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ABSTRACT: This study sought to evaluate the relationship between microalbuminuria (MA) and the development and progression of atherosclerosis, as assessed by incident and progression of coronary artery calcification (CAC).
MA is associated with an increased risk of cardiovascular disease, but the mechanism by which MA imparts this increased risk is not known.
The MESA (Multi-Ethnic Study of Atherosclerosis) study is a prospective cohort study of 6,814 self-identified White, African-American, Hispanic, or Chinese participants free of clinical cardiovascular disease at entry. Of the 6,775 individuals with available urine albumin data, we excluded 97 subjects with macroalbuminuria and 1,023 with missing follow-up CAC data. The final study population consists of 5,666 subjects.
At baseline, individuals with MA were more likely to have CAC >0 compared with those without MA (62% vs. 48%, p < 0.0001). During a mean follow-up of 2.4 +/- 0.8 years, those with MA and no CAC at baseline were more likely to develop CAC (relative risk [RR]: 2.05, 95% confidence interval [CI]: 1.41 to 3.02, p < 0.0001) as compared with those without MA in demographic-adjusted analyses. After multivariant adjustment, the relationship was attenuated but remained statistically significant (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005). Among those with CAC at baseline, those with versus those without MA had a 15 (95% CI: 8 to 22, p < 0.0001) volume units higher median increase in CAC in demographic-adjusted analyses. After multivariant adjustment, MA remained associated with incident CAC (RR: 1.76, 95% CI: 1.19 to 2.61, p = 0.005) and with progression of CAC (median increase in CAC volume score of 9 [95% CI: 2 to 16, p = 0.009]), relative to those without MA.
This large multiethnic, population-based study of asymptomatic individuals demonstrates an increased risk of incident CAC as well as greater CAC progression among those with MA. Further study is needed to determine the degree to which MA precedes and predicts progression of atherosclerosis and how this information can be used to reduce cardiovascular events.
JACC. Cardiovascular imaging 06/2010; 3(6):595-604. · 14.29 Impact Factor
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ABSTRACT: The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC (coronary artery calcium), which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as "zero-inflated data" and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms.
PLoS ONE 01/2010; 5(8):e12036. · 4.09 Impact Factor
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A Michael Lincoff,
Neal S Kleiman,
Dean J Kereiakes,
Frederick Feit,
John A Bittl,
J Daniel Jackman,
Ian J Sarembock,
David J Cohen,
Douglas Spriggs,
Ramin Ebrahimi,
Gadi Keren, Jeffrey Carr,
Eric A Cohen,
Amadeo Betriu,
Walter Desmet,
Wolfgang Rutsch,
Robert G Wilcox,
Pim J de Feyter,
Alec Vahanian,
Eric J Topol
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ABSTRACT: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI).
To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year.
Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.
Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.
Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment.
At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P =.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P =.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P =.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P =.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients.
Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.
JAMA The Journal of the American Medical Association 09/2004; 292(6):696-703. · 30.03 Impact Factor
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A Michael Lincoff,
John A Bittl,
Robert A Harrington,
Frederick Feit,
Neal S Kleiman,
J Daniel Jackman,
Ian J Sarembock,
David J Cohen,
Douglas Spriggs,
Ramin Ebrahimi, [......], Jeffrey Carr,
Eric A Cohen,
Amadeo Betriu,
Walter Desmet,
Dean J Kereiakes,
Wolfgang Rutsch,
Robert G Wilcox,
Pim J de Feyter,
Alec Vahanian,
Eric J Topol
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ABSTRACT: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI).
To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications.
The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.
Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.
The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization.
Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P =.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P =.40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001).
Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.
JAMA The Journal of the American Medical Association 02/2003; 289(7):853-63. · 30.03 Impact Factor
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A. Michael Lincoff,
John A. Bittl,
Robert A. Harrington,
Frederick Feit,
Neal S. Kleiman,
J. Daniel Jackman,
Ian J. Sarembock,
David J. Cohen,
Douglas Spriggs,
Ramin Ebrahimi, [......],
Eric A. Cohen,
Amadeo Betriu,
Walter Desmet,
Dean J. Kereiakes,
Wolfgang Rutsch,
Robert G. Wilcox,
Pim J. de Feyter,
Alec Vahanian,
Eric J. Topol,
for the Investigators
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ABSTRACT: Context
The direct thrombin inhibitor bivalirudin has been associated with better
efficacy and less bleeding than heparin during coronary balloon angioplasty
but has not been widely tested during contemporary percutaneous coronary intervention
(PCI).Objective
To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa
(Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI,
compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection
from periprocedural ischemic and hemorrhagic complications.Design, Setting, and Participants
The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical
Events (REPLACE)–2 trial, a randomized, double-blind, active-controlled
trial conducted among 6010 patients undergoing urgent or elective PCI at 233
community or referral hospitals in 9 countries from October 2001 through August
2002.Interventions
Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg
bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional
Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned
Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups
received daily aspirin and a thienopyridine for at least 30 days after PCI.Main Outcome Measures
The primary composite end point was 30-day incidence of death, myocardial
infarction, urgent repeat revascularization, or in-hospital major bleeding;
the secondary composite end point was 30-day incidence of death, myocardial
infarction, or urgent repeat revascularization.Results
Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients
in the bivalirudin group. By 30 days, the primary composite end point had
occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients
in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval,
0.77-1.09; P = .32). The secondary composite end
point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients
in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval
0.90-1.32; P = .40). Prespecified statistical criteria
for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end
points. In-hospital major bleeding rates were significantly reduced by bivalirudin
(2.4% vs 4.1%; P<.001).Conclusions
Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not
inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary
PCI with regard to suppression of acute ischemic end points and is associated
with less bleeding.
Figures in this Article
Unfractionated heparin has been the standard of adjunctive antithrombin
therapy during percutaneous coronary intervention (PCI) for more than 25 years.
Yet heparin is subject to important intrinsic limitations, including unpredictable
pharmacokinetics, inhibition by plasma proteins, and the potential to activate
platelets.1- 4 Considerable
reductions in periprocedural complications have been achieved with administration
of glycoprotein IIb/IIIa (Gp IIb/IIIa) antagonists in addition to heparin.5 These potent platelet inhibitors are not used universally,
however, in part because of concerns about cost and increased bleeding risk.
The direct thrombin inhibitor bivalirudin was approved for clinical
use in December 2000 as an alternative to heparin for patients with unstable
angina during PCI, based primarily on the results of a randomized trial conducted
between 1993 and 1994. In that study of 4312 patients, ischemic events were
decreased by 22% and hemorrhagic complications by 62% with bivalirudin compared
with heparin.6- 7 The relevance
of these data to current interventional practice is unknown, given that coronary
artery stents, Gp IIb/IIIa inhibitors, low-dose heparin regimens, and thienopyridines
were not used at the time of that trial. Two smaller more contemporary pilot
studies did suggest, however, that by replacing heparin with bivalirudin during
PCI, adjunctive Gp IIb/IIIa blockade might be used selectively rather than
for all patients.8- 9 If validated,
such an approach might offer potential advantages with regard to cost, hemorrhagic
risk, and procedural simplicity.
Our current randomized trial was therefore performed to determine if
bivalirudin, with Gp IIb/IIIa inhibitors used in a provisional fashion if
necessary during the procedure, could provide protection from ischemic and
bleeding complications of PCI comparable with the current efficacy standard
of low-dose heparin plus routine Gp IIb/IIIa blockade.
JAMA The Journal of the American Medical Association 289(7):853-863. · 30.03 Impact Factor
