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Beta-Blockers and Reduction of Cardiac Events in Noncardiac Surgery

Scientific Review

Andrew D. Auerbach, MD, MPH; Lee Goldman, MD

nical approach while definitive trials are awaited.

JAMA. 2002;287:1435-1444

JAMA. 2002;287:1435-1444 Abstract quote

Recent studies suggest that perioperatively administered -blockers may reduce the risk of adverse cardiac events in patients undergoing major noncardiac surgery.

To review the efficacy of perioperative -blockade in reducing myocardial ischemia, myocardial infarction, and cardiac or all-cause mortality from randomized trials.

Data Sources
A MEDLINE and conventional search of English-language articles published since 1980 was performed to gather information related to perioperative cardiac complications and -blockade. Reference lists from all relevant articles and published recommendations for perioperative cardiac risk management were reviewed to identify additional studies.

Study Selection and Data Extraction
Prospective randomized studies (6) were included in the analysis if they discussed the impact of -blockade on perioperative cardiac ischemia, myocardial infarction, and mortality for patients undergoing major noncardiac surgery. Articles were examined for elements of trial design, treatment protocols, important biases, and major findings. These elements were then qualitatively compared.

Data Synthesis
We identified 5 randomized controlled trials: 4 assessed myocardial ischemia and 3 reported myocardial infarction, cardiac, or all-cause mortality. All studies sought to achieve -blockade before the induction of anesthesia by titrating doses to a target heart rate. Of studies reporting myocardial ischemia, numbers needed to treat were modest (2.5-6.7). Similarly modest numbers needed to treat were observed in studies reporting a significant impact on cardiac or all-cause mortality (3.2-8.3). The most marked effects were seen in patients at high risk; the sole study reporting a nonsignificant result enrolled patients with low baseline risk. As a group, studies of perioperative -blockade have enrolled relatively few carefully selected patients. In addition, differences in treatment protocols leave questions unanswered regarding optimal duration of therapy.

Despite heterogeneity of trials, a growing literature suggests a benefit of -blockade in preventing perioperative cardiac morbidity. Evidence from these trials can be used to formulate an effective clinical approach while definitive trials are awaited.

Preoperative beta-Blocker Use and Mortality and Morbidity Following CABG Surgery in North America.

Ferguson TB Jr, Coombs LP, Peterson ED.

Departments of Surgery and Physiology, Louisiana State University Health Sciences Center, 1542 Tulane Ave, 7th Floor, New Orleans, LA 70012-2822.

JAMA 2002 May 1;287(17):2221-7 Abstract quote

CONTEXT: beta-Blockade therapy has recently been shown to convey a survival benefit in preoperative noncardiac vascular surgical settings. The effect of preoperative beta-blocker therapy on coronary artery bypass graft surgery (CABG) outcomes has not been assessed.

OBJECTIVES: To examine patterns of use of preoperative beta-blockers in patients undergoing isolated CABG and to determine whether use of beta-blockers is associated with lower operative mortality and morbidity.

DESIGN, SETTING, AND PATIENTS: Observational study using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database (NCD) to assess beta-blocker use and outcomes among 629 877 patients undergoing isolated CABG between 1996 and 1999 at 497 US and Canadian sites.

MAIN OUTCOME MEASURE: Influence of beta-blockers on operative mortality, examined using both direct risk adjustment and a matched-pairs analysis based on propensity for preoperative beta-blocker therapy.

RESULTS: From 1996 to 1999, overall use of preoperative beta-blockers increased from 50% to 60% in the NCD (P<.001 for time trend). Major predictors of use included recent myocardial infarction; hypertension; worse angina; younger age; better left ventricular systolic function; and absence of congestive heart failure, chronic lung disease, and diabetes. Patients who received beta-blockers had lower mortality than those who did not (unadjusted 30-day mortality, 2.8% vs 3.4%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.78-0.82). Preoperative beta-blocker use remained associated with slightly lower mortality after adjusting for patient risk and center effects using both risk adjustment (OR, 0.94; 95% CI, 0.91-0.97) and treatment propensity matching (OR, 0.97; 95% CI, 0.93-1.00). Procedural complications also tended to be lower among treated patients. This treatment advantage was seen among the majority of patient subgroups, including women; elderly persons; and those with chronic lung disease, diabetes, or moderately depressed ventricular function. Among patients with a left ventricular ejection fraction of less than 30%, however, preoperative beta-blocker therapy was associated with a trend toward a higher mortality rate (OR, 1.13; 95% CI, 0.96-1.33; P =.23).

CONCLUSIONS: In this large North American observational analysis, preoperative beta-blocker therapy was associated with a small but consistent survival benefit for patients undergoing CABG, except among patients with a left ventricular ejection fraction of less than 30%. This analysis further suggests that preoperative beta-blocker therapy may be a useful process measure for CABG quality improvement assessment.


Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial.

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF).


JAMA 2002 Mar 27;287(12):1531-40 Abstract quote

CONTEXT: Decompensated congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients older than 65 years.

OBJECTIVE: To compare the efficacy and safety of intravenous nesiritide, intravenous nitroglycerin, and placebo.

DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial of 489 inpatients with dyspnea at rest from decompensated CHF, including 246 who received pulmonary artery catheterization, that was conducted at 55 community and academic hospitals between October 1999 and July 2000.

INTERVENTIONS: Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143), or placebo (n = 142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added to standard medication for 24 hours.

MAIN OUTCOME MEASURES: Change in pulmonary capillary wedge pressure (PCWP) among catheterized patients and patient self-evaluation of dyspnea at 3 hours after initiation of study drug among all patients. Secondary outcomes included comparisons of hemodynamic and clinical effects between nesiritide and nitroglycerin at 24 hours.

RESULTS: At 3 hours, the mean (SD) decrease in PCWP from baseline was -5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P =.03), -3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P =.09), and -2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement in dyspnea compared with placebo (P =.03), but there was no significant difference in dyspnea or global clinical status with nesiritide compared with nitroglycerin. At 24 hours, the reduction in PCWP was greater in the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3 mm Hg), but patients reported no significant differences in dyspnea and only modest improvement in global clinical status.

CONCLUSION: When added to standard care in patients hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and some self-reported symptoms more effectively than intravenous nitroglycerin or placebo.

Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.

Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O'Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M; The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators.

Northwestern University Medical School, Division of Cardiology, 201 E Huron St, Galter 10-240, Chicago, IL 60611, USA.

JAMA 2002 Mar 27;287(12):1541-7 Abstract quote

CONTEXT: Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain.

OBJECTIVE: To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure.

DESIGN: Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999.

SETTING: Seventy-eight community and tertiary care hospitals in the United States.

PARTICIPANTS: A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%).

INTERVENTION: Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 microg/kg per minute initially (n = 477), or saline placebo (n = 472).

MAIN OUTCOME MEASURE: Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization. RESULTS: The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P =.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P =.004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P =.19), 60-day mortality (10.3% vs 8.9%; P =.41), or the composite incidence of death or readmission (35.0% vs 35.3%; P =.92)

CONCLUSION: These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.

Cognitive Outcome After Off-Pump and On-Pump Coronary Artery Bypass Graft Surgery

A Randomized Trial

Diederik Van Dijk, MD; Erik W. L. Jansen, MD, PhD; Ron Hijman, PhD; Arno P. Nierich, MD, PhD; Jan C. Diephuis, MD; Karel G. M. Moons, PhD; Jaap R. Lahpor, MD, PhD; Cornelius Borst, MD, PhD; Annemieke M. A. Keizer, MSc; Hendrik M. Nathoe, MD; Diederick E. Grobbee, MD, PhD; Peter P. T. De Jaegere, MD, PhD; Cor J. Kalkman, MD, PhD; for the Octopus Study Group


JAMA. 2002;287:1405-1412 Abstract quote

Coronary artery bypass graft (CABG) surgery is associated with a decline in cognitive function, which has largely been attributed to the use of cardiopulmonary bypass (on-pump procedures). Cardiac stabilizers facilitate CABG surgery without use of cardiopulmonary bypass (off-pump procedures) and should reduce the cognitive decline associated with on-pump procedures.

To compare the effect of CABG surgery with (on-pump) and without (off-pump) cardiopulmonary bypass on cognitive outcome.

Design and Setting
Randomized controlled trial conducted in the Netherlands of CABG surgery patients enrolled from March 1998 through August 2000, with 3- and 12-month follow-up.

Participants and Intervention
Patients scheduled for their first CABG surgery (mean age, 61 years; n = 281) were randomly assigned to off-pump surgery (n = 142) or on-pump surgery (n = 139).

Main Outcome Measures
Cognitive outcome at 3 and 12 months, which was determined by psychologists (blinded for randomization) who administered 10 neuropsychological tests before and after surgery. Quality of life, stroke rate, and all-cause mortality at 3 and 12 months were secondary outcome measures.

Cognitive outcome could be determined at 3 months in 248 patients. Cognitive decline occurred in 21% in the off-pump group and 29% in the on-pump group (relative risk [RR], 0.65; 95% confidence interval [CI], 0.36-1.16; P = .15). The overall standardized change score (ie, improvement of cognitive performance) was 0.19 in the off-pump vs 0.13 in the on-pump group (P = .03). At 12 months, cognitive decline occurred in 30.8% in the off-pump group and 33.6% in the on-pump group (RR, 0.88; 95% CI, 0.52-1.49; P = .69). The overall standardized change score was 0.19 in the off-pump vs 0.12 in the on-pump group (P = .09). No statistically significant differences were observed between the on-pump and off-pump groups in quality of life, stroke rate, or all-cause mortality at 3 and 12 months.

Patients who received their first CABG surgery without cardiopulmonary bypass had improved cognitive outcomes 3 months after the procedure, but the effects were limited and became negligible at 12 months.

Sirolimus-Eluting Stents vs Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease

Meta-analysis of Randomized Trials

Adnan Kastrati, MD; Alban Dibra, MD; Sonja Eberle, Dipl Stat; Julinda Mehilli, MD; José Suárez de Lezo, MD; Jean-Jacque Goy, MD; Kurt Ulm, PhD; Albert Schömig, MD

JAMA. 2005;294:819-825. Abstract quote

Context  Placement of sirolimus-eluting stents or paclitaxel-eluting stents has emerged as the predominant percutaneous treatment strategy in patients with coronary artery disease (CAD). Whether there are any differences in efficacy and safety between these 2 drug-eluting stents is unclear.

Objective  To compare outcomes of sirolimus-eluting and paclitaxel-eluting coronary stents on the basis of data generated by randomized head-to-head clinical trials.

Data Sources  PubMed and the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to April 2005.

Study Selection  Randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD reporting the outcomes of interest (target lesion revascularization, angiographic restenosis, stent thrombosis, myocardial infarction [MI], death, and the composite of death or MI) during a follow-up of at least 6 months.

Data Extraction  Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest.

Data Synthesis  Six trials, including 3669 patients, met the selection criteria. No significant heterogeneity was found across trials. Target lesion revascularization, the primary outcome of interest, was less frequently performed in patients who were treated with the sirolimus-eluting stent (5.1%) vs the paclitaxel-eluting stent (7.8%) (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.49-0.84; P = .001). Similarly, angiographic restenosis was less frequently observed among patients assigned to the sirolimus-eluting stent (9.3%) vs the paclitaxel-eluting stent (13.1%) (OR, 0.68; 95% CI, 0.55-0.86; P = .001). Event rates for sirolimus-eluting vs paclitaxel-eluting stents were 0.9% and 1.1%, respectively, for stent thrombosis (P = .62); 1.4% and 1.6%, respectively, for death (P = .56); and 4.9% and 5.8%, respectively, for the composite of death or MI (P = .23).

Conclusions  Patients receiving sirolimus-eluting stents had a significantly lower risk of restenosis and target vessel revascularization compared with those receiving paclitaxel-eluting stents. Rates of death, death or MI, and stent thrombosis were similar.

Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial.

Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, Schuhlen H, Schmitt C, Dirschinger J, Schomig A; ISAR-DESIRE Study Investigators.

Deutsches Herzzentrum, Technische Universitat, Munich, Germany.
JAMA. 2005 Jan 12;293(2):165-71. Abstract quote

CONTEXT: In patients with de novo coronary lesions, drug-eluting stents have drastically reduced restenosis risk compared with bare metal stents and conventional balloon angioplasty. It is less clear whether drug-eluting stents are superior to conventional balloon angioplasty for the treatment of patients with in-stent restenosis.

OBJECTIVES: To assess if drug-eluting stents are a more effective treatment of in-stent restenosis than conventional balloon angioplasty, and to assess the relative merits of 2 drug-eluting stents, a sirolimus-eluting stent and a paclitaxel-eluting stent.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, active-controlled trial conducted among 300 patients with angiographically significant in-stent restenosis in 2 tertiary German centers from June 1, 2003, to October 20, 2003.

INTERVENTIONS: After pretreatment with 600 mg of clopidogrel for at least 2 hours before intervention, all patients were randomly assigned to 1 of 3 treatment groups: sirolimus stent, paclitaxel stent, or balloon angioplasty (100 patients in each group).

MAIN OUTCOME MEASURES: Primary end point: angiographic restenosis (diameter stenosis > or =50%) at 6-month follow-up angiography based on "in-segment" analysis. Primary analysis was comparison between stent groups and balloon angioplasty groups; a secondary analysis compared sirolimus and paclitaxel stents.

RESULTS: Follow-up angiography was performed in 275 (92%) of 300 patients. The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.

CONCLUSIONS: In patients with in-stent restenosis, a strategy based on sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.


Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients.

Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.


Lancet 1994 Feb 5;343(8893):311-22 Abstract quote

Large randomised trials have demonstrated that fibrinolytic therapy can reduce mortality in patients with suspected acute myocardial infarction (AMI). The indications for, and contraindications to, this treatment in some categories of patient are disputed, examples being late presentation, elderly patients, and those in cardiogenic shock.

This overview aims to help resolve some of the remaining uncertainties. From all trials of fibrinolytic therapy versus control that randomised more than 1000 patients with suspected AMI, information was sought and checked on deaths during the first 5 weeks and on major adverse events occurring during hospitalisation.

The nine trials included 58,600 patients, among whom 6177 (10.5%) deaths, 564 (1.0%) strokes, and 436 (0.7%) major non-cerebral bleeds were reported. Fibrinolytic therapy was associated with an excess of deaths during days 0-1 (especially among patients presenting more than 12 h after symptom onset, and in the elderly) but this was outweighed by a much larger benefit during days 2-35. This "early hazard" should not obscure the very clear overall survival advantage that is produced by fibrinolytic therapy. Benefit was observed among patients presenting with ST elevation or bundle-branch block (BBB)--irrespective of age, sex, blood pressure, heart rate, or previous history of myocardial infarction or diabetes--and was greater the earlier treatment began. Among the 45,000 patients presenting with ST elevation or BBB the relation between benefit and delay from symptom onset indicated highly significant absolute mortality reductions of about 30 per 1000 for those presenting within 0-6 h and of about 20 per 1000 for those presenting 7-12 h from onset, and a statistically uncertain benefit of about 10 per 1000 for those presenting at 13-18 h (with more randomised evidence needed in this latter group to assess reliably the net effects of treatment).

Fibrinolytic therapy was associated with about 4 extra strokes per 1000 during days 0-1: of these, 2 were associated with early death and so were already accounted for in the overall mortality reduction, 1 was moderately or severely disabling, and 1 was not. This overview indicates that fibrinolytic therapy is beneficial in a much wider range of patients than is currently given such treatment routinely.

Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial Infarction: GUSTO V Randomized Trial.

Lincoff AM, Califf RM, Van De Werf F, Willerson JT, White HD, Armstrong PW, Guetta V, Gibler WB, Hochman JS, Bode C, Vahanian A, Steg PG, Ardissino D, Savonitto S, Bar F, Sadowski Z, Betriu A, Booth JE, Wolski K, Waller M, Topol EJ.

Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

JAMA 2002 Nov 6;288(17):2130-5 Abstract quote

CONTEXT: Among patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished.

OBJECTIVE: To determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year.

DESIGN, SETTING, AND PATIENTS: One-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%).

INTERVENTION: Patients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 micro g/kg per minute infusion [maximum 10 micro g/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart).

MAIN OUTCOME MEASURE: One-year all-cause mortality rates.

RESULTS: All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status.

CONCLUSION: Combination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.

Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ.

Division of Cardiology, University of North Carolina, CB#7075, 338 Burnett-Womack Bldg, Chapel Hill, NC 27599.

JAMA 2002 Nov 20;288(19):2411-20 Abstract quote

CONTEXT: Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied.

OBJECTIVES: To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy.

DESIGN, SETTING, AND PARTICIPANTS: The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001.

INTERVENTIONS: Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study.

MAIN OUTCOME MEASURES: One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. RESULTS: At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P =.23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P =.051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P =.07). CONCLUSIONS: Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Thrombolytic Therapy vs Primary Percutaneous Coronary Intervention for Myocardial Infarction in Patients Presenting to Hospitals Without On-site Cardiac Surgery

A Randomized Controlled Trial

Thomas Aversano, MD; Lynnet T. Aversano, RN, BSN; Eugene Passamani, MD; Genell L. Knatterud, PhD; Michael L. Terrin, MD; David O. Williams, MD; Sandra A. Forman, MA; for the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT)

JAMA. 2002;287:1943-1951 Abstract quote

Trials comparing primary percutaneous coronary intervention (PCI) and thrombolytic therapy for treatment of acute myocardial infarction (MI) suggest primary PCI is the superior therapy, although they differ with respect to the durability of benefit. Because PCI is often limited to hospitals that have on-site cardiac surgery programs, most acute MI patients do not have access to this therapy.

To determine whether treatment of acute MI with primary PCI is superior to thrombolytic therapy at hospitals without on-site cardiac surgery and, if so, whether superiority is durable.

The Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial, a prospective, randomized trial conducted from July 1996 through December 1999.

Eleven community hospitals in Massachusetts and Maryland without on-site cardiac surgery or extant PCI programs.

Four hundred fifty-one thrombolytic-eligible patients with acute MI of less than 12 hours' duration associated with ST-segment elevation on electrocardiogram.

After a formal primary PCI development program was completed at all sites, patients were randomly assigned to receive primary PCI (n = 225) or accelerated tissue plasminogen activator (bolus dose of 15 mg and an infusion of 0.75 mg/kg for 30 minutes followed by 0.5 mg/kg for 60 minutes; n = 226). After initiation of assigned treatment, all care was determined by treating physicians.

Main Outcome Measures
Six-month composite incidence of death, recurrent MI, and stroke; median hospital length of stay.

The incidence of the composite end point was reduced in the primary PCI group at 6 weeks (10.7% vs 17.7%; P = .03) and 6 months (12.4% vs 19.9%; P = .03) after index MI. Six-month rates for individual outcomes were 6.2% vs 7.1% for death (P = .72), 5.3% vs 10.6% for recurrent MI (P = .04), and 2.2% vs 4.0% for stroke (P = .28) for primary PCI vs thrombolytic therapy, respectively. Median length of stay was also reduced in the primary PCI group (4.5 vs 6.0 days; P = .02).

Compared with thrombolytic therapy, treatment of patients with primary PCI at hospitals without on-site cardiac surgery is associated with better clinical outcomes for 6 months after index MI and a shorter hospital stay.


Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women

Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial

Elizabeth Barrett-Connor, MD; Deborah Grady, MD; Andreas Sashegyi, PhD; Pamela W. Anderson, MD; David A. Cox, PhD; Krzysztof Hoszowski, MD; Pentti Rautaharju, MD; Kristine D. Harper, MD; for the MORE Investigators
JAMA. 2002;287:847-857 Abstract quote

Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown.

To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women.

Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999.

Outpatient and community settings at 180 sites in 25 countries.

Participants A total of 7705 osteoporotic postmenopausal women (mean age, 67 years).

Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.

Main Outcome Measures
Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure.

In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94), or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60).

Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.


Effects of a Dietary Portfolio of Cholesterol-Lowering Foods vs Lovastatin on Serum Lipids and C-Reactive Protein.

Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Wong JM, De Souza R, Emam A, Parker TL, Vidgen E, Lapsley KG, Trautwein EA, Josse RG, Leiter LA, Connelly PW.

Clinical Nutrition and Risk Factor Modification Center, St Michael's Hospital, and Departments of Nutritional Sciences, Medicine, Biochemistry, and Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario.


JAMA. 2003 Jul 23;290(4):502-10 Abstract quote

CONTEXT: To enhance the effectiveness of diet in lowering cholesterol, recommendations of the Adult Treatment Panel III of the National Cholesterol Education Program emphasize diets low in saturated fat together with plant sterols and viscous fibers, and the American Heart Association supports the use of soy protein and nuts.

OBJECTIVE: To determine whether a diet containing all of these recommended food components leads to cholesterol reduction comparable with that of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins).

DESIGN: Randomized controlled trial conducted between October and December 2002.

Setting and PARTICIPANTS: Forty-six healthy, hyperlipidemic adults (25 men and 21 postmenopausal women) with a mean (SE) age of 59 (1) years and body mass index of 27.6 (0.5), recruited from a Canadian hospital-affiliated nutrition research center and the community.

INTERVENTIONS: Participants were randomly assigned to undergo 1 of 3 interventions on an outpatient basis for 1 month: a diet very low in saturated fat, based on milled whole-wheat cereals and low-fat dairy foods (n = 16; control); the same diet plus lovastatin, 20 mg/d (n = 14); or a diet high in plant sterols (1.0 g/1000 kcal), soy protein (21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (n = 16; dietary portfolio).

MAIN OUTCOME MEASURES: Lipid and C-reactive protein levels, obtained from fasting blood samples; blood pressure; and body weight; measured at weeks 0, 2, and 4 and compared among the 3 treatment groups.

RESULTS: The control, statin, and dietary portfolio groups had mean (SE) decreases in low-density lipoprotein cholesterol of 8.0% (2.1%) (P =.002), 30.9% (3.6%) (P<.001), and 28.6% (3.2%) (P<.001), respectively. Respective reductions in C-reactive protein were 10.0% (8.6%) (P =.27), 33.3% (8.3%) (P =.002), and 28.2% (10.8%) (P =.02). The significant reductions in the statin and dietary portfolio groups were all significantly different from changes in the control group. There were no significant differences in efficacy between the statin and dietary portfolio treatments.

CONCLUSION: In this study, diversifying cholesterol-lowering components in the same dietary portfolio increased the effectiveness of diet as a treatment of hypercholesterolemia.

Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.

Serruys PW, De Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B.

Interventional Cardiology, Thoraxcenter, Bd 418, Academic Hospital, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

JAMA 2002 Jun 26;287(24):3215-22 Abstract quote

CONTEXT: Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE).

OBJECTIVE: To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI.

DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil.

PATIENTS: A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L).

INTERVENTIONS: Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years.

MAIN OUTCOME MEASURE: Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups.

RESULTS: Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group.

CONCLUSION: Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.

Long-term persistence in use of statin therapy in elderly patients.

Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J.

Division of Pharmacoepidemiology & Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Suite 341, Boston, MA 02115, USA.

JAMA 2002 Jul 24-31;288(4):455-61 Abstract quote

CONTEXT: Knowledge of long-term persistence with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy is limited because previous studies have observed patients for short periods of time, in closely monitored clinical trials, or in other unrepresentative settings.

OBJECTIVE: To describe the patterns and predictors of long-term persistence with statin therapy in an elderly US population.

DESIGN, SETTING, AND PATIENTS: Retrospective cohort study including 34 501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance to the Aged and Disabled programs who were 65 years of age and older, initiated statin treatment between 1990 and 1998, and who were followed up until death, disenrollment, or December 31, 1999.

MAIN OUTCOME MEASURES: Proportion of days covered (PDC) by a statin in each quarter during the first year of therapy and every 6 months thereafter; predictors of suboptimal persistence during each interval (PDC <80%) were identified using generalized linear models for repeated measures.

RESULTS: The mean PDC was 79% in the first 3 months of treatment, 56% in the second quarter, and 42% after 120 months. Only 1 patient in 4 maintained a PDC of at least 80% after 5 years. The proportion of patients with a PDC less than 80% increased in a log-linear manner, comprising 40%, 61%, and 68% of the cohort after 3, 12, and 120 months, respectively. Independent predictors of poor long-term persistence included nonwhite race, lower income, older age, less cardiovascular morbidity at initiation of therapy, depression, dementia, and occurrence of coronary heart disease events after starting treatment. Patients who initiated therapy between 1996-1998 were 21% to 25% more likely to have a PDC of at least 80% than those who started in 1990.

CONCLUSIONS: Persistence with statin therapy in older patients declines substantially over time, with the greatest drop occurring in the first 6 months of treatment. Despite slightly better persistence among patients who began treatment in recent years, long-term use remains low. Interventions are needed early in treatment and among high-risk groups, including those who experience coronary heart disease events after initiating treatment.

Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy.

Waters DD, Schwartz GG, Olsson AG, Zeiher A, Oliver MF, Ganz P, Ezekowitz M, Chaitman BR, Leslie SJ, Stern T; MIRACL Study Investigators.

Circulation 2002 Sep 24;106(13):1690-5 Abstract quote

BACKGROUND: This report describes the effect of intensive cholesterol lowering with atorvastatin on the incidence of nonfatal stroke, a secondary end point, in a randomized, placebo-controlled trial of patients with unstable angina or non-Q-wave myocardial infarction. The primary end point, a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization, was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group over the 16 weeks of the trial (P=0.048).

METHODS AND RESULTS: Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. The outcomes of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time to first occurrence during the 16-week trial. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% confidence intervals, 0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% confidence intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred in the placebo group.

CONCLUSION: Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with acute coronary syndromes reduced the overall stroke rate by half and did not cause hemorrhagic stroke. These findings need to be confirmed in future trials.

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