in vivo, we tested its role in promotion of cardiovascular events in CRF. Twenty-two never-dialyzed CRF patients and 18 control patients were screened for renal function, plasma and urine 8-isoprostane, and plasma Hb, Hp, thiobarbituric-acid-reactants (TBARS), C-reactive-protein (CRP), and soluble (s) ICAM-1 and sCD163. HCAEC exposed to 8-isoprostane were tested for ICAM-1 and apoptosis. In CRF, urine 8-isoprostane was significantly elevated and correlated with free-Hb and TBARS. The increased free-Hb, Hp, and sCD163 in CRF suggested 8-isoprostane-mediated suppression of Hb catabolism through CD163 receptor shedding. 8-Isoprostane enhanced ICAM-1 expression and apoptosis in HCAEC. CRF patients showed elevated sICAM-1. In conclusion, free-Hb, via 8-isoprostane, paradoxically blocks its own catabolism. Free-Hb and/or 8-isoprostane may intensify cardiovascular events in CRF.

Lack of effect on coronary atherosclerotic disease biomarkers with modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type-1 receptor blocker, and the combination.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, used alone or in combination, have been shown to improve outcomes in certain populations, primarily when administered in high doses. For stable coronary atherosclerotic disease, however, the relative physiologic effect of these therapies is unclear. Furthermore, because of the notorious subtarget dosing of such agents in clinical practice, we explored the influence of a modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blockers, and the combination on common biologic markers of coronary atherosclerotic disease. METHODS: This randomized, cross-over study enrolled stable coronary atherosclerotic disease patients (n=20), each receiving three treatments: candesartan 16 mg daily, ramipril 5 mg daily, and candesartan 8 mg plus ramipril 2.5 mg daily. Treatments were administered for 2 weeks with a 2-week washout. Blood samples were collected before and after each treatment. Markers of endothelial function, fibrinolytic balance, and vascular inflammation were measured. RESULTS: No significant differences were observed in the pretreatment concentrations of angiotensin-converting enzyme or of any measured biologic marker. Relative to pretreatment levels, candesartan alone was the only therapy to exhibit an action on any measured biomarker--a trend toward increased nitric oxide concentrations (P=0.054). Otherwise, no effects on biologic markers were observed with the treatments. CONCLUSION: This study of various methods of the renin-angiotensin system inhibition in stable coronary atherosclerotic disease patients demonstrates negligible effects of a modest dosing of ramipril and the combination of ramipril plus candesartan on common biologic markers of coronary atherosclerotic disease. Candesartan at modest doses may favorably influence endothelial function. Overall, however, the results indicate that the commonly practiced subtarget dosing of such treatments provides little, if any, benefit pertaining to key physiologic components of coronary atherosclerotic disease.

Effects of three fluoroquinolones on QT analysis after standard treatment courses.

BACKGROUND: Fluoroquinolone (FQ) agents have been speculated to influence the risk of Torsades de pointes (Tdp). Methods of evaluating this risk are varied and not systematic. QTc interval (QTc) prolongation is the most commonly used marker of Tdp, but has questionable utility. QT dispersion (QTd) may be a more selective marker of Tdp. No assessment of QTd for FQs has been reported. The current study evaluates the effects of three commonly prescribed FQs by comprehensive QT analysis. METHODS: In an open-label crossover study, 13 healthy participants received 3 treatments in random order: ciprofloxacin 500 mg twice daily, levofloxacin 500 mg once daily, and moxifloxacin 400 mg once daily. Each treatment was given for 7 days with a 1-week washout period. Twelve-lead electrocardiographic measurements were performed prior to the first dose, 2 hours after the first dose, and following the 7-day medication course. QTc prolongation was determined by measurement of lead II, and QTd from the difference between the maximum and minimum QTc intervals among the 12 leads. The data were analyzed using Friedman ANOVA, with the Wilcoxon signed rank test post hoc analysis, with P < 0.05 significance. RESULTS AND CONCLUSIONS: No difference was seen in baseline QTc (P = 0.48) or QTd (P = 0.92). Following 7 days of moxifloxacin, the QTc was prolonged by 6 ms relative to baseline (408 ms, P = 0.022), and 11 ms from the 2-hour measurement (403 ms, P = 0.003). Ciprofloxacin and levofloxacin had no effect on QTc, and no FQ changed the QTd. Within our study population, ciprofloxacin and levofloxacin did not display an increased risk for Tdp. Moxifloxacin, while showing QTc prolongation, did not affect QTd, and an increased Tdp risk is questionable.

The use of angiotensin receptor blockers in the treatment of chronic heart failure.

Angiotensin receptor blockers (ARBs) have a pharmacological role in the treatment of heart failure through their blockade of the effects of angiotensin II. ARBs, however, lack the potential benefits of inhibiting the breakdown of bradykinin that is seen with ACE-Is. Historically, the medical literature assessing ARBs in the treatment of chronic heart failure have been short in duration and primarily focused on surrogate markers of disease severity. Recent, well-designed clinical trials have shed new light on the potential roles of ARBs in the treatment of chronic heart failure and their effects on mortality in this patient population. In comparison to captopril, losartan has been shown to have similar benefits in cardiovascular mortality and morbidity. In patients with systolic dysfunction who are intolerant to ACE-Is, candesartan has been shown to reduce cardiovascular mortality and hospital admissions for heart failure. In combination with ACE-Is, candesartan and valsartan have been shown to improve heart failure morbidity and, with candesartan, reduced cardiovascular mortality in those with systolic dysfunction. These 2 trials show conflicting mortality information regarding the use of triple therapy with ACE-Is, ARBs, and beta-blockers for systolic dysfunction. In patients with heart failure but preserved systolic dysfunction, candesartan showed no effects on mortality and only modest effects on morbidity.

Potential in vitro interaction between tenecteplase and unfractionated heparin.

STUDY OBJECTIVE: To explore the potential of a direct drug interaction between unfractionated heparin (UFH) and tenecteplase that lowers the pharmacologic propensity of UFH to prolong the activated partial thromboplastin time (aPTT). DESIGN: In vitro experiment. SETTING: Texas Tech University School of Pharmacy, with sample analysis performed at an independent, contract laboratory. Samples. Blood samples collected from healthy volunteers. INTERVENTION: Three separate in vitro experiments were conducted to explore the relative influence of various thrombolytic agents with and without UFH on aPTT prolongation. In each experiment, blood from healthy volunteers (12 for each experiment) was treated with different concentrations and combinations of tenecteplase and UFH. MEASUREMENTS AND MAIN RESULTS: When the effects of tenecteplase plus UFH versus UFH alone on aPTT prolongation were compared, each experiment demonstrated attenuation of aPTT with the combination versus UFH alone. In contrast, findings for other thrombolytic agents combined with UFH demonstrate elevation of the aPTT compared with UFH alone. CONCLUSION: The results indicate a possible drug interaction between tenecteplase and UFH, with tenecteplase attenuating the intensity of anticoagulation of UFH in vitro. Further investigation into this possible interaction is warranted in the clinical setting.

Comparison of effects of quinapril versus enalapril on vasoactive substances following acute myocardial infarction.

The true existence of a class effect in angiotensin-converting enzyme (ACE) inhibitors remains controversial. The present trial explored the effects of 2 ACE inhibitors after acute myocardial infarction and found no difference in endothelin-1 production but a greater increase in the production of total nitric oxide with quinapril than with enalapril.

Cost effectiveness of ibutilide with prophylactic magnesium in the treatment of atrial fibrillation.

BACKGROUND: In the Treatment with Ibutilide and Magnesium Evaluation (TIME) study, a retrospective multicentre cohort trial, prophylactic magnesium was found to improve the antiarrhythmic efficacy of ibutilide as demonstrated by an increase in the rate of successful chemical conversion and reduction in the need for direct current cardioversion (DCC). OBJECTIVE: The primary objective of this piggyback cost-effectiveness analysis of the TIME study was to compare the cost per successful conversion of atrial fibrillation (AF) for ibutilide in the presence and absence of magnesium prophylaxis. A secondary objective was to determine whether specific factors predict costs in the conversion of AF. METHOD: The study was conducted from the US hospital-payer perspective. Direct medical costs (USD, 2002 values) including drugs, intravenous admixture and administration, DCC, electrocardiographs and physicians' fees were obtained directly from the provider. Nonparametric bootstrapping was conducted to calculate confidence intervals for the incremental cost-effectiveness ratios. One-way sensitivity analysis was conducted varying efficacy, and drug, hospital and physician costs. Multivariate analysis was conducted to determine whether specific baseline factors were predictors of total cost. RESULTS: Total costs per patient were lower in the ibutilide plus magnesium group compared with ibutilide alone (USD1075 vs USD1201); however, the difference was not statistically significant (p = 0.116). Patients receiving ibutilide plus magnesium had lower DCC costs compared with those receiving ibutilide alone (USD261 vs USD399; p = 0.036), but higher magnesium-associated costs (USD0.50 vs USD0; p < 0.001). Bootstrapping revealed that the ibutilide plus magnesium strategy would result in lower costs and greater efficacy 93.4% of the time. These results remained robust to changes in both cost and efficacy. No baseline factors were found to be independent predictors of total costs. CONCLUSION: Our data suggest that adding prophylactic magnesium to ibutilide may be cost effective, from a US hospital-payer perspective, for the acute conversion of patients in AF or flutter compared with ibutilide alone.

Exploring the effects of ACE inhibitor tissue penetration on vascular inflammation following acute myocardial infarction.

BACKGROUND: Questions remain as to the existence of a class effect amongst angiotensin converting enzyme (ACE) inhibitors, and some literature suggests that pharmacological effects and outcomes may be determined by an ACE inhibitor's propensity to penetrate and inhibit the ACE enzyme at the vascular tissue level. Because vascular inflammation contributes to adverse outcomes following acute myocardial infarction (AMI), and angiotensin II influences inflammation at the vascular level, we hypothesized that high-tissue penetrating ACE inhibitors would provide more favorable effects on C-reactive protein (CRP) after AMI compared to low-tissue penetrating ACE inhibitors. METHODS AND RESULTS: In a randomized open-label trial, patients received the high-tissue penetrating quinapril (n = 15) or low-tissue penetrating enalapril (n = 15) following AMI. C-reactive protein was measured at baseline and periodically over 14 days following drug initiation. All baseline characteristics and blood pressure response to treatment between groups were equivalent. Prior to initiating study medication, CRP concentrations (mg/g) were similar between enalapril and quinapril (0.327 +/- 0.571 versus 0.273 +/- 0.380, respectively, p = 0.77). The percent magnitude of change in CRP concentrations favored quinapril at all time points, starting 12 h after treatment initiation. When characterizing CRP production during treatments, the time courses were significantly different and demonstrated lower CRP concentrations with quinapril (p = 0.0107). CONCLUSIONS: Overall, this investigation into the importance of ACE inhibitor tissue penetration on a common marker of vascular inflammation, suggests a potential vascular anti-inflammatory benefit with a more highly tissue penetrating ACE inhibitor following AMI. Further investigation into the true pharmacological similarities and differences amongst this class of drugs is warranted.

Preventing contrast nephropathy: what is the best strategy? A review of the literature.

Patients receiving radiocontrast for diagnostic and interventional procedures are at risk for developing contrast nephropathy (CN). In fact, radiocontrast nephropathy is currently the third leading cause of hospital-acquired renal failure. Understanding that CN has been associated with increased length of hospitalization and mortality, determining the best prevention strategy is of utmost importance. Patients at the greatest risk for developing acute renal failure are patients with diabetes and underlying renal insufficiency. Several therapies have been investigated for the prevention of CN; unfortunately, very few have shown a consistent benefit. Therapies that have been studied include saline hydration, N-acetylcysteine (NAC), theophylline, calcium channel blockers, diuretics, dopamine, endothelin receptor antagonists, atrial natriuretic peptide, angiotensin-converting enzyme inhibitors, and prostaglandin E-1. Using adequate hydration, using low-osmolar dyes, and minimizing the dose of contrast have all been shown to be effective in reducing CN and are considered the standard of care. While trials with many pharmacologic agents have produced conflicting results, intervention with NAC has also been promising. This article reviews the pathophysiology, risk factors, and therapies that are currently available for the prevention of CN.

Questioning a class effect: does ACE inhibitor tissue penetration influence the degree of fibrinolytic balance alteration following an acute myocardial infarction?

There is a common belief in a class effect among angiotensin-converting enzyme (ACE) inhibitors. This is unsubstantiated for acute myocardial infarction (AMI). Because vascular tissue is a source of the endogenous fibrinolytic markers, and ACE inhibition in vascular tissue favorably influences the fibrinolytic system, the authors hypothesized that a high-tissue-penetrating ACE inhibitor would provide a more favorable reduction in plasminogen activator inhibitor-1 (PAI-1) and an increase in tissue plasminogen activator (t-PA) after AMI compared to a low-tissue-penetrating ACE inhibitor. In a randomized open-label trial, patients received the high-tissue-penetrating quinapril (n = 15) or low-tissue-penetrating enalapril (n = 15) immediately following an AMI. PAI-1 and t-PA antigen (ng/mL) were measured at baseline and through 14 days of treatment. There was no difference in baseline PAI-1 or t-PA antigen between treatments. PAI-1 antigen trended toward being lower with quinapril versus enalapril on day 1 (24.44 +/- 14.96 vs. 36.94 +/- 19.49, respectively, p = 0.059) and was significantly lower on day 3 (17.32 +/- 9.57 vs. 27.49 +/- 9.61, respectively, p = 0.009). Analysis of PAI-1 antigen over time by two-factor ANOVA with replication found significantly lower concentrations of PAI-1 antigen over the entire treatment period with quinapril versus enalapril (p < 0.003). This investigation of ACE inhibitor tissue-penetrating influence on markers of reinfarction risk suggests there may be a greater early reduction in PAI-1 with a more highly tissue-penetrating ACE inhibitor.

Impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation or flutter.

The impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation and flutter to normal sinus rhythm was studied. In this multicenter cohort study, all patients in three large, tertiary care centers who received ibutilide for acute chemical conversion of atrial fibrillation or flutter from August 1996 through December 2001 were identified through pharmacy or billing records. Patients who did not receive magnesium before or during ibutilide therapy served as the control group, while those who received magnesium less than two hours before or during ibutilide administration served as the study group. The rate of administration of direct-current cardioversion (DCC) and the occurrence of ventricular arrhythmia were compared between those who did and did not receive magnesium. The rates of successful cardioversion were also assessed. Categorical data were analyzed using chi-square analysis or Fisher's exact test. Demographic data were analyzed using Student's t test. The medical records of 321 patients were analyzed. Successful chemical cardioversion in the study group was approximately 19% higher than in those who did not receive magnesium (p = 0.040). The use of DCC in the group who received magnesium was reduced by approximately 34% (p = 0.045). The conversion rate of atrial fibrillation or flutter with ibutilide was enhanced by magnesium administration (p = 0.040), and the rate of administration of DCC was reduced (p = 0.045) in patients who received magnesium. There was a nonsignificant reduction in the occurrence of ventricular arrhythmias (p = 0.533). The efficacy of ibutilide was enhanced by concomitant administration with intravenous magnesium.

Pharmacologic blockade of the renin-angiotensin system: vascular benefits beyond commonly understood pharmacologic actions.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin-angiotensin system--a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor-1, endothelin-1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule-1 and C-reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.

Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide.

STUDY OBJECTIVE: To determine the effect of intravenous magnesium sulfate on the QT and QTc intervals in patients receiving ibutilide for immediate chemical cardioversion of atrial flutter or fibrillation. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Hospital cardiology unit. PATIENTS: Twenty patients (mean age 72 +/- 14 yrs) with atrial fibrillation (12 patients) or atrial flutter (8 patients) who were scheduled to receive ibutilide. INTERVENTION: After determining that the patients' baseline QTc intervals were less than 440 msec and baseline serum magnesium levels were within normal limits (mean 2.1 +/- 0.29 mg/dl), the patients were randomly assigned to receive either a 10-minute infusion of magnesium sulfate 2 g in 50 ml of 0.9% sodium chloride or placebo immediately before ibutilide therapy. An additional 2 g of intravenous magnesium sulfate or placebo was given over 1 hour, 10 minutes after the first dose of ibutilide. MEASUREMENTS AND MAIN RESULTS: QT interval duration was measured manually in all 12 leads by using a 0.5-mm-scale precision ruler and magnifying lens. The QT interval increased 29% from baseline at 30 minutes after ibutilide therapy in the placebo group (p=0.007), but no significant change from baseline occurred in the magnesium sulfate group. The 30-minute QTc interval in the placebo group was 18% higher than the baseline value (p=0.01) but did not change significantly in the magnesium sulfate group. QTc changes from baseline were greater in the placebo group than in the magnesium sulfate group at 30 minutes (75 vs 19 msec, respectively, p=0.04). Magnesium sulfate reduced the risk of an ibutilide-induced QTc interval increase of greater than 30 msec or greater than 60 msec and reduced the risk of a QTc interval value of more than 500 msec by 65%, 60%, and 68%, respectively (p=0.07, p=0.175, and p=0.160). CONCLUSIONS: Prophylactic administration of intravenous magnesium sulfate prevents increases in the QT and QTc interval 30 minutes after the last infusion of ibutilide.

Plasminogen activator inhibitor-1: physiologic role, regulation, and the influence of common pharmacologic agents.

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of endogenous thrombolysis, thereby promoting thrombosis. PAI-1 is also a primary contributor to the development and recurrence of acute myocardial infarction. The renin angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and estrogen all influence the fibrinolytic system and PAI-1 in particular. Available data strongly suggest that angiotensin-converting enzyme (ACE) inhibitors and hormone replacement therapy with estrogen beneficially reduce PAI-1 production. Metformin, an agent commonly used for non-insulin-dependent diabetes mellitus (NIDDM), appears to favorably decrease PAI-1 production in NIDDM patients but not nondiabetic patients. Among the cholesterol-lowering statins, clinical literature evaluating pravastatin provides the most compelling data to support this agent's favorable effect on PAI-1. Other available statins either have not displayed an effect on PAI-1 or do not have clear data to conclusively define their effects on the fibrinolytic system.

A comparison of two individual amiodarone regimens to placebo in open heart surgery patients.

BACKGROUND: This study compares the ability of two oral amiodarone regimens to reduce the risk of atrial fibrillation (AF) as compared with the placebo among elderly open heart surgery (OHS) patients receiving beta blockade. METHODS: This is a randomized, double-blinded, placebo-controlled trial of 220 patients undergoing OHS. Patients (average age, 73 years) received 7 g of oral amiodarone more than 10 days starting 5 days before OHS (slow load; n = 56), a 6 g oral amiodarone regimen more than 6 days starting 1 day before OHS (fast load; n = 64), or matching placebo in one of the two previously mentioned regimens (n = 100). RESULTS: Patients receiving the slow load amiodarone regimen had a significant reduction in the risk of AF (48.4%; p = 0.013), AF lasting more than 24 hours (76.5%; p = 0.003), symptomatic AF (90.0%; p = 0.002), and recurrent AF (64.5%; p = 0.025) as compared with the placebo. Patients receiving the fast load amiodarone regimen had significant reductions in the risk of AF lasting more than 24 hours (52.6%; p = 0.038) and symptomatic AF (65.0%; p = 0.024), but the incidence of any AF or any recurrence of AF only showed a trend toward significance (34.0% and 45.5%; p = 0.054 and 0.09, respectively). CONCLUSIONS: Oral amiodarone in a slow loading regimen provides significant suppression of all AF factors and can be used when a patient has started it at least 5 days before OHS. If a patient has less than 5 days before OHS, the fast loading regimen is an efficacious alternative as it provides significant benefits in preventing AF from lasting more than 24 hours and for preventing symptomatic AF. Both regimens were well tolerated and safe in elderly patients receiving beta blockade according to the hospital's standard protocol.

An economic analysis of amiodarone versus placebo for the prevention of atrial fibrillation after open heart surgery.

STUDY OBJECTIVE: To determine if the additional costs of oral amiodarone in patients undergoing open heart surgery would be offset by reductions in the frequency of atrial fibrillation. DESIGN: Piggyback cost analysis of the data from a randomized, double-blind, placebo-controlled trial. SETTING: Urban academic hospital. PATIENTS: Two hundred twenty elderly patients (> or = 60 yrs old) undergoing open heart surgery. INTERVENTION: Hospital costs of open heart surgery in patients given amiodarone for the prevention of atrial fibrillation and in prespecified subgroups were compared with those for patients given placebo (i.e., standard care with beta-blockers alone). MEASUREMENTS AND MAIN RESULTS: Total hospital costs incurred were $15,565 +/- $9832 and $16,126 +/- $8043 in the amiodarone and placebo groups, respectively (p=0.12). General ward, intensive care unit, operating room, pharmacy, and costs in all other departments were similar between the groups (p>0.05 for all comparisons). Because costs were similar but amiodarone was more effective than placebo, amiodarone was cost-effective compared with placebo. Amiodarone remained cost-effective compared with placebo regardless of the following subgroup characteristics: rapid or slow loading strategy, no history of atrial fibrillation or heart failure, age older than 70 years, and no tolerance to preoperative beta-blockers. Moreover, in the one-way sensitivity analysis, the findings remained robust to changes in effectiveness and cost of amiodarone. CONCLUSION: Routine prophylaxis with amiodarone is cost-effective compared with placebo. Future studies should examine the cost-effectiveness of selective prophylaxis, and primary cost-effectiveness studies should be conducted to validate these findings.