Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention: insights into the STRATEGY Study.

OBJECTIVES: The purpose of this study was to evaluate the value of platelet reactivity (PR) in predicting the response to treatment and outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention assisted by glycoprotein (GP) IIb/IIIa inhibition. BACKGROUND: There is limited prognostic information on the role of spontaneous or drug-modulated PR in STEMI patients. METHODS: The PR was measured with Platelet Function Analyzer (PFA)-100 and light transmission aggregometry (LTA) using adenosine diphosphate as agonist in 70 consecutive STEMI patients at entry (PR-T0), 10 min after GP IIb/IIIa bolus (PR-T1), and discharge (PR-T2) and in 30 stable angina (SA) patients (PR-SA). Complete platelet inhibition (CPI) was based on closure time >300 s by PFA-100 and percentage inhibition of platelet aggregation >95% by LTA. Clinical, electrocardiographic, and angiographic responses to treatment during 1-year follow-up were collected. RESULTS: According to both techniques, PR-T0 was higher than: 1) PR-T2 and PR-SA; 2) in those without CPI at T1; and 3) in patients with final Thrombolysis In Myocardial Infarction (TIMI) flow grade <3. The PR-T0 assessed with PFA-100 correlated with: 1) corrected TIMI frame count (r = -0.6, p < 0.001); 2) ST-segment resolution (r = 45, p < 0.001); and 3) creatine kinase-MB (r = -0.47, p < 0.001). At 1 year, patients with high PR-T0 showed an adjusted 5- to 11-fold increase in the risk of death, reinfarction, and target vessel revascularization (hazard ratio [HR] 11, 95% confidence interval [CI] 1.5 to 78 [p = 0.02] in PFA-100; HR 5.2, 95% CI 1.1 to 23 [p = 0.03] in LTA). CONCLUSIONS: The PR at entry affects response to GP IIb/IIIa inhibition, mechanical treatment, and long-term outcome in STEMI patients undergoing primary intervention.

Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial.

CONTEXT: Bare-metal stenting with abciximab pretreatment is currently considered a reasonable reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus-eluting stents significantly reduce the need for target-vessel revascularization (TVR) vs bare-metal stents but substantially increase procedural costs. At current European list prices, the use of tirofiban instead of abciximab would absorb the difference in cost between stenting with sirolimus-eluting vs bare-metal stents. OBJECTIVE: To evaluate the clinical and angiographic impact of single high-dose bolus tirofiban plus sirolimus-eluting stenting vs abciximab plus bare-metal stenting in patients with STEMI. DESIGN, SETTING, AND PATIENTS: Prospective, single-blind, randomized controlled study (Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction [STRATEGY]) of 175 patients (median age, 63 [interquartile range, 55-72] years) presenting to a single referral center in Italy with STEMI or presumed new left bundle-branch block and randomized between March 6, 2003, and April 23, 2004. INTERVENTION: Single high-dose bolus tirofiban regimen plus sirolimus-eluting stenting (n = 87) vs standard-dose abciximab plus bare-metal stenting (n = 88). MAIN OUTCOME MEASURES: The primary end point was a composite of death, nonfatal myocardial infarction, stroke, or binary restenosis at 8 months. Secondary outcomes included freedom, at day 30 and month 8, from major cardiac or cerebrovascular adverse events (composite of death, reinfarction, stroke, and repeat TVR). RESULTS: Cumulatively, 14 of 74 patients (19%; 95% confidence interval [CI], 10%-28%) in the tirofiban plus sirolimus-eluting stent group and 37 of 74 patients (50%; 95% CI, 44%-56%) in the abciximab plus bare-metal stent group reached the primary end point (hazard ratio, 0.33; 95% CI, 0.18-0.60; P<.001 [P<.001 by Fischer exact test]). The cumulative incidence of death, reinfarction, stroke, or TVR was significantly lower in the tirofiban plus sirolimus-eluting stent group (18%) vs the abciximab plus bare-metal stent group (32%) (hazard ratio, 0.53; 95% CI, 0.28-0.92; P = .04), predominantly reflecting a reduction in the need for TVR. Binary restenosis was present in 6 of 67 (9%; 95% CI, 2%-16%) and 24 of 66 (36%; 95% CI, 26%-46%) patients in the tirofiban plus sirolimus-eluting stent and abciximab plus bare-metal stent groups, respectively (P = .002). CONCLUSION: Tirofiban-supported sirolimus-eluting stenting of infarcted arteries holds promise for improving outcomes while limiting health care expenditure in patients with myocardial infarction undergoing primary intervention.

Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) study.

BACKGROUND: Tumor necrosis factor alpha-alpha (TNF-alpha) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. METHODS AND RESULTS: We performed a systematic evaluation of TNF-alpha and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64+/-12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-alpha and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65+/-6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. CONCLUSIONS: sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.

High-dose bolus tirofiban and sirolimus eluting stent versus abiciximab and bare metal stent in acute myocardial infarction (STRATEGY) study--protocol design and demography of the first 100 patients.

BACKGROUND: Primary bare metal stenting and abciximab infusion are currently considered the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus eluting stents (SES), compared to bare metal stent (BMS), greatly reduce the incidence of binary restenosis and target vessel revascularisation (TVR), but their use on a routine basis results in a significant increase in medical costs. With current European list prices, the use of tirofiban instead of abciximab would save enough money to absorb the difference between SES and BMS. AIM: To assess whether in patients with STEMI the combination of SES with high dose bolus (HDB) tirofiban results in a similar incidence of major cardiovascular events (MACE) but in a lower binary restenosis rate after six months compared to BMS and abciximab. METHODS AND RESULTS: 160 patients are required to satisfy the primary composite end-point, including MACE and binary restenosis. The study is ongoing: the current paper focuses on the methodology and demography of the first 100 patients so far enrolled. Patients randomised to HDB tirofiban (n = 50, mean age: 62 +/- 12, 40 males) and abciximab (n = 50, mean age: 63 +/- 12, 38 males) do not differ for medical history, presentation profile, medications at discharge, angiographic profile and creatine-kinase MB-fraction at peak. CONCLUSIONS: The results of the trial will be available by the end of 2004: they will be crucial for the cardiologists to know whether the gold standard for AMI treatment should be reconsidered after the introduction of SES into the clinical practice.

Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction.

OBJECTIVES: We used acetylsalicylic acid (ASA) as a probing agent to quantify hydroxyl radical ((*)OH) in Controls and patients with coronary artery disease and to prospectively investigate (*)OH production in patients with myocardial infarction (MI) complicated by heart failure (HF). BACKGROUND: Oxidative stress status (OSS) is a mechanism for transition to HF in experimental heart injury models, but evidence for its causal role in humans is still limited. METHODS: Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and 74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250 mg Flectadol was given intravenously before each blood collection to determine the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified vitamin E and coenzyme Q(10) to monitor antioxidant reserve, as well as tumor necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL-1ra to assess inflammatory status. All measurements were repeated at month 6 in Group 2. RESULTS: There were no differences between Controls and Group 1. Group 2 showed increased (*)OH production, peaking at 24 h, whereas vitamin E and coenzyme Q(10) progressively declined. Group 2 patients developing HF during hospitalization (Group 2Bi) presented with an increase of both (*)OH production at discharge and inflammatory status, as compared with patients without HF (Group 2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii). CONCLUSIONS: We found a distinct pattern of (*)OH generation in post-MI patients who show progression to HF. The interplay between OSS and inflammatory status should be targeted as a possible mechanism of progression to post-MI left ventricular dysfunction.

Endothelial dysfunction in acute and chronic coronary syndromes: evidence for a pathogenetic role of oxidative stress.

The past two decades have highlighted the pivotal role of the endothelium in preserving vascular homeostasis. Among others, nitric oxide (NO) is currently believed to be the main component responsible for endothelium dependent vasorelaxation and therefore for endothelial function integrity. Reduced NO bioavailability causes the so-called "endothelial dysfunction," which seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions or acute plaque rupture causing unstable angina or myocardial infarction. Compelling evidence is accumulating, stressing the role of oxidative stress in causing reduced NO bioavailability and subsequently endothelial dysfunction (ED). More recently, the role of endothelial cell (EC) apoptosis as a possible final stage of ED and plaque activation has been suggested. In vitro and in vivo evidence suggests a role of oxidative stress also as a putative mechanism finally leading to plaque denudation and activation through increased EC apoptosis. Thus, oxidative stress, irrespective of atherosclerotic disease stages, seems to represent a key phenomenon in vascular disease progression and possible prevention.