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1.
Diabetes Obes Metab ; 18(1): 82-91, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26450639

ABSTRACT

AIMS: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. METHODS: CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. RESULTS: Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. CONCLUSIONS: In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.


Subject(s)
Canagliflozin/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Incretins/administration & dosage , Aged , Biomimetics , Blood Pressure/drug effects , Diabetes Mellitus, Type 2/blood , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Double-Blind Method , Drug Therapy, Combination , Female , Glucagon-Like Peptide-1 Receptor/agonists , Glycated Hemoglobin/analysis , Glycated Hemoglobin/drug effects , Humans , Hypoglycemia/chemically induced , Male , Middle Aged , Sodium-Glucose Transporter 2 Inhibitors , Urologic Diseases/chemically induced , Urologic Diseases/microbiology , Weight Loss/drug effects
2.
J Hum Hypertens ; 30(3): 204-9, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26040438

ABSTRACT

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.


Subject(s)
Blood Pressure/drug effects , Calcimimetic Agents/therapeutic use , Cardiovascular Diseases/prevention & control , Cinacalcet/therapeutic use , Vascular Stiffness , Adult , Aged , Calcimimetic Agents/pharmacology , Cardiovascular Diseases/mortality , Cinacalcet/pharmacology , Female , Humans , Male , Middle Aged
3.
J Clin Pharmacol ; 54(8): 917-27, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24668660

ABSTRACT

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.


Subject(s)
Atrial Fibrillation/metabolism , Factor Xa Inhibitors , Models, Biological , Morpholines , Thiophenes , Aged , Aged, 80 and over , Blood Coagulation/drug effects , Double-Blind Method , Factor Xa/metabolism , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/blood , Factor Xa Inhibitors/pharmacokinetics , Female , Humans , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/blood , Morpholines/pharmacokinetics , Prothrombin Time , Renal Insufficiency/metabolism , Rivaroxaban , Thiophenes/administration & dosage , Thiophenes/blood , Thiophenes/pharmacokinetics
4.
Emerg Med J ; 25(8): 492-7, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18660397

ABSTRACT

OBJECTIVES: To describe the presenting characteristics and risk stratification of patients presenting to the emergency department with chest pain who have a normal initial troponin level followed by a raised troponin level within 12 h (evolving myocardial infarction (EMI)). METHODS: Data from the Internet Tracking Registry for Acute Coronary Syndromes (i*trACS), a registry of patients presenting with undifferentiated chest pain, were used. This analysis included patients without ST segment elevation with at least two troponin assay results < or = 12 h apart. Patients were stratified into three groups: EMI (initial troponin assay negative, second troponin assay positive), non-ST elevation myocardial infarction (NSTEMI) (initial troponin assay positive) and no MI (all troponin assays negative). RESULTS: Of 4136 eligible patients, 5% had EMI, 8% had NSTEMI and 87% had no MI. Patients with EMI were more similar to those with NSTEMI than those with no MI with respect to demographic characteristics, presentation, admission patterns and revascularisation. The initial ECG in patients with EMI was most commonly non-diagnostic (51%), but physicians' initial impressions commonly reflected MI, unstable angina or high-risk chest pain (76%). This risk assessment was followed by a high rate of critical care admissions (32%) and revascularisation (percutaneous coronary intervention 17%) among patients with EMI. CONCLUSION: Patients with EMI appear similar at presentation to those with NSTEMI. Patients with EMI are perceived as being at high risk, evidenced by similar diagnostic impressions, admission practices and revascularisation rates to patients with NSTEMI.


Subject(s)
Angina Pectoris/etiology , Myocardial Infarction/diagnosis , Adolescent , Adult , Age Factors , Electrocardiography , Emergency Service, Hospital/statistics & numerical data , Emergency Treatment , Female , Humans , Male , Middle Aged , Prospective Studies , Risk Assessment , Sex Factors , Troponin/metabolism
5.
Heart ; 94(7): 867-73, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18332062

ABSTRACT

OBJECTIVE: To assess variables associated with the occurrence of atrial fibrillation (AF) and the relation of AF with short- and long-term outcomes and with other in-hospital complications in patients with acute coronary syndromes (ACS) with and without ST-segment elevation. DESIGN: Pooled database of 120 566 patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation (NSTE) ACS enrolled in 10 clinical trials. Multivariable logistic regression and Cox proportional hazards modelling were used to identify factors associated with AF and its relation with clinical outcomes. SETTING: ACS complicated by AF. PATIENTS: 120,566 patients with STEMI and NSTE-ACS in 10 clinical trials. INTERVENTIONS: None evaluated. MAIN OUTCOME MEASURE: Short- and long-term mortality. RESULTS: Occurrence of AF was 7.5% in the overall population (STEMI 8.0% (n = 84 161); NSTE-ACS = 6.4% (n = 36,405)). Seven-day mortality was higher for patients with AF (5.1%) than for those without (1.6%). After adjusting for confounders, association of AF with 7-day mortality was present in STEMI (hazards ratio (HR) = 1.65; 95% CI 1.44 to 1.90) and NSTE-ACS (HR = 2.30; 95% CI 1.83 to 2.90; p interaction = 0.015). Risk of long-term mortality (day 8 to 1 year) was also higher in STEMI (HR = 2.37; 95% CI 1.79 to 3.15) and NSTE-ACS (HR = 1.67; 95% CI 1.41 to 1.99). AF had a larger impact in NSTE-ACS on risk of short-term mortality (p<0.001), stroke (p<0.001), ischaemic stroke (p<0.001) and moderate or severe bleeding (p<0.001). CONCLUSIONS: AF is more common in patients with STEMI. An association of AF with short- and long-term mortality among patients with STEMI and NSTE-ACS was found. Understanding these findings may lead to better care of patients with this common arrhythmia.


Subject(s)
Acute Coronary Syndrome/epidemiology , Atrial Fibrillation/epidemiology , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/physiopathology , Age Factors , Aged , Atrial Fibrillation/drug therapy , Atrial Fibrillation/physiopathology , Electrocardiography , Epidemiologic Methods , Female , Hospitalization , Humans , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/physiopathology , Prognosis
6.
Eur Heart J ; 25(4): 313-21, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14984920

ABSTRACT

AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017). CONCLUSIONS: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.


Subject(s)
Coronary Disease/enzymology , Creatine Kinase/metabolism , Isoenzymes/metabolism , Acute Disease , Aged , Biomarkers/blood , Coronary Disease/mortality , Coronary Disease/therapy , Creatine Kinase, MB Form , Female , Hospital Mortality , Humans , Male , Middle Aged , Multivariate Analysis , Patient Selection , Treatment Outcome
7.
Eur Heart J ; 24(6): 522-31, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12643885

ABSTRACT

BACKGROUND: Although the prognostic value of admission ST changes in patients with non-ST elevation acute coronary syndrome (ACS) is established, the utility of the discharge ECG is unknown. Accordingly, using the PARAGON-B Troponin substudy, we assessed the prevalence of ST depression on both admission and discharge ECG, the likelihood of developing new Q-waves at discharge and the additional prognostic value of these changes. METHODS AND RESULTS: Nine hundred and eighteen patients were studied; 542 patients (59%) had admission ST downward arrow > or =1mm and 376 patients (41%) did not and their 6-month mortality was 4.4 vs 0.8%, P=0.002, respectively. Of patients with ST downward arrow on admission, 320 (59%) normalized their ST segment at discharge. Of patients without ST downward arrow on admission, 35 (9.3%) developed new ST downward arrow at discharge. Patients with persistent ST downward arrow on discharge had a higher 6-month mortality (6.0 vs 0.9%), (re)MI (16.3 vs 7.4%), and death/(re)MI (20.0 vs 8.3%) than those who never had ST downward arrow (all P< or =0.002). Two hundred and fifty-six patients had Q-waves on admission whereas by discharge 320 had Q-waves. Patients with Q-waves on discharge vs those without had a higher mortality (4.8 vs 1.9%), (re)MI (13.8 vs 8.3%), and death/(re)MI (16.4 vs 9.6%) at 6 months (all P< or =0.021). CONCLUSIONS: This study highlights that the dynamic ECG changes which occur between admission and discharge in non-ST elevation ACS patients allows further risk stratification in determining the likelihood of 6-month death and/or re(MI).


Subject(s)
Arrhythmias, Cardiac/physiopathology , Coronary Disease/physiopathology , Tyrosine/analogs & derivatives , Acetates/therapeutic use , Acute Disease , Aged , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/surgery , Coronary Disease/drug therapy , Coronary Disease/surgery , Disease-Free Survival , Electrocardiography , Female , Hospitalization , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/therapeutic use , Prognosis , Survival Analysis , Troponin T/analysis , Tyrosine/therapeutic use
8.
J Am Coll Cardiol ; 38(6): 1608-13, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11704394

ABSTRACT

OBJECTIVES: We performed a multicenter, double-blind placebo-controlled trial to examine the efficacy and safety of enoxaparin in patients at high risk for stent thrombosis (ST). BACKGROUND: The optimal antithrombotic regimen for such patients is unknown. METHODS: We randomized 1,102 patients with clinical, angiographic or ultrasonographic features associated with an increased risk of ST to receive either twice-daily injections of weight-adjusted enoxaparin or placebo for 14 days after stenting. All patients received aspirin and ticlopidine. The primary end point was a 30-day composite end point of death, myocardial infarction (MI) or urgent revascularization. RESULTS: The target enrollment for the study was 2,000 patients. However, the trial was terminated prematurely at 1,102 patients after interim analysis revealed an unexpectedly low event rate. The primary outcome occurred in 1.8% enoxaparin-treated patients versus 2.7% treated with placebo (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.29 to 1.5, p = 0.30); for death or MI the rates were 0.9% vs. 2.2%, respectively (OR 0.41, 95% CI 0.14 to 1.2, p =0.13); and for MI, 0.4% vs. 1.6%, respectively (OR 0.22, 95% CI 0.05 to 0.99, p = 0.04). The groups had comparable rates of major bleeding (3.3% for enoxaparin, 1.6% for placebo, p =0.08), but minor nuisance bleeding was increased with enoxaparin (25% vs. 5.1%, p < 0.001). CONCLUSIONS: The clinical outcomes of patients at increased risk of ST are more favorable than previously reported, rendering routine oral antiplatelet therapy adequate for most. However, given its relative safety and potential to reduce the risk of subsequent infarction, a 14-day course of enoxaparin may be considered for carefully selected patients.


Subject(s)
Anticoagulants/therapeutic use , Coronary Thrombosis/prevention & control , Enoxaparin/therapeutic use , Stents/adverse effects , Aged , Analysis of Variance , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Aspirin/therapeutic use , Coronary Disease/therapy , Double-Blind Method , Drug Administration Routes , Drug Therapy, Combination , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Female , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Ticlopidine/therapeutic use , Treatment Outcome
9.
Curr Cardiol Rep ; 3(5): 362-70, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11504572

ABSTRACT

Heparin-induced thrombocytopenia (HIT) is not uncommon in clinical practice, and may go unrecognized in a substantial number of patients. The pathophysiology of HIT has only recently been better understood. Patients with HIT may require anticoagulation for thrombotic complications that result in severe morbidity and mortality. These patients may also require anticoagulation for acute coronary syndromes (ACS), or during percutaneous coronary interventions (PCIs). The direct thrombin inhibitors are currently the anticoagulant of choice in HIT patients with ACS or those undergoing PCI, based on data from several large clinical trials in ACS and PCI populations, and data from smaller experiences, specifically in patients with HIT.


Subject(s)
Angina, Unstable/drug therapy , Angioplasty, Balloon, Coronary , Anticoagulants/therapeutic use , Heparin/adverse effects , Myocardial Infarction/drug therapy , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy , Ancrod/therapeutic use , Anticoagulants/adverse effects , Antithrombins/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Heparinoids/therapeutic use , Humans , Platelet Aggregation Inhibitors/therapeutic use , Thrombocytopenia/physiopathology
12.
J Am Coll Cardiol ; 37(1): 9-18, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11153779

ABSTRACT

Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.


Subject(s)
Coronary Circulation/physiology , Myocardial Infarction/therapy , Myocardial Reperfusion Injury/prevention & control , Myocardial Revascularization , Animals , Diagnostic Imaging , Humans , Microcirculation/physiopathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/physiopathology , Treatment Outcome
13.
Circulation ; 101(4): 366-71, 2000 Feb 01.
Article in English | MEDLINE | ID: mdl-10653826

ABSTRACT

BACKGROUND: In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). METHODS AND RESULTS: We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year. CONCLUSIONS: Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.


Subject(s)
Angina, Unstable/drug therapy , Myocardial Infarction/drug therapy , Peptides/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Angina, Unstable/economics , Cost-Benefit Analysis , Eptifibatide , Female , Follow-Up Studies , Humans , Length of Stay , Male , Middle Aged , Myocardial Infarction/economics , Peptides/economics , Platelet Aggregation Inhibitors/economics , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Prospective Studies , Risk Factors , United States
14.
Eur Heart J ; 21(5): 371-81, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10666351

ABSTRACT

AIMS: Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial. METHODS: In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect. RESULTS: Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment. CONCLUSION: The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process.


Subject(s)
Coronary Disease/drug therapy , Peptides/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Aged , Coronary Disease/mortality , Double-Blind Method , Eptifibatide , Europe , Female , Humans , Latin America , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/mortality , North America , Odds Ratio , Time Factors , Treatment Outcome
15.
JAMA ; 283(3): 347-53, 2000 Jan 19.
Article in English | MEDLINE | ID: mdl-10647797

ABSTRACT

CONTEXT: Controversy surrounds the diagnostic and prognostic importance of slightly elevated cardiac markers in patients with acute coronary syndromes without ST-segment elevation. OBJECTIVES: To investigate the relationship between peak creatine kinase (CK)-MB level and outcome and to determine whether a threshold CK-MB level exists below which risk is not increased. DESIGN AND SETTING: Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997. PATIENTS: A total of 8250 patients with acute coronary syndromes without ST-segment elevation who had at least 1 CK-MB sample collected during their index hospitalization. MAIN OUTCOME MEASURE: Mortality at 30 days and 6 months, was assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3, >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic regression was used to determine the independent prognostic significance of peak CK-MB level after adjustment for baseline predictors of 30-day and 6-month mortality. RESULTS: Mortality at 30 days and 6 months increased from 1.8% and 4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2 % at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3 to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10 times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30-day and 6-month mortality (P<.001 for both). CONCLUSIONS: Our data show that elevation of CK-MB level is strongly related to mortality in patients with acute coronary syndromes without ST-segment elevation, and that the increased risk begins with CK-MB levels just above normal. In the appropriate clinical context, even minor CK-MB elevations should be considered indicative of myocardial infarction.


Subject(s)
Creatine Kinase/blood , Myocardial Ischemia/blood , Myocardial Ischemia/mortality , Acute Disease , Biomarkers/blood , Female , Humans , Isoenzymes , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/blood , Myocardial Infarction/mortality , Prognosis , Regression Analysis , Retrospective Studies
17.
J Am Coll Cardiol ; 34(6): 1711-20, 1999 Nov 15.
Article in English | MEDLINE | ID: mdl-10577561

ABSTRACT

OBJECTIVES: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. BACKGROUND: Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects. METHODS: The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke). RESULTS: In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89). CONCLUSIONS: Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.


Subject(s)
Adenosine/therapeutic use , Myocardial Infarction/drug therapy , Thrombolytic Therapy , Vasodilator Agents/therapeutic use , Adult , Aged , Female , Humans , Male , Middle Aged , Myocardial Infarction/diagnostic imaging , Prospective Studies , Radiography , Tomography, Emission-Computed, Single-Photon , Treatment Outcome
18.
Am Heart J ; 138(3 Pt 1): 493-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10467200

ABSTRACT

BACKGROUND: Intracranial hemorrhage is an uncommon but very dangerous complication in patients receiving thrombolytic therapy for acute myocardial infarction. Neurosurgical evacuation is often an available treatment option. However, the association between neurosurgical evacuation and clinical outcomes in these patients has yet to be determined. METHODS: The GUSTO-I trial randomly assigned 41,021 patients with acute myocardial infarction to 1 of 4 thrombolytic strategies in 1081 hospitals in 15 countries. A total of 268 patients (0.65%) had an intracranial hemorrhage. We assessed differences in clinical characteristics, neuroimaging features, Glasgow coma scale scores, functional status (disabled: moderate or severe deficit; not disabled: no or minor deficit) and 30-day mortality rate between the 46 patients who underwent neurosurgical evacuation and the 222 patients who did not. RESULTS: Mortality rate at 30 days for all patients with intracranial hemorrhage was 60%; an additional 27% were disabled. Evacuation was associated with significantly higher 30-day survival (65% versus 35%, P <.001) and a trend toward improved functional status (nondisabling stroke: 20% versus 12%, P =.15). CONCLUSIONS: Although intracranial hemorrhage is uncommon after thrombolysis for acute myocardial infarction, 87% of patients die or have disabling stroke. Although not definitive, these data indicate that neurosurgical evacuation may be associated with improved clinical outcomes. Physicians treating such patients should consider early neurosurgical consultation and intervention in these patients.


Subject(s)
Cerebral Hemorrhage/surgery , Myocardial Infarction/drug therapy , Neurosurgical Procedures , Outcome Assessment, Health Care , Thrombolytic Therapy/adverse effects , Aged , Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/mortality , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/etiology , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Prognosis , Risk Assessment , Survival Analysis
19.
Circulation ; 99(18): 2371-7, 1999 May 11.
Article in English | MEDLINE | ID: mdl-10318656

ABSTRACT

BACKGROUND: The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates. METHODS AND RESULTS: We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke. CONCLUSIONS: Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.


Subject(s)
Angina, Unstable/complications , Cerebrovascular Disorders/epidemiology , Peptides/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Acute Disease , Age Factors , Aged , Angina, Unstable/drug therapy , Aspirin/therapeutic use , Brain Damage, Chronic/epidemiology , Brain Damage, Chronic/etiology , Brain Damage, Chronic/prevention & control , Cerebral Hemorrhage/epidemiology , Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/prevention & control , Cerebral Infarction/epidemiology , Cerebral Infarction/etiology , Cerebral Infarction/prevention & control , Cerebrovascular Disorders/etiology , Cerebrovascular Disorders/prevention & control , Comorbidity , Diabetes Mellitus/epidemiology , Double-Blind Method , Drug Therapy, Combination , Electrocardiography , Eptifibatide , Female , Heart Rate , Heparin/therapeutic use , Humans , Hyperlipidemias/epidemiology , Hypertension/epidemiology , Incidence , Male , Middle Aged , Obesity/epidemiology , Odds Ratio , Prospective Studies , Recurrence , Risk Factors , Smoking/epidemiology , Treatment Outcome
20.
J Am Coll Cardiol ; 33(1): 88-96, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9935014

ABSTRACT

OBJECTIVES: We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide. BACKGROUND: Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain. METHODS: Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n=3,535) and CK-MB (n=2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site's upper normal limit). RESULTS: Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure. CONCLUSIONS: Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI.


Subject(s)
Coronary Disease/therapy , Creatine Kinase/blood , Myocardial Infarction/therapy , Peptides/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Aged , Angioplasty, Balloon, Coronary , Angioplasty, Laser , Atherectomy, Coronary , Coronary Disease/diagnosis , Coronary Disease/enzymology , Eptifibatide , Female , Follow-Up Studies , Humans , Isoenzymes , Male , Middle Aged , Myocardial Infarction/diagnosis , Myocardial Infarction/enzymology , Peptides/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Recurrence , Risk , Stents , Treatment Outcome
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