Bupropion For Smoking Cessation Research Articles

Efficacy of varenicline versus bupropion for smoking cessation: A systematic review and meta-analysis of randomized controlled trials.

According to the Global Burden of Disease (GBD) Study conducted in 2019, smoking tobacco leads to over 8 million deaths each year. Hence, it is crucial to identify optimal smoking cessation therapy. To compare the efficacy of varenicline versus bupropion for smoking cessation by performing a meta-analysis of randomized controlled trials (RCTs). Protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The Patient intervention comparison outcome time (PICOT) format is used in the study. Patients having nicotine use disorder treated with varenicline or bupropion were included, and the continuous abstinence rate (CAR) was assessed at 12, 24, and 52 weeks. The PubMed and Google Scholar databases were systematically searched, and after the screening, RCTs involving a comparison of varenicline and bupropion in smoking cessation were included. We performed a meta-analysis of three RCTs (10110 patients) by RevMan 5.4.1 statistical software to determine the efficacy of varenicline compared with bupropion in smoking cessation. The CAR at 9- to 12-week follow-up of varenicline is superior to bupropion (OR = 1.79, CI range: 1.59-2.02, P < 0.001). Similarly, the CAR of varenicline is superior to bupropion for weeks 9-24 (1.51, 1.32 to 1.72) and weeks 9-52 (1.60, 1.22 to 2.12), suggesting the absolute advantage of varenicline over bupropion for smoking cessation in terms of efficacy. Both varenicline and bupropion are efficacious therapies for smoking cessation. Compared with bupropion, varenicline can significantly improve the CAR at the end of treatment, at 24 weeks, and at 52 weeks of follow-up.

Bupropion for smoking cessation in adolescents.

An adolescent who smokes regularly came to my clinic for help quitting. While I am aware that bupropion is a first-line medication for smoking cessation among adults, is it effective and safe for adolescents? Most adolescent smokers in Canada would like to quit, but more than 90% of the attempts are unsuccessful. Bupropion appears to be more effective than other pharmacologic options in improving abstinence among adolescents who smoke in the short term; however, it is not approved by Health Canada for those younger than 18 years. Bupropion has not been associated with an increase in adverse events in smoking cessation trials. More research is needed on the long-term effectiveness and safety of bupropion in this population.

Combination therapy of varenicline and bupropion in smoking cessation: A meta-analysis of the randomized controlled trials

BackgroundThe effects of the combination therapy of varenicline and bupropion in smoking cessation are still controversial. MethodsDatabases including PubMed, EMBASE, Cochrane Library and Web of Science were scanned without time and language limitation. Subgroup analysis was performed to assess the effect of combination therapy in smokers with different level of nicotine dependence and cigarette consumption. ResultsFour randomized controlled trials involving a total of 1230 smokers were included. Compared with varenicline monotherapy, combination treatment with varenicline and bupropion could significantly improve the abstinence rate at the end of treatment (RR 1.153, 95% CI 1.019 to 1.305, P=0.024). The benefit existed at 6months follow-up (RR 1.231, 95% CI 1.017 to 1.490, P=0.033), disappeared at 12months follow-up (RR 1.130, 95% CI 0.894 to 1.428, P=0.305), and mainly concentrated in highly dependent smokers (RR 1.631, 95% CI 1.290 to 2.061, P<0.001) and heavy smokers (RR 1.515, 95% CI 1.226 to 1.873, P<0.001) rather than individuals with low nicotine dependence (RR 0.989, 95% CI 0.815 to 1.199, P=0.907) or low cigarette consumption (RR 0.985, 95% CI 0.800 to 1.212, P=0.252). For safety outcomes, the combination treatment was associated with more anxiety (RR 1.717, 95% CI 1.176 to 2.505, P=0.005) and insomnia (RR 1.268, 95% CI 1.076 to 1.494, P=0.005) symptoms compared with varenicline monotherapy. ConclusionCompared with varenicline monotherapy, combination treatment with varenicline and bupropion can significantly improve the abstinence rate at the end of treatment and 6months follow-up, mainly in highly dependent smokers and heavy smokers.

An RCT with the combination of varenicline and bupropion for smoking cessation: clinical implications for front line use.

Despite the availability of several efficacious smoking cessation treatments, fewer than 25% of smokers who quit remain abstinent 1year post-treatment. This study aimed to determine if varenicline and bupropion combination treatment would result in higher abstinence rates than varenicline alone. A double-blind, randomized, parallel-group smoking cessation clinical trial in which participants were exposed to 12weeks of treatment and followed for 12months. Hospital-based out-patient clinic in Texas, USA specializing in cancer prevention. A total of 385 community smokers (58.44% male) who smoked 1 pack of cigarettes/day [mean=19.66 cigarettes/day, standard deviation (SD)=9.45]; had average carbon monoxide (CO) of 26.43parts per million (SD=13.74); and were moderately dependent (Fagerström Test for Cigarette Dependence =4.79; SD=2.07). Smokers were randomized in a 3:1 (active: Placebo) ratio to 12weeks of treatment as follows: placebo (n=56), varenicline (Var; n=166), and varenicline + bupropion (Combo; n=163). A priori primary outcome: prolonged abstinence at 12months. 7-day point prevalence abstinence and continuous abstinence; all abstinence measures at end of treatment and 6-month follow-ups. Intention-to-treat analysis: the Combo group (n=163) failed to demonstrate superiority to the Var group (n=166) for prolonged abstinence at 12months [odds ratio (OR)=0.91, 95% confidence interval (CI)=0.50-1.64], supported by Bayes factor=0.06. Both the Var (OR=6.66, 95% CI=1.61-59.27) and Combo groups (OR=6.06, 95% CI=1.45-54.09) demonstrated superiority to the Placebo group (n=56; score=8.38, P<0.016). The addition of bupropion to varenicline treatment does not appear to increase smoking abstinence rates above that of varenicline alone. The findings support previous research showing a consistently favorable effect of both varenicline and the combination of varenicline and bupropion on smoking cessation compared with placebo.

Managing cardiovascular disease risk in patients with severe mental illness

Managing cardiovascular disease risk in patients with severe mental illness

21P - The efficacy of combination therapy with varenicline and bupropion for smoking cessation

21P - The efficacy of combination therapy with varenicline and bupropion for smoking cessation

A comparison of the efficacy of varenicline and bupropion and an evaluation of the effect of the medications in the context of the smoking cessation programme

BackgroundWithin the context of the support program for smoking cessation, initiated by the Turkish Ministry of Health in 2011, those who present at ‘smoking cessation’ centres and are found to be suitable for pharmacological treatment are given varenicline and bupropion free of charge. As the smoking cessation programme is centralized, the selection of the medication is made randomly to provide a fixed distribution rate. The aim of this study was to evaluate the efficacy of both varenicline and bupropion in smoking cessation and to evaluate the effect of the smoking cessation programme.MethodsA total of 405 individuals who met the study criteria were included in the study. Smoking habits and degree of dependence were determined in all the participants with the Fagerstrom test for nicotine dependence (FTND) and bupropion or varenicline therapy was initiated in those who were eligible. Patients were followed up at 15 days then at 1, 2, 3, 6 and 12 months after smoking cessation. A level of CO < 5 ppm and ‘point prevalence abstinence’ were used as the criteria of success for smoking cessation and this evaluation showed the non-smoking status in the previous 7 days.ResultsThe mean age of the participants was 35.19 ± 7.73 years and 82.8% (n = 334) were male. Of the participants, 60.2% (n = 244) were given varenicline and 39.8% (n = 161) bupropion. The mean FTND and package/year was not significantly different between the groups. The rates of success in the 1st and 2nd weeks, and 1st, 3rd and 6th months were significantly higher in the varenicline group than in the bupropion group (p < 0.05). At the end of one year, the rate of smoking cessation was determined as 13.9% (n = 34) in the varenicline group and 6.2% (n = 10) in the bupropion gruop. The difference was statistically significant (p = 0.015). At the end of 1 year when the previous 7 days smoking status was evaluated with the ‘point prevalence abstinence’ measurement as the success criteria, success rates were 20.5% with varenicline and 18.6% with bupropion and the difference was not significant (p = 0.646). The individuals who used the medications for 45 days or longer were more successful in smoking cessation (p < 0.001). The most common reasons given for discontinuing the medication were the side-effects (31.5%). No significant difference was determined between the groups in respect of the side-effects observed.ConclusionsAlthough the rates of smoking cessation in all the other control points were higher with varenicline than with bupropion, no significant difference was found between the success rates of varenicline and bupropion used in smoking cessation based on the last 7 days at the end of one year. Those who used the medications for 45 days or longer were more successful in smoking cessation.

Sex Differences in Smoking Cessation Pharmacotherapy Comparative Efficacy: A Network Meta-analysis.

Converging clinical and biological evidence suggest sex is an important factor when selecting a pharmacological intervention for smoking cessation. The current investigation used network meta-analyses to estimate sex differences in the comparative efficacy of transdermal nicotine (TN), varenicline, and sustained release (SR) bupropion for smoking cessation. Systematically searched previously published reviews and databases (Medline, PsycINFO, Embase) of randomized, double-blind, placebo-controlled trials of bupropion-SR, TN, and varenicline for cigarette smoking cessation in primary care/general community samples were included. Thirty-two studies met all criteria and 28 (88%) were included in the final analyses, representing 14 389 smokers (51% female). Results of the full sample (women and men combined) mirrored those from a Cochrane Tobacco Addiction Group network meta-analysis of smoking cessation pharmacotherapy, showing VAR>TN=BUP. All medications improved quit rates over placebo for both women and men. Relative to placebo, varenicline efficacy was similar for women and men. Significant sex differences were evident when comparing varenicline versus TN and varenicline versus bupropion. For women, varenicline was more efficacious than TN (RR = 1.41; 95% CI = 1.12,1.76) and bupropion (RR = 1.38; 95% CI = 1.08,1.77). For men, outcomes for those treated with TN and bupropion were similar to those treated with varenicline. There were no differences in efficacy when comparing bupropion versus TN. The advantage of varenicline over bupropion SR and TN is greater for women than men. Clinicians should strongly consider varenicline as the first option treatment for women. Among men, the advantage of varenicline over TN or bupropion is less clear. This study provides information for the sex-informed treatment of nicotine addiction among cigarette smokers. Relative to placebo, women and men achieved similar outcomes when treated with varenicline; however the advantages of varenicline over transdermal patch and bupropion were greater for women compared to men.

Depressive Symptoms Among Patients Receiving Varenicline and Bupropion for Smoking Cessation

While the combination therapy of varenicline and sustained release bupropion (bupropion SR) for cigarette smoking cessation can increase smoking abstinence rates, it has also been associated with increases in self-reported depressive symptoms. We conducted an analysis of the Beck Depression Inventory, second edition (BDI-II), data completed by 505 patients from a large randomized clinical trial, evaluating the efficacy of 12weeks of combination therapy (varenicline+bupropion SR) compared to varenicline alone. At medication treatment week 2 (1week after target quit date [TQD]), increased depressive symptoms were observed in patients receiving combination therapy (effect estimate=0.61, 95% CI [0.03, 1.19], P=.039) and those with a history of depression (effect estimate=0.82, 95% CI [0.07, 1.57], P=.033). For treatment weeks 2 to 4, smokers with a history of depression on combination therapy had a greater decline in depressive symptoms compared to those on varenicline alone (effect estimate=−1.99, 95% CI [−3.99, 0.00], P=.050). After treatment week 4, no significant effects of treatment or depression history on BDI-II scores were observed. A history of depression did not moderate the efficacy of combination therapy for smoking abstinence. Our study suggests that for combination therapy with varenicline and bupropion SR, an increase in depressive symptoms over the first 2weeks may be observed; however, the effects on depressive symptoms do not last beyond 4weeks. We conclude that among smokers without active moderate or severe depression, the decision to use this combination treatment approach should not be based upon a self-reported history of depression.

Cardiovascular and mortality risks in older Medicare patients treated with varenicline or bupropion for smoking cessation: an observational cohort study

To compare cardiovascular and mortality risks in elderly patients treated with varenicline or bupropion for smoking cessation. Elderly Medicare beneficiaries were entered into new-user cohorts of varenicline or bupropion for smoking cessation and followed on therapy for primary outcomes of acute myocardial infarction (AMI), stroke, mortality, and a composite of any of these events. Secondary outcomes were unstable angina, coronary revascularization, and a composite of any primary or secondary outcome event. Propensity score stratification was used to adjust for baseline differences in potential confounding factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards, with bupropion as reference. In cohorts of 74 824 varenicline and 14 133 bupropion users, there were 164 AMI, 96 stroke, 87 death, 317 primary composite, and 814 secondary composite events while on therapy. The HRs (95%CI) were 0.79 (0.50-1.24) for AMI, 1.27 (0.63-2.55) for stroke, 0.58 (0.30-1.13) for death, 0.84 (0.58-1.23) for the primary composite, and 0.92 (0.73-1.14) for the secondary composite. The risk of AMI or the primary composite outcome did not differ in subgroups defined by age, diabetes status, or presence of underlying ischemic heart disease. Only 30% of patients remained on either study drug beyond their first prescription. Cardiovascular and mortality risks were not increased in older patients treated with varenicline compared with bupropion for smoking cessation. A potential increase in the risk of stroke with varenicline could not be excluded. Treatment persistence with either drug was low. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

A case of hypomania during nicotine cessation treatment with bupropion

Antidepressants can increase the spontaneous risk of hypomania or mania when used for treatment in affective disorders. When prescribed as an antidepressant, bupropion is generally considered to have a lower relative risk of inducing mood shifts. We describe the case of a 67-year-old man known for dysthymic disorder in remission on quetiapine and venlafaxine who experienced a first lifetime episode of hypomania with the introduction of bupropion SR for smoking cessation. To the best of our knowledge, this is the first case report of bupropion-induced mood shift when used specifically for nicotine cessation in a nonbipolar patient. This case highlights the need for clinicians who prescribe bupropion for smoking cessation to perform regular and systematic mood follow-ups during treatment. These follow-ups could even be more important when bupropion is selected to quit smoking in a patient already taking an antidepressant.

Randomized trial of nicotine replacement therapy (NRT), bupropion and NRT plus bupropion for smoking cessation: effectiveness in clinical practice.

Background and aimsBupropion was introduced for smoking cessation following a pivotal trial showing that it gave improved efficacy over the nicotine patch and also suggesting combination treatment was beneficial. We tested in clinical practice for an effectiveness difference between bupropion and nicotine replacement therapy (NRT), whether the combination improves effectiveness and whether either treatment might be more beneficial for certain subgroups of smokers.DesignOpen-label randomized controlled trial with 6-month follow-up.SettingFour UK National Health Service (NHS) smoking cessation clinics.ParticipantsSmokers (n = 1071) received seven weekly behavioural support sessions and were randomized to an NRT product of their choice (n = 418), bupropion (n = 409) or NRT plus bupropion (n = 244).MeasuresThe primary outcome was self-reported cessation over 6 months, with biochemical verification at 1 and 6 months. Also measured were baseline demographics, health history, smoking characteristics and unwanted events during treatment.FindingsAbstinence rates for bupropion (27.9%) and NRT (24.2%) were not significantly different (odds ratio = 1.21, 95% confidence interval = 0.883–1.67), and the combination rate (24.2%) was similar to that for either treatment alone. There was some evidence that the relative effectiveness of bupropion and NRT differed according to depression (χ2 = 2.86, P = 0.091), with bupropion appearing more beneficial than NRT in those with a history of depression (29.8 versus 18.5%). Several unwanted symptoms were more common with bupropion.ConclusionThere is no difference in smoking cessation effectiveness among bupropion, nicotine replacement therapy and their combination when used with behavioural support in clinical practice. There is some evidence that bupropion is more beneficial than nicotine replacement therapy for smokers with a history of depression.

Bupropion for Smoking Cessation in Patients Hospitalized With Acute Myocardial Infarction

The purpose of this study was to examine smoking cessation rates among smokers with AMI to determine whether bupropion, started in-hospital, is safe and can improve cessation rates at 1 year.Bupropion doubles quit rates in otherwise healthy smokers and patients with stable cardiovascular disease. Although 2 previous trials examined the use of bupropion in patients hospitalized with acute cardiovascular disease, these studies have been inconclusive with respect to its safety and efficacy in patients with acute myocardial infarction (AMI).We conducted a multicenter, double-blind, placebo-controlled, randomized trial in smokers hospitalized with AMI. Participants received bupropion or placebo for 9 weeks and were followed for 12 months. Both groups received low-intensity counseling. Point prevalence abstinence was assessed by 7-day recall and biochemical validation of expired carbon monoxide.A total of 392 patients were randomized (mean age 53.9 ± 10.3 years); 83.5% were male; 64.9% had ST-segment elevation myocardial infarction). Patients smoked a mean of 23.2 ± 10.6 cigarettes/day for a mean of 32.9 ± 12.4 years. At 12 months, point prevalence abstinence rates were 37.2% in the bupropion group and 32.0% in the placebo group (p = 0.33; % difference after adjusting for between center differences 3.9%). Continuous abstinence rates were 26.8% and 22.2%, respectively (p = 0.34). Major adverse cardiac event rates were similar (13.0% vs. 11.0%, respectively; p = 0.64).Two-thirds of patients return to smoking by 12 months after AMI. Bupropion is well tolerated and seems to be safe to use in the immediate post-AMI period. However, bupropion is not effective for smoking cessation in patients post-AMI.

Use of varenicline for smoking cessation and risk of serious cardiovascular events: nationwide cohort study

Objective To investigate whether varenicline is associated with an increased risk of serious cardiovascular events compared with another drug used for smoking cessation, bupropion.Design Nationwide historical cohort study.Setting Denmark, 2007-10.Participants...

Comparisons of high-dose and combination nicotine replacement therapy, varenicline, and bupropion for smoking cessation: A systematic review and multiple treatment meta-analysis

Aim. This review compared the effect of high-dose nicotine replacement therapy (NRT) and combinations of NRT for increasing smoking abstinence rates compared to standard-dose NRT patch, varenicline, and bupropion on smoking abstinence.Methods. Ten electronic databases were searched (up to January 2012) for randomized controlled trials (RCT) of standard-dose (≤ 22 mg) or high-dose nicotine patch therapy (> 22 mg), combination NRT (e.g. nicotine patch + nicotine inhaler), bupropion, and varenicline. Analysis consisted of random-effects pairwise meta-analysis and a Bayesian multiple treatment comparison (MTC).Results. We identified 146 RCTs (65 standard-doses of the nicotine patch (≤ 22 mg); 6 high-dose NRT patch (> 22 mg); 5 high versus standard-dose NRT patch; 5 combination NRT versus inert controls; 6 combination versus single NRT patch; 48 bupropion; and 11 varenicline). The MTC found that all therapies offered treatment benefits at most time points over controls. Combination NRT and higher-dose NRT did not demonstrate consistent effects over other interventions. With the exception of varenicline, the benefits of treatments over standard-dose NRT were not retained in the long term.Conclusions. All pharmacologic treatments were significantly more effective than inert controls. Varenicline was the only treatment demonstrating effects over other options. These results should be considered in the development of clinical practice guidelines.

Journal Digest

Journal Digest

Bupropion for Smoking Cessation in African American Light Smokers: A Randomized Controlled Trial

Previous research demonstrated the efficacy of sustained release bupropion (bupropion SR) for smoking cessation in whites as well as moderate to heavy (≥10 cigarettes per day [CPD]) African American smokers. We evaluated whether bupropion SR was effective for smoking cessation among African American light smokers (≤10 CPD). A randomized, double-blind placebo-controlled trial was conducted from December 27, 2007, to May 13, 2010. All participants were African American light smokers (≤10 CPD), aged 18 years or older. Participants were randomly assigned to receive 300 mg bupropion SR (150 mg once daily for 3 days and then 150 mg twice daily) (n = 270 participants) or placebo (n = 270 participants) for 7 weeks, and up to six sessions of health education counseling. Serum cotinine was measured at baseline (week 0). The primary outcome was salivary cotinine-verified 7-day point prevalence smoking abstinence at week 26; a cut point of 15 ng/mL differentiated smokers from nonsmokers. Salivary cotinine-verified smoking abstinence at end of medication treatment at week 7 was also examined. Odds ratios (OR) for smoking abstinence and 95% confidence intervals (CIs) were calculated using logistic regression models. All statistical tests were two-sided. Participants at baseline visit (week 0) smoked an average of 8.0 CPD and had a mean serum cotinine level of 275.8 ng/mL (SD = 155.8 ng/mL); most used menthol cigarettes (83.7%) and smoked within 30 minutes of waking (72.2%). After imputing those lost to follow-up as smokers, no statistically significant difference in long-term smoking abstinence rates at week 26 was observed between bupropion SR and placebo groups (13.3% vs 10.0%, OR = 1.39, 95% CI = 0.82 to 2.35, P = .23). Cotinine-verified smoking abstinence rate at end of medication week 7 was higher in the bupropion SR vs placebo group (23.7% vs 9.6%, OR = 2.92, 95% CI = 1.78 to 4.77, P < .001). Bupropion SR was effective in promoting smoking cessation during the medication phase of treatment but showed no effect on long-term smoking cessation among African American light smokers. More research is needed to identify strategies for sustaining abstinence among African American light smokers.

Systematic review of the cost-effectiveness of varenicline vs. bupropion for smoking cessation

The purpose of this systematic review was to review the cost-effectiveness of first-line non-nicotine therapies (varenicline and bupropion SR) for smoking cessation, identify differences in the models used and their conclusions of cost-effectiveness, and to determine which variables, if any, impact conclusions of cost-effectiveness. A systematic literature search was conducted in MEDLINE, PsychINFO, the National Health Service Economic Evaluation Database, the Health Technology Database and the Tufts Cost-effectiveness Analysis Registry from the earliest possible date through May 2011. To be included, studies had to compare cost-effectiveness of varenicline to bupropion using either a Markov model or discrete event simulation and be published as a full text manuscript in English or Spanish. Study selection and data extraction were done in duplicate with disagreement resolved through discussion. Data regarding the model characteristics, results and conclusions were extracted as were details to assess the quality of the study. Model characteristics and cost-effectiveness results were compared across studies and summarised qualitatively. Ten unique studies were included, all of which were Markov models. Eight studies used the Benefits of Smoking Cessation on Outcomes (BENESCO) model and all found varenicline to dominate bupropion. The two non-BENESCO models found varenicline to be cost-effective. Conclusions regarding the cost-effectives were changed upon sensitivity analysis with the following variables: time horizon, cost of bupropion, efficacy of either drug, age and the incidence of smoking related disease. Varenicline dominated bupropion in most cost-effectiveness models. However, applicability of models to clinical practice and variables which changed conclusion of cost-effectiveness should be considered in the interpretation of results.

Suicidal behavior and depression in smoking cessation treatments.

BackgroundTwo treatments for smoking cessation—varenicline and bupropion—carry Boxed Warnings from the U.S. Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown.MethodologyFrom the FDA's Adverse Event Reporting System (AERS) database from 1998 through September 2010 we selected domestic, serious case reports for varenicline (n = 9,575), bupropion for smoking cessation (n = 1,751), and nicotine replacement products (n = 1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug.ResultsOverall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7). The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment.ConclusionsVarenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.

905 Bupropion for smoking cessation in patients hospitalized with acute myocardial infarction: A randomized, placebo-controlled trial

905 Bupropion for smoking cessation in patients hospitalized with acute myocardial infarction: A randomized, placebo-controlled trial