Pericardial effusion coincident with sirolimus therapy: a review of Wyeth's safety database.

Sirolimus is an immunosuppressive agent approved for prophylaxis of acute rejection in renal transplant patients aged 13 years or older. A retrospective review of pericardial effusion coincident with sirolimus therapy was conducted from key clinical trials and spontaneous reporting sources. A significantly higher rate of pericardial effusion occurred with sirolimus versus azathioprine treatment in a cardiac transplantation trial (28.6% versus 9.3%, respectively). Cases of pericardial effusion were also observed in the sirolimus treatment arms of three de novo renal transplant studies (rates 0.5 to 1.9%). Although most of the pericardial effusions occurred in cardiac transplantation, sirolimus is not approved for this use. As of January 31, 2007, the Wyeth safety database (which includes clinical trial data and spontaneous reports) contained reports of pericardial effusion in 56 sirolimus-treated patients, 31 of whom required pericardial drainage. These data suggest that pericardial effusion should be considered in the differential diagnosis of a clinical deterioration in posttransplant patients treated with sirolimus. The adverse reaction of pericardial effusion has been added to product labeling.

Impact of different platelet glycoprotein IIb/IIIa receptor inhibitors among diabetic patients undergoing percutaneous coronary intervention: : Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-year follow-up.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor inhibitor abciximab, a monoclonal antibody, has been shown to improve early and late outcomes among diabetic patients undergoing percutaneous coronary intervention (PCI). It is unknown whether small-molecule agents confer similar benefits. METHODS AND RESULTS: In 18 countries, 4809 patients undergoing PCI with stent implantation were randomized to tirofiban or abciximab. At the time of enrollment, patients were stratified according to diabetes status. As compared with non-diabetic patients, patients with diabetes (n=1117) showed similar 30-day ischemic outcomes, an increased incidence of any target vessel revascularization (TVR) at 6 months (10.3% versus 7.8%; P= 0.008), and a trend toward higher 1-year mortality (2.5% versus 1.6%; P=0.056). Among diabetic patients randomized to tirofiban (n=560), the incidence of death, myocardial infarction (MI), or urgent TVR at 30 days was 6.2%, and among those randomized to abciximab (n=557) it was 5.4% (hazard ratio [HR] 1.16; P=0.540). At 6 months, the composite of death, MI, or any TVR occurred in 15.7% and in 16.9% of tirofiban and abciximab patients, respectively (HR 0.93; P=0.610). Any TVR occurred in 9.5% and 11.1%, respectively (HR 0.84; P= 0.366). The 1-year mortality was 2.1% in the tirofiban group and 2.9% in the abciximab group (HR 0.74; P= 0.436). CONCLUSIONS: Among diabetic patients undergoing PCI, tirofiban and abciximab were associated with comparable event rates, including similar rates of 6-month TVR and 1-year mortality. These findings suggest that the non-glycoprotein IIb/IIIa properties of abciximab do not translate into a discernible long-term clinical benefit among diabetic patients.

Implications of upstream glycoprotein IIb/IIIa inhibition and coronary artery stenting in the invasive management of unstable angina/non-ST-elevation myocardial infarction: a comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial.

BACKGROUND: TIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI. METHODS AND RESULTS: Patients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for acute coronary syndromes (OR, 0.62; P<0.0001). Across both trials, the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low-risk, 0.80 in intermediate-risk, and 0.57 in high-risk patients (P< or =0.004 for interactions). After adjustment for baseline risk, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95% CI, 0.56 to 1.11). CONCLUSIONS: Advances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting, were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward a greater benefit of an early invasive strategy.

Elevations in troponin T and I are associated with abnormal tissue level perfusion: a TACTICS-TIMI 18 substudy. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction.

BACKGROUND: Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear. METHODS AND RESULTS: We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 ("closed" microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%; P=0.007) and after percutaneous coronary intervention (55.4% versus 35.6%; P=0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL; P=0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all P<0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81; P=0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months. CONCLUSIONS: Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.

Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy.

BACKGROUND: Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction (TIMI) biomarker core laboratory. We examined the relationship between gender and elevated biomarkers. Of 1865 patients from TACTICS-TIMI 18, 34% were women. Fewer women had elevated creatine kinase-MB or troponins, whereas more had elevated high-sensitivity C-reactive protein or brain natriuretic peptide. Presence of ST-segment deviation and TIMI risk scores were not significantly different. This pattern was confirmed in TIMI 11 and OPUS-TIMI 16. The prognostic value of the markers in TACTICS-TIMI 18 was similar in women and men. When a multimarker approach was examined, a greater proportion of high-risk women were identified. Marker-positive patients of both genders had improved outcome with an invasive strategy; however, marker-negative women appeared to have improved outcomes with a conservative strategy. CONCLUSIONS: In patients with UA/NSTEMI, there was a different pattern of presenting biomarkers. Men were more likely to have elevated creatine kinase-MB and troponins, whereas women were more likely to have elevated C-reactive protein and brain natriuretic peptide. This suggests that a multimarker approach may aid the initial risk assessment of UA/NSTEMI, especially in women. Further research is necessary to elucidate whether gender-related pathophysiological differences exist in presentation with acute coronary syndromes.

Prospective analysis of creatine kinase muscle-brain fraction and comparison with troponin T to predict cardiac risk and benefit of an invasive strategy in patients with non-ST-elevation acute coronary syndromes.

OBJECTIVE: We sought to determine whether elevation of plasma creatine kinase muscle-brain fraction (CK-MB) would be useful to triage patients with acute coronary syndromes (ACS) to early angiography/revascularization. BACKGROUND: It is unknown whether the measurement of CK-MB is effective for triage to an aggressive management strategy. METHOD: Patients in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS-TIMI) 18 study received aspirin, heparin, and tirofiban for treatment of ACS, were randomized to an invasive or a conservative strategy (angiography/revascularization between 4 and 48 h), and were followed up for a composite end point of death, myocardial infarction, or rehospitalization for ACS. Of 2,220 patients, CK-MB was elevated in 826 (37%). Of the patients with negative CK-MB, troponin T was elevated in 361 (31.2%). Event rates at 30 and 180 days were twice as high in patients with elevated CK-MB than in patients without elevated CK-MB. Both groups had similar benefit from an invasive strategy; there was no evidence of interaction between CK-MB elevation and strategy on the composite end point at 30 or 180 days. When patients were stratified according to both CK-MB and troponin status, there was evidence of a benefit in the invasive strategy among patients who were CK-negative but troponin-positive (odds ratios [95% confidence interval]: 0.13 [0.04 to 0.39] at 30 days and 0.29 [0.16 to 0.52] at 180 days). CONCLUSION: Patients with minimal amounts of recent onset myonecrosis but elevated risk as indicated by CK-MB and troponin, respectively, benefit most from invasive management. Determination of troponin levels yielded significant information regarding triage to an invasive strategy, particularly in CK-MB-negative patients.

Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy- Thrombolysis in Myocardial Infarction 18 trial)substudy.

OBJECTIVES: This study was designed to determine the relationship between baseline white blood cell (WBC) count and angiographic and clinical outcomes in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and to see if WBC count was a significant predictor of outcomes independent of other biomarkers. BACKGROUND: Inflammation has been shown to play a role in atherosclerosis and acute coronary syndromes. METHODS: We evaluated the relationship between baseline WBC count, other baseline variables and biomarkers, angiographic findings, and clinical outcomes in 2,208 patients in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial. RESULTS: Higher baseline WBC counts were associated with lower Thrombolysis In Myocardial Infarction (TIMI) flow grades (p = 0.0045) and TIMI myocardial perfusion grades (p = 0.03) as well as a greater extent of coronary artery disease (CAD) (p < 0.0001). A higher baseline WBC count was predictive of higher six-month mortality, ranging from 1.5% to 3.6% to 5.1% for patients with low, intermediate, and high WBC counts, respectively (p = 0.0017). In a multivariable proportional hazards model, patients with a low C-reactive protein (CRP) but an elevated WBC remained at significantly higher risk of death at six months (hazard ratio [HR] 4.3, p = 0.049), and patients with a high CRP were at even higher risk (HR 8.6, p = 0.004). conclusions: In patients with UA/NSTEMI, elevations in a simple, widely available blood test, the WBC count, were associated with impaired epicardial and myocardial perfusion, more extensive CAD, and higher six-month mortality. After adjustment for traditional risk factors and other biomarkers, assessment of two inflammatory markers, WBC count and CRP, can be used to stratify patients across an eightfold gradation of six-month mortality risk.

Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18.

OBJECTIVES: This study was designed to evaluate B-type natriuretic peptide (BNP) for risk assessment and clinical decision making over a range of cut points, alone and with cardiac troponin I (cTnI), in patients with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: B-type natriuretic peptide holds promise for risk stratification. Additional evidence regarding optimal decision limits, use in combination with troponin, and use in targeting therapy is needed before acceptance into clinical use for ACS. METHODS: We evaluated BNP at baseline in 1,676 patients with non-ST-elevation ACS randomized to early invasive versus conservative management. RESULTS: Patients with elevated BNP (>80 pg/ml; n = 320) were at higher risk of death at seven days (2.5% vs. 0.7%, p = 0.006) and six months (8.4% vs. 1.8%, p < 0.0001). The association between BNP and mortality at six months (adjusted odds ratio [OR] 3.3; 95% confidence interval [CI] 1.7 to 6.3) was independent of important clinical predictors, including cTnI and congestive heart failure (CHF). Patients with elevated BNP had a fivefold higher risk of developing new CHF by 30 days (5.9% vs. 1.0%, p < 0.0001). B-type natriuretic peptide added prognostic information to cTnI, discriminating patients at higher mortality risk among those with negative (OR 6.9; 95% CI 1.9 to 25.8) and positive (OR 4.1; 95% CI 1.9 to 9.0) baseline cTnI results. No difference was observed in the effect of invasive versus conservative management when stratified by baseline levels of BNP (p(interaction) > or = 0.6). CONCLUSIONS: Elevated BNP (>80 pg/ml) at presentation identifies patients with non-ST-elevation ACS who are at higher risk of death and CHF and adds incremental information to cTnI. Additional work is needed to identify therapies that may reduce the risk associated with increased BNP.

The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: Although increasing age is an important risk factor for adverse outcome among patients with acute coronary syndromes, elderly patients are more often managed conservatively. OBJECTIVE: To examine outcome according to age and management strategy for patients with unstable angina and non-ST-segment elevation myocardial infarction (MI). DESIGN: Randomized, controlled trial conducted from December 1997 to June 2000. SETTING: 169 community and tertiary care hospitals in 9 countries. PATIENTS: 2220 patients hospitalized with unstable angina and non-ST-segment elevation MI who were randomly assigned to an early invasive or conservative management strategy. INTERVENTIONS: Medical therapy and coronary angiography at 4 to 48 hours versus medical therapy and predischarge exercise testing. MEASUREMENTS: Rates of 30-day and 6-month mortality, nonfatal MI, rehospitalization, stroke, and hemorrhagic complications. RESULTS: Among patients 65 years of age and older, the early invasive strategy compared with the conservative strategy yielded an absolute reduction of 4.8 percentage points (8.8% vs. 13.6%; P = 0.018) and a relative reduction of 39% in death or MI at 6 months. Outcomes of the 2 strategies were similar, however, among patients younger than 65 years of age (6.1% vs. 6.5%; P > 0.2). Among patients older than 75 years of age, the early invasive strategy conferred an absolute reduction of 10.8 percentage points (10.8% vs. 21.6%; P = 0.016) and a relative reduction of 56% in death or MI at 6 months. The additional cost per death or MI prevented with the early invasive strategy was lower for elderly patients, but major bleeding rates were higher with this strategy in patients older than 75 years of age (16.6% vs. 6.5%; P = 0.009). LIMITATIONS: Because this study involved patients in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial, its generalizability to elderly patients with excluded comorbid conditions is unknown. CONCLUSION: Despite an increased risk for major bleeding in patients older than 75 years of age, a routine early invasive strategy can significantly improve ischemic outcomes in elderly patients with unstable angina and non-ST-segment elevation MI.

Association between duration of tirofiban therapy before percutaneous intervention and tissue level perfusion (a TACTICS-TIMI 18 substudy).

In the setting of acute coronary syndromes, thrombotic embolization and activation of platelets with release of vasoconstrictors into the downstream microvasculature may occur before cardiac catheterization. In the Treat Angina with tirofiban and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial angiographic substudy, a shorter duration of tirofiban infusion before percutaneous coronary intervention was associated with impaired myocardial perfusion before and after intervention.

Time for contrast material to traverse the epicardial artery and the myocardium in ST-segment elevation acute myocardial infarction versus unstable angina pectoris/non-ST-elevation acute myocardial infarction.

Although the time for contrast material to fill the epicardial artery in the setting of acute coronary syndromes has been studied extensively, the time for contrast material to fill the myocardium has not been evaluated. We compared differences in myocardial contrast material transit among patients with unstable angina pectoris/non-ST-elevation acute myocardial infarction (UAP/NSTEAMI) with patients with ST-elevation acute myocardial infarction (STEAMI). The time it took for contrast material to first appear and to arrive at peak intensity in the myocardium was compared in 224 patients with STEAMI enrolled in the LIMIT-AMI study versus 430 patients with UAP/NSTEAMI enrolled in the TACTICS-TIMI 18 trial. In patients with STEAMI, there was a delay in both the time for contrast material to first enter the myocardium (5,619 +/- 1,789 vs 4,663 +/- 1,626 ms, p <0.0001) and the time from entrance to peak blush intensity (2,387 +/- 1,359 vs 1,959 +/- 1,244 ms, p = 0.003) compared with patients with UAP/NSTEAMI. STEAMI remained significantly associated with impaired entrance of contrast material into the myocardium (p <0.0001) in a multivariate model controlling for known correlates of impaired epicardial flow (presence of thrombus, percent diameter stenosis, left anterior descending artery location, and contrast material inflow in the epicardial artery [corrected TIMI frame count]). The time for contrast material to enter the myocardium is impaired to a greater degree in STEAMI compared with UAP/NSTEAMI, even after adjusting for other variables known to delay flow in the epicardial artery. These data provide insight into potential mechanistic differences between these 2 clinical syndromes.

The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy.

The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.

Early invasive strategy improves outcomes in patients with acute coronary syndrome with previous coronary artery bypass graft surgery: a report from TACTICS-TIMI 18.

BACKGROUND: Patients with previous coronary artery bypass graft surgery (CABG) have been classified as a high-risk subset of patients who experience non-ST elevation acute coronary syndrome (ACS). Recent studies suggest that an early invasive strategy is beneficial in moderate- and high-risk patients with non-ST elevation ACS. We hypothesized that an early invasive strategy is associated with improved outcomes in patients with non-ST elevation ACS with prior CABG. METHODS AND RESULTS: In the Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 trial (TACTICS-TIMI 18), 2220 patients with non-ST segment elevation ACS were randomized to an early invasive or conservative (selectively invasive) strategy. All patients were treated with aspirin, heparin, and tirofiban. Four hundred eighty-four (22%) of these patients had undergone CABG before enrollment. We analyzed whether patients with previous CABG had different 6-month outcomes and whether an early invasive strategy was associated with an improvement in long-term outcomes. Prior CABG was associated with a higher risk of adverse outcomes by 6 months, including a higher rate of readmission for ACS (17.4% vs 11.0%, P < 0.001) and a higher incidence of the composite end point of death, myocardial infarction, or rehospitalization for ACS (22.3% vs 16.4%, P = 0.002). There was a trend toward a higher incidence of myocardial infarction (7.1% vs 5.3%, P = 0.051). An early invasive strategy was associated with a reduction in the composite of death or myocardial infarction (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.31-1.0; P = 0.089) and a significant reduction in the incidence of myocardial infarction at 6 months (OR, 0.44; 95% CI, 0.21-0.93; P=0.032). CONCLUSIONS: Patients with non-ST segment elevation ACS who have had previous CABG are a high-risk subset. An early invasive strategy reduces risk of myocardial infarction in this high-risk group.

Benefit of an early invasive management strategy in women with acute coronary syndromes.

CONTEXT: Women who present with acute coronary syndromes (ACSs) have different characteristics than men. Reports have conflicted about whether different outcomes exist for women with use of a routine invasive management strategy. However, these studies were performed prior to the widespread use of platelet glycoprotein IIb/IIIa inhibitors and intracoronary stents. OBJECTIVE: To determine sex differences in baseline characteristics and outcomes in ACS and whether women benefit from a contemporary early invasive management strategy. DESIGN AND SETTING: Prospective analysis of women and men enrolled in the TACTICS-TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers in 9 countries in North America and Europe, with follow-up at 1 and 6 months. PARTICIPANTS: A total of 2220 patients (757 women and 1463 men) with ACS. INTERVENTIONS: All patients received aspirin, 325 mg/d; intravenous unfractionated heparin; and tirofiban for 48 hours or until revascularization, with tirofiban administered for at least 12 hours after percutaneous coronary revascularization. Patients assigned to the early invasive strategy (n = 1114) underwent coronary angiography 4 to 48 hours after randomization and revascularization when appropriate. Patients assigned to the early conservative strategy (n = 1106) were treated medically and underwent coronary angiography and appropriate revascularization only if they met specified criteria. MAIN OUTCOME MEASURES: Baseline characteristics and the primary composite end point of death, myocardial infarction, or rehospitalization for ACS at 6 months in women and men assigned to early invasive vs conservative management. RESULTS: Women were older and more frequently had hypertension (P<.001 for both). Women less frequently had previous myocardial infarction, coronary artery bypass grafting, and elevations in cardiac markers (P<.001 for all), but there was no difference in distribution of TIMI risk scores (P =.76). Angiography and intervention rates were similar, but women had less severe coronary artery disease, including no critical lesions in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the primary end point with an early invasive strategy (adjusted odds ratio [OR], 0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted for baseline characteristics, the benefit of invasive therapy in women with elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26-0.83). CONCLUSIONS: Despite differences between women and men in baseline characteristics, the benefit of an early invasive strategy incorporating tirofiban and intracoronary stents was similar in women and men and was enhanced in women presenting with markers of increased risk.

Greater benefit of early invasive strategy for unstable angina and non-ST elevation myocardial infarction in United States compared with non-United States patients: a TACTICS-TIMI 18 substudy.

BACKGROUND: The TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial Infarction 18) trial compared routine invasive to conservative care for the management of patients with unstable angina and non ST-elevation myocardial infarction, and included the routine use of the platelet glycoprotein IIb/IIIa inhibitor tirofiban in the initial medical stabilization of all patients. METHODS: Because previous trials utilizing IIb/IIIa inhibition for acute coronary syndrome (ACS) patients have demonstrated different outcomes in non-US and US patients, the authors sought to determine whether differences in baseline characteristics and practice patterns between 1844 US and 376 non-US patients and physicians would affect outcomes in the TACTICS-TIMI 18 trial. Event rates were stratified by treatment strategy and adjusted for baseline and treatment differences between cohorts. RESULTS: Although US subjects were more likely women, hypertensive, and diabetic, the US and non-US patients did not differ with respect to low, intermediate, or high TIMI risk scores. For US patients, the primary composite end point of death, myocardial infarction (MI), and rehospitalization for ACS was reduced with an invasive strategy by 40% (95% CI: 0.43-0.83) at 30 days and by 30% (95% CI: 0.55-0.88) at 180 days. Non-US patients managed conservatively had 35% fewer events at 180 days than their invasive counterparts resulting in no benefit for the invasive strategy (P = 0.016 for the interaction term between country and treatment group). Similar results were observed for the additional outcome of death and MI, and in troponin-positive patients. Adjustment for baseline characteristics, medications during the initial hospitalization, and the use of cardiac procedures suggested that a higher cross-over rate from conservative to invasive care in non-US patients (59% versus 49%, P = 0.02) was the most likely explanation for the lower event rate in the conservatively managed patients outside the US. CONCLUSION: US patients treated with tirofiban and early routine cardiac catheterization had a 30% reduction in major cardiac events by 6 months compared with those treated with tirofiban and a conservative (selective invasive) approach. Non-US patients treated conservatively had fewer events than US patients, which appears to be related to a higher rate of cross-over to invasive care. These findings emphasize the importance of both risk stratification and invasive management for ACS patients.

Timing of angiography and revascularization in acute coronary syndromes: an analysis of the TACTICS-TIMI-18 trial.

BACKGROUND: In aggregate, published randomized trials of invasive versus conservative treatment in patients with unstable angina and non-ST-segment elevation myocardial infarction support an invasive strategy, but the optimal timing of an invasive approach is not fully established. The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) Thrombolysis in Myocardial Infarction (TIMI)-18 Trial treated all patients with upstream intravenous tirofiban and heparin for 48 hours or until revascularization, and randomized subjects to an invasive or conservative approach. We hypothesized that patients who underwent earlier intervention in the invasive arm would have improved outcomes. METHODS: We evaluated 1,078 participants from the invasive arm, who underwent angiography stratified by time after randomization to the procedure. The composite outcome was death, myocardial infarction (MI), or rehospitalization. RESULTS: At 6 months, the rates of the composite outcome were 15.4 and 19.5% for those undergoing catheterization before and after 48 hours after randomization, respectively, P = 0.34. Rates of individual endpoints were similar except MI, which occurred in 2.9 versus 6.5%, in those who underwent angiography before or after 48 hours, respectively, P = 0.08. CONCLUSION: We could not identify a benefit to early intervention on hard endpoints. There were level time-dependent risks of cardiac events during a period of 48 hours prior to cardiac catheterization possibly due to the effect of glycoprotein IIb/IIIa receptor inhibition. Considering that the groups were not randomized based on time and the potential selection bias in this analysis, these data should be considered only hypothesis generating. A prospective, randomized trial is warranted to explore whether immediate invasive strategy is better than an early invasive strategy in the setting of glycoprotein IIb/IIIa receptor inhibition.

Outcomes at 6 months for the direct comparison of tirofiban and abciximab during percutaneous coronary revascularisation with stent placement: the TARGET follow-up study.

BACKGROUND: Two placebo-controlled trials testing intravenous platelet glycoprotein IIb/IIIa antagonists in the setting of percutaneous coronary revascularisation with intracoronary stents have shown a durable reduction in ischaemic events to 6 months. These trials differed regarding their patient population, IIb/IIIa inhibitor, and reported extent of benefit. Whether a small-molecule agent affecting only the IIb/IIIa receptor would provide a similar outcome for ischaemic events and clinical restenosis at 6 months when directly compared with a monoclonal antibody known to affect several integrin receptors is unknown. METHODS: In 18 countries at 149 hospitals, 4809 patients undergoing elective or urgent stent implantation were randomly assigned a bolus and infusion of tirofiban or abciximab. Patients were followed for 6 months for the occurrence of death, myocardial infarction, and any target-vessel revascularisation. The results at 30 days have been reported previously. FINDINGS: At 6 months the composite endpoint of death, myocardial infarction, and target-vessel revascularisation occurred in 356 (14.8%) patients who received tirofiban and 345 (14.3%) patients who received abciximab (hazard ratio 1.04, 95% CI 0.90-1.21; p=0.591). The rates for the individual endpoints were 191 (8.0%) versus 159 (6.6%) for myocardial infarction (hazard ratio 1.21, 95% CI 0.98-1.50; p=0.074), 26 (1.1%) versus 25 (1.0%) for death (1.04, 0.60-1.80; p=0.893), and 194 (8.1%) versus 208 (8.6%) for target-vessel revascularisation (0.93, 0.77-1.14; p=0.495). INTERPRETATION: At 6 months, tirofiban provided a similar level of overall protection to abciximab against the composite of death, myocardial infarction, and any target-vessel revascularisation.

Cost and cost-effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non-ST-segment elevation myocardial infarction.

CONTEXT: In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-Thrombolysis in Myocardial Infarction (TIMI) 18 trial, patients with either unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI) treated with the platelet glycoprotein (Gp IIb/IIIa) inhibitor tirofiban had a significantly reduced rate of major cardiac events at 6 months with an early invasive vs a conservative strategy. OBJECTIVE: To examine total 6-month costs and long-term cost-effectiveness of an invasive vs a conservative strategy. DESIGN: Randomized controlled trial including a priori economic end points. SETTING: Hospitalization for UA/NSTEMI with 6-month follow-up period. PATIENTS: A total of 2220 patients with UA/NSTEMI; economic data from 1722 patients at US-non-VA hospitals. INTERVENTION: Early invasive strategy with routine catheterization and revascularization as appropriate vs a conservative strategy with catheterization performed only for recurrent ischemia or a positive stress test. MAIN OUTCOME MEASURE: Total 6-month costs and incremental cost-effectiveness ratio. RESULTS: The average initial hospitalization costs among those in the invasive strategy group were $15714 vs $14047 among those in the conservative strategy group, a difference of $1667 (95% confidence interval [CI], $387-3091). The in-hospital costs were offset significantly at the 6-month follow-up, with an average cost in the invasive group of $6098 vs $7180 in the conservative group, a difference of $1082 (95% CI, -$2051 to $76). The average total costs at 6 months, including productivity costs, for the invasive group was $21 813 vs $21 227 for the conservative group, a $586 difference (95% CI, -$1087 to $2486). The average 6-month costs excluding productivity costs in the invasive group was $19 780 vs $19 111 in the conservative group, a difference of $670, 95% CI; (-$1035 to $2321). Estimated cost per year of life gained for the invasive strategy, based on projected life expectancy, was $12739 for the base case, and ranged from $8371 to $25769, based on model assumptions. CONCLUSIONS: In patients with UA/NSTEMI treated with the Gp IIb/IIIa inhibitor tirofiban, the clinical benefit of an early invasive strategy was achieved with a small increase in cost, yielding favorable projected estimates of cost per year of life gained. These results support the broader use of an early invasive strategy in these patients.