Publications by authors named "Judith Hsia"

85 Publications

Reduction in Acute Limb Ischemia with Rivaroxaban versus Placebo in Peripheral Artery Disease after Lower Extremity Revascularization: Insights from VOYAGER PAD.

Circulation 2021 Oct 12. Epub 2021 Oct 12.

Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; CPC Clinical Research, Aurora, CO.

Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Prior lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. VOYAGER PAD (NCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan Meier estimates, and Cox proportional-hazards models were used to generate hazard ratios and associated confidence intervals. Analyses were performed as intention-to-treat. Among 6,564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, prior LER, baseline ABI <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (HR 2.59, 95% CI 1.98-3.39) and major amputation (HR 24.87, 95% CI 18.68-33.12). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction 2.6% at 3 years, HR 0.67, 95% CI 0.55-0.82, P=0.0001), with benefit starting early (HR 0.45, 95% CI 0.24-0.85, P=0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and ICU stay, HR 0.58, 95% CI 0.40-0.83, P=0.003) and regardless of LER type (surgical vs endovascular revascularization, p-interaction=0.42) or clopidogrel use (p-interaction=0.59). After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055146DOI Listing
October 2021

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.

JAMA Intern Med 2021 Oct 7. Epub 2021 Oct 7.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Importance: Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown.

Objective: To evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19.

Design, Setting, And Participants: The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US.

Interventions: Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status.

Main Outcomes And Measures: The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data.

Results: Of 257 patients randomized, 253 were included in the analysis (mean [SD] age, 66.7 [14.0] years; men, 136 [53.8%]; women, 117 [46.2%]); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk [RR], 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71).

Conclusions And Relevance: In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT04401293.
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http://dx.doi.org/10.1001/jamainternmed.2021.6203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498934PMC
October 2021

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

Eur Heart J 2021 10;42(39):4040-4048

CPC Clinical Research, 2115 N Scranton Street, Suite 2040, Aurora, CO, USA.

Aims: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described.

Methods And Results: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding).

Conclusion: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.
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http://dx.doi.org/10.1093/eurheartj/ehab408DOI Listing
October 2021

Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y inhibitors: Insights from the EUCLID trial.

Vasc Med 2021 Jun 3:1358863X211017641. Epub 2021 Jun 3.

CPC Clinical Research, Aurora, CO, USA.

Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45-59, and < 45 mL/min/1.73 m, respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR ( for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively ( for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment ( < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. .
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http://dx.doi.org/10.1177/1358863X211017641DOI Listing
June 2021

Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial.

Sci Transl Med 2021 04;13(590)

Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.
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http://dx.doi.org/10.1126/scitranslmed.abb0602DOI Listing
April 2021

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

Am Heart J 2021 05 9;235:12-23. Epub 2021 Feb 9.

CPC Clinical Research, Aurora, CO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.

Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established.

Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events.

Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.
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http://dx.doi.org/10.1016/j.ahj.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871775PMC
May 2021

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations.

Circ Heart Fail 2017 Apr;10(4)

From the Department of Medicine, Stony Brook University, NY (J.B., C.E.H.); Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston, MA (J.E.U.); Division of Cardiology, Inova Heart & Vascular Institute, Falls Church, VA (C.O'C.); Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI (H.N.S.); Division of Cardiology, University of Brescia and Civil Hospital, Italy (M.M.); Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S., C.Y.); Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiology, University of California San Francisco (J.R.T.); Merck & Co., Kenilworth, NJ (H.S.B., J.K.); Gilead Sciences, Foster City, CA (G.B., J.H., C.S.); Amgen Inc., Thousand Oaks, CA (C.D., M.K.); Bristol-Myers Squibb, Princeton, NJ (M.M.D., M.D., R.J.F., P.M., S.M., C.R.); Bayer, Wuppertal, Germany (W.D., M.v.d.L.); Department of Cardiology, HELIOS Clinic Wuppertal, University Hospital Witten/Herdecke, Germany (W.D.); AstraZeneca, Gaithersburg, MD (R.F.-D., J.H., L.-M.G.); AstraZeneca, Gothenburg, Sweden (R.F.-D., J.H., L.-M.G.); Relypsa Inc., Redwood City, CA (D.G., M.M.); Vifor Pharma, Opfikon, Switzerland (U.-M.G.); Department of Cardiology, Nippon Medical School Musashi-Kosugi Hospital, Kawasaki, Japan (S.I.); Novartis Pharmaceuticals Inc., East Hanover, NJ (P.K.-M., V.S.); Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (C.J.L.); Bayer Pharma AG, Wuppertal, Germany (L.R.); Cardiology Division, Columbia University Medical Center, New York, NY (C.R.); Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT (A.S.); Moderna Therapeutics, Cambridge, MA (B.T.); Division of Cardiovascular and Renal Products, United States Food and Drug Administration, Silver Spring, MD (N.S.); Center for Cardiovascular Innovation, Feinberg School of Medicine, Northwestern University, Chicago, IL (M.G.).

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.116.003800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400283PMC
April 2017

An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers.

Int J Clin Pharmacol Ther 2015 Feb;53(2):182-9

Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally.

Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post-ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study.

Results: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80-125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated.

Conclusions: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and ARC124910XX at early timepoints.
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http://dx.doi.org/10.5414/CP202202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302705PMC
February 2015

Evaluation of the pharmacokinetic interaction between ticagrelor and venlafaxine, a cytochrome P-450 2D6 substrate, in healthy subjects.

Clin Ther 2014 Sep 26;36(9):1217-25. Epub 2014 Jul 26.

AstraZeneca LP, Wilmington, Delaware.

Purpose: Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated.

Methods: Healthy subjects (N = 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study.

Findings: Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m(2). Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC0-τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27-114.52]). Venlafaxine Cmax was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80-132.75]). ODV AUC0-τ and Cmax were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61-100.85] and 101.44 ng/mL [90% CI, 98.34-104.65], respectively). Venlafaxine had no effect on the Cmax or AUC0-∞ of ticagrelor (96.54 ng/mL [90% CI, 85.03-109.61] and 89.67 ng · h/mL [90% CI, 82.78-97.14]) or AR-C124910XX (106.39 ng/mL [90% CI, 96.10-117.78] and 106.32 ng · h/mL [90% CI, 97.28-116.21], respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination.

Implications: Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor.
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http://dx.doi.org/10.1016/j.clinthera.2014.06.024DOI Listing
September 2014

Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers.

Clin Drug Investig 2014 Aug;34(8):529-36

Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA,

Background And Objective: Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y(12) receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug-drug interaction between ticagrelor and cyclosporine.

Methods: In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of ≥14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed.

Results: Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 2.83 (2.63-3.06), and the maximum plasma concentration (C(max)) was 2.30 (2.06-2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC(∞) (1.33 [1.23-1.42]) and decreased C(max) (0.85 [0.76-0.94]). Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80-1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated.

Conclusion: Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine's effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.
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http://dx.doi.org/10.1007/s40261-014-0205-2DOI Listing
August 2014

Proteomic risk markers for coronary heart disease and stroke: validation and mediation of randomized trial hormone therapy effects on these diseases.

Genome Med 2013 27;5(12):112. Epub 2013 Dec 27.

Department of Clinical Cancer Prevention, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, 6767 Bertner Street, Houston, TX 77030, USA.

Background: We previously reported mass spectrometry-based proteomic discovery research to identify novel plasma proteins related to the risk of coronary heart disease (CHD) and stroke, and to identify proteins with concentrations affected by the use of postmenopausal hormone therapy. Here we report CHD and stroke risk validation studies for highly ranked proteins, and consider the extent to which protein concentration changes relate to disease risk or provide an explanation for hormone therapy effects on these outcomes.

Methods: Five proteins potentially associated with CHD (beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), thrombospondin-1(THBS1), complement factor D pre-protein (CFD), and insulin-like growth factor binding protein 1 (IGFBP1)) and five potentially associated with stroke (B2M, IGFBP2, IGFBP4, IGFBP6, and hemopexin (HPX)) had high discovery phase significance level ranking and an available ELISA assay, and were included in case-control validation studies within the Women's Health Initiative (WHI) hormone therapy trials. Protein concentrations, at baseline and 1 year following randomization, were assessed for 358 CHD cases and 362 stroke cases, along with corresponding disease-free controls. Disease association, and mediation of estrogen-alone and estrogen plus progestin effects on CHD and stroke risk, were assessed using logistic regression.

Results: B2M, THBS1, and CFD were confirmed (P <0.05) as novel CHD risk markers, and B2M, IGFBP2, and IGFBP4 were confirmed as novel stroke disease risk markers, while the assay for HPX proved to be unreliable. The change from baseline to 1 year in B2M was associated (P <0.05) with subsequent stroke risk, and trended similarly with subsequent CHD risk. Change from baseline to 1 year in IGFBP1 was also associated with CHD risk, and this change provided evidence of hormone therapy effect mediation.

Conclusions: Plasma B2M is confirmed to be an informative risk marker for both CHD and stroke. The B2M increase experienced by women during the first year of hormone therapy trial participation conveys cardiovascular disease risk. The increase in IGFBP1 similarly conveys CHD risk, and the magnitude of the IGFBP1 increase following hormone therapy may be a mediator of hormone therapy effects. Plasma THBS1 and CFD are confirmed as CHD risk markers, and plasma IGFBP4 and IGFBP2 are confirmed as stroke risk markers.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00000611.
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http://dx.doi.org/10.1186/gm517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971342PMC
May 2014

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

JAMA 2013 Oct;310(13):1353-68

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Importance: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.

Objective: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.

Design, Setting, And Participants: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.

Interventions: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.

Main Outcomes And Measures: Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.

Results: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.

Conclusions And Relevance: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Trial Registration: clinicaltrials.gov Identifier: NCT00000611.
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http://dx.doi.org/10.1001/jama.2013.278040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963523PMC
October 2013

Relationships of coronary heart disease with 27-hydroxycholesterol, low-density lipoprotein cholesterol, and menopausal hormone therapy.

Circulation 2012 Sep 29;126(13):1577-86. Epub 2012 Aug 29.

National Heart, Lung, and Blood Institute, Rockledge 2 Bldg, Room 9192, Bethesda, MD 20892, USA.

Background: Menopausal hormone therapy (MHT) increases the risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block the beneficial effects of estrogen on the cardiovascular system.

Methods And Results: We conducted a nested case-control study in the Women's Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval, 1.08-1.23) and was unchanged at 1.14 (95% confidence interval, 1.07-1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (P=0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (P for interaction=0.02), and adding 27OHC did not affect this result. With the use of log scales, the effect of MHT on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at ≈3.36 mmol/L (130 mg/dL).

Conclusions: This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.103218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482942PMC
September 2012

Comparing the effectiveness of rosuvastatin and atorvastatin in preventing cardiovascular outcomes: estimates using the Archimedes model.

J Med Econ 2012 6;15(6):1118-29. Epub 2012 Jul 6.

Archimedes Inc., San Francisco, CA 94105, USA.

Objective: This study used simulation to compare the effectiveness of rosuvastatin 20 mg vs atorvastatin 40 mg, and rosuvastatin 40 mg vs atorvastatin 80 mg in preventing MACE in a range of patient populations with varying baseline cardiovascular risk.

Research Design And Methods: The Archimedes Model was used to simulate head-to-head clinical trials in nine patient populations: Framingham Risk Score (FRS)≥5%, 5-10%, 10-20%, >20%, EURO-SCORE≥5% and >10%, diagnosed diabetes, secondary prevention (history of myocardial infarction or stroke, CVD), and acute coronary syndrome (ACS). Simulated patients, aged 45-70 at trial start, were based on the NHANES 1999-2006. Treatments were modeled using results from the STELLAR, JUPITER, CARDS, ASCOT-LLA, and TNT trials. Treatment models were confirmed using trial validations.

Results: Comparing rosuvastatin 20 mg vs atorvastatin 40 mg, the 5-year numbers needed to treat to prevent one MACE event (NNT) were 525, 70, and 55 for the FRS≥5%, CVD, and ACS groups, respectively. Comparing rosuvastatin 40 mg vs atorvastatin 80 mg the corresponding NNT values were 468, 63, and 51. The 20-year relative risks of MACE in the FRS≥5% population were 0.907 (0.901-0.913) for rosuvastatin 20 mg vs atorvastatin 40 mg and 0.892 (0.884-0.901) for rosuvastatin 40 mg vs atorvastatin 80 mg. The relative risks were similar for the remaining populations.

Conclusions: This study found that rosuvastatin 20 mg and 40 mg lowers the risk of MACE more than atorvastatin 40 mg and atorvastatin 80 mg. While simulation models cannot replace real-world clinical trials, this study bridges gaps in the evidence, and identifies high risk cohorts that would likely see additional benefit from treatment with rosuvastatin rather than atorvastatin.
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http://dx.doi.org/10.3111/13696998.2012.704459DOI Listing
April 2013

Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).

J Am Coll Cardiol 2011 Apr;57(16):1666-75

AstraZeneca LP, 1800 Concord Pike, Wilmington, DE 19850-5437, USA.

Objectives: The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels <50 mg/dl with rosuvastatin in apparently healthy adults in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial.

Background: The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain.

Methods: A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C <130 mg/dl were randomly allocated to rosuvastatin 20 mg daily or placebo, and followed up for all-cause mortality, major cardiovascular events, and adverse events. In a post-hoc analysis, participants allocated to rosuvastatin were categorized as to whether or not they had a follow-up LDL-C level <50 mg/dl.

Results: During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C <50 mg/dl (n = 4,000) or with LDL-C <50 mg/dl (n = 4,154), respectively (fully-adjusted hazard ratio: 0.76; 95% confidence interval: 0.57 to 1.00 for subjects with no LDL-C <50 mg/dl vs. placebo and 0.35, 95% confidence interval: 0.25 to 0.49 for subjects attaining LDL-C <50 mg/dl; p for trend <0.0001). For all-cause mortality, corresponding event rates were 0.67, 0.65, and 0.39 (p for trend = 0.004). Rates of myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes mellitus were not significantly different among rosuvastatin-allocated participants with and without LDL-C <50 mg/dl.

Conclusions: Among adults with LDL-C <130 mg/dl and high-sensitivity C-reactive protein ≥2 mg/l, rosuvastatin-allocated participants attaining LDL-C <50 mg/dl had a lower risk of cardiovascular events without a systematic increase in reported adverse events.
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http://dx.doi.org/10.1016/j.jacc.2010.09.082DOI Listing
April 2011

Estrogen receptor polymorphisms and the vascular effects of hormone therapy.

Arterioscler Thromb Vasc Biol 2011 Feb 24;31(2):464-9. Epub 2010 Nov 24.

National Heart, Lung, and Blood Institute, 6701 Rockledge Ave., Bethesda, MD 20892, USA.

Objective: To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thromboembolism.

Methods And Results: The design was a nested case-control study in the Women's Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: 359 cases of coronary heart disease, 248 of stroke, and 217 of venous thromboembolism. Six estrogen receptor-α polymorphisms and 1 estrogen receptor-β polymorphism were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and 1 year after randomization. The polymorphisms were not associated with risk of vascular events and did not modify the increased risks of coronary heart disease, stroke, or venous thromboembolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin to hormone therapy was noted for estrogen receptor-1 IVS1 (intron number 1)-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and estrogen receptor-1 IVS1-1415 (interaction P<0.0001, corrected P=0.014).

Conclusions: Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on plasmin-antiplasmin, a marker of coagulation and fibrinolysis. However, screening for estrogen receptor polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful in making decisions about hormone therapy treatment.
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http://dx.doi.org/10.1161/ATVBAHA.110.215087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074605PMC
February 2011

Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling.

Genome Med 2010 Jul 28;2(7):48. Epub 2010 Jul 28.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98102, USA.

Background: Coronary heart disease (CHD) and stroke were key outcomes in the Women's Health Initiative (WHI) randomized trials of postmenopausal estrogen and estrogen plus progestin therapy. We recently reported a large number of changes in blood protein concentrations in the first year following randomization in these trials using an in-depth quantitative proteomics approach. However, even though many affected proteins are in pathways relevant to the observed clinical effects, the relationships of these proteins to CHD and stroke risk among postmenopausal women remains substantially unknown.

Methods: The same in-depth proteomics platform was applied to plasma samples, obtained at enrollment in the WHI Observational Study, from 800 women who developed CHD and 800 women who developed stroke during cohort follow-up, and from 1-1 matched controls. A plasma pooling strategy, followed by extensive fractionation prior to mass spectrometry, was used to identify proteins related to disease incidence, and the overlap of these proteins with those affected by hormone therapy was examined. Replication studies, using enzyme-linked-immunosorbent assay (ELISA), were carried out in the WHI hormone therapy trial cohorts.

Results: Case versus control concentration differences were suggested for 37 proteins (nominal P < 0.05) for CHD, with three proteins, beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), and insulin-like growth factor binding protein acid labile subunit (IGFALS) having a false discovery rate < 0.05. Corresponding numbers for stroke were 47 proteins with nominal P < 0.05, three of which, apolipoprotein A-II precursor (APOA2), peptidyl-prolyl isomerase A (PPIA), and insulin-like growth factor binding protein 4 (IGFBP4), have a false discovery rate < 0.05. Other proteins involved in insulin-like growth factor signaling were also highly ranked. The associations of B2M with CHD (P < 0.001) and IGFBP4 with stroke (P = 0.005) were confirmed using ELISA in replication studies, and changes in these proteins following the initiation of hormone therapy use were shown to have potential to help explain hormone therapy effects on those diseases.

Conclusions: In-depth proteomic discovery analysis of prediagnostic plasma samples identified B2M and IGFBP4 as risk markers for CHD and stroke respectively, and provided a number of candidate markers of disease risk and candidate mediators of hormone therapy effects on CHD and stroke.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00000611.
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http://dx.doi.org/10.1186/gm169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923740PMC
July 2010

Cost effectiveness of rosuvastatin in patients at risk of cardiovascular disease based on findings from the JUPITER trial.

J Med Econ 2010 ;13(3):428-37

Texas A&M Health Science Center, College Station, TX, USA.

Objective: This study assessed the long-term cost effectiveness of rosuvastatin therapy compared with placebo in reducing the incidence of major cardiovascular (CVD) events and mortality.

Methods: A probabilistic Monte Carlo simulation model estimated long-term cost effectiveness of rosuvastatin therapy (20 mg daily) for the prevention of CVD mortality and morbidity. The model included three stages: (1) CVD prevention simulating the 4 years of the JUPITER trial, (2) initial CVD prevention beyond the trial, and (3) subsequent CVD event prevention. A US payer perspective was assessed reflecting direct medical costs, and up to a lifetime horizon. Sensitivity analyses tested the robustness of the model estimates.

Results: For a hypothetical cohort of 100,000 patients at moderate and high risk of CVD events based on Framingham risk of ≥10%, estimated quality-adjusted life-years (QALYs) gained with rosuvastatin therapy compared with placebo was 33,480 over a lifetime horizon, and 25,380 and 9916 over 20-year and 10-year horizons, respectively. Approximately 12,073 events were avoided over the lifetime; 6,146 non-fatal MIs, 2905 non-fatal strokes, and 4030 CVD deaths avoided. Estimated incremental cost-effectiveness ratio (ICER) for cost per QALY was $7062 (lifetime), $10,743 (20-year horizon), and $44,466 (10-year horizon). For a hypothetical cohort similar to the overall JUPITER population, the cost per QALY ICER was $11,025 for the lifetime and $60,112 for a 10-year horizon.

Limitations: The cost-effectiveness comparison of rosuvastatin 20 mg was against no active treatment (as opposed to an alternative statin) due to lack of comparative cardiovascular morbidity and mortality risk reduction data for other statins in a population similar to the JUPITER trial population. The analysis was conducted from the payer perspective and lack of inclusion of indirect costs limit interpretability of results from a societal perspective.

Conclusions: Treatment with rosuvastatin 20 mg daily, is a cost-effective treatment alternative to no treatment in patients at a higher risk (Framingham risk≥10%) of CVD.
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http://dx.doi.org/10.3111/13696998.2010.499758DOI Listing
June 2011

Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative.

Menopause 2010 Jul;17(4):683-91

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo.

Methods: In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments.

Results: Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar.

Conclusions: Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.
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http://dx.doi.org/10.1097/gme.0b013e3181d683b5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940244PMC
July 2010

Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia.

J Am Coll Cardiol 2010 Mar;55(11):1121-6

Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Objectives: This study was undertaken to evaluate the efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia.

Background: Familial hypercholesterolemia is a common inherited disorder causing markedly elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and resulting in premature atherosclerosis. In children, statins have been shown to be effective in reducing LDL-C, restoring flow-mediated dilation, and slowing carotid intima-media thickening. However, few children in these trials achieved current LDL-C goals.

Methods: This study comprised a 12-week double-blind, randomized, placebo-controlled trial, followed by a 40-week open-label, titration-to-goal extension phase in 177 pubertal children, ages 10 to 17 years, with familial hypercholesterolemia. Participants were randomly assigned to placebo or rosuvastatin 5, 10, or 20 mg once daily.

Results: Compared with placebo, rosuvastatin 5, 10, and 20 mg reduced LDL-C by 38%, 45%, and 50%, respectively (p < 0.001 for each group vs. placebo). With a maximum allowed dose of 20 mg, 40% achieved the treatment goal of <110 mg/dl during the open-label, titration-to-goal phase. Rosuvastatin was well tolerated, with no apparent adverse impact on growth or development.

Conclusions: In children with familial hypercholesterolemia, rosuvastatin 20 mg daily reduced LDL-C by 50%. Nonetheless, only 40% attained the consensus LDL-C target of <110 mg/dl, reflecting these patients' high baseline LDL-C levels (mean, 232 mg/dl). (Pediatric Lipid-Reduction Trial of Rosuvastatin [PLUTO]; NCT00355615).
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http://dx.doi.org/10.1016/j.jacc.2009.10.042DOI Listing
March 2010

Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials.

Circulation 2010 Mar 22;121(9):1069-77. Epub 2010 Feb 22.

Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Background: Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and synthesized the results with prior trials.

Methods And Results: JUPITER participants included 6801 women > or =60 years of age and 11 001 men > or =50 years of age with high-sensitivity C-reactive protein > or =2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women; >276 CVD events; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002) and men (hazard ratio, 0.58; 95% confidence interval, 0.45 to 0.73; P<0.001). In women, there was significant reduction in revascularization/unstable angina and nonsignificant reductions in other components of the primary end point. Meta-analysis of 13 154 women (240 CVD events; 216 total deaths) from exclusively primary prevention trials found a significant reduction in primary CVD events with statins by a third (relative risk, 0.63; 95% confidence interval, 0.49 to 0.82; P<0.001; P for heterogeneity=0.56) with a smaller nonsignificant effect on total mortality (relative risk, 0.78; 95% confidence interval, 0.53 to 1.15; P=0.21; P for heterogeneity=0.20). Similar results were obtained for trials that were predominantly but not exclusively primary prevention.

Conclusions: JUPITER demonstrated that in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention statin trials. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.109.906479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439924PMC
March 2010

Evaluation of the American Heart Association cardiovascular disease prevention guideline for women.

Circ Cardiovasc Qual Outcomes 2010 Mar 16;3(2):128-34. Epub 2010 Feb 16.

George Washington University, Washington, DC, USA.

Background: The 2007 update to the American Heart Association (AHA) guidelines for cardiovascular disease prevention in women recommend a simplified approach to risk stratification. We assigned Women's Health Initiative participants to risk categories as described in the guideline and evaluated clinical event rates within and between strata.

Methods And Results: The Women's Health Initiative enrolled 161 808 women ages 50 to 79 years and followed them prospectively for 7.8 years (mean). Applying the 2007 AHA guideline categories, 11% of women were high risk, 72% at-risk, and 4% at optimal risk; 13% of women did not fall into any category, that is, lacked risk factors but did not adhere to a healthy lifestyle (moderate intensity exercise for 30 minute most days and <7% of calories from saturated fat). Among high risk, at-risk, and optimal risk women, rates of myocardial infarction/coronary death were 12.5%, 3.1%, and 1.1% per 10 years (P for trend <0.0001); the event rate was 1.3% among women who could not be categorized. We observed a graded relationship between risk category and cardiovascular event rates for white, black, Hispanic, and Asian women, although event rates differed among ethnic groups (P for interaction=0.002). The AHA guideline predicted coronary events with accuracy similar to current Framingham risk categories (area under receiver operating characteristic curve for Framingham risk, 0.665; for AHA risk, 0.664; P=0.94) but less well than proposed Framingham 10-year risk categories of <5%, 5% to 20%, and >20% (area under receiver operating characteristic curve for Framingham risk, 0.724; for AHA risk, 0.664; P<0.0001).

Conclusions: Risk stratification as proposed in the 2007 AHA guideline is simple, accessible to patients and providers, and identifies cardiovascular risk with accuracy similar to that of the current Framingham algorithm. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00000611.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.108.842385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841216PMC
March 2010

Postmenopausal estrogen and progestin effects on the serum proteome.

Genome Med 2009 Dec 24;1(12):121. Epub 2009 Dec 24.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.

Background: Women's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated.

Methods: Baseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool.

Results: In total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways.

Conclusions: Serum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects.
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http://dx.doi.org/10.1186/gm121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808737PMC
December 2009

Predictors of heart failure in patients with stable coronary artery disease: a PEACE study.

Circ Heart Fail 2009 May 14;2(3):209-16. Epub 2009 Apr 14.

Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass 02115, USA.

Background: Heart failure (HF) is a disease commonly associated with coronary artery disease. Most risk models for HF development have focused on patients with acute myocardial infarction. The Prevention of Events with Angiotensin-Converting Enzyme Inhibition population enabled the development of a risk model to predict HF in patients with stable coronary artery disease and preserved ejection fraction.

Methods And Results: In the 8290, Prevention of Events with Angiotensin-Converting Enzyme Inhibition patients without preexisting HF, new-onset HF hospitalizations, and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if P<0.05. A risk score was developed and converted to an integer-based scoring system. Among the Prevention of Events with Angiotensin-Converting Enzyme Inhibition population (age, 64+/-8; female, 18%; prior myocardial infarction, 55%), there were 268 cases of fatal and nonfatal HF. Twelve characteristics were associated with increased risk of HF along with several baseline medications, including older age, history of hypertension, and diabetes. Randomization to trandolapril independently reduced the risk of HF. There was no interaction between trandolapril treatment and other risk factors for HF. The risk score (range, 0 to 21) demonstrated excellent discriminatory power (c-statistic 0.80). Risk of HF ranged from 1.75% in patients with a risk score of 0% to 33% in patients with risk score >or=16.

Conclusions: Among patients with stable coronary artery disease and preserved ejection fraction, traditional and newer factors were independently associated with increased risk of HF. Trandolopril decreased the risk of HF in these patients with preserved ejection fraction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.108.820696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009573PMC
May 2009

Application of serum proteomics to the Women's Health Initiative conjugated equine estrogens trial reveals a multitude of effects relevant to clinical findings.

Genome Med 2009 Apr 29;1(4):47. Epub 2009 Apr 29.

Molecular Diagnostics Program, Fred Hutchinson Cancer Research Center, Fairview Avenue North, Seattle, WA 98109, USA.

Background: The availability of serum collections from the Women's Health Initiative (WHI) conjugated equine estrogens (CEE) randomized controlled trial provides an opportunity to test the potential of in-depth quantitative proteomics to uncover changes in the serum proteome related to CEE and to assess their relevance to trial findings, including elevations in the risk of stroke and venous thromboembolism and a reduction in fractures.

Methods: Five independent large scale quantitative proteomics analyses were performed, each comparing a set of pooled serum samples collected from 10 subjects, 1 year following initiation of CEE at 0.625 mg/d, relative to their baseline pool. A subset of proteins that exhibited increased levels with CEE by quantitative proteomics was selected for validation studies.

Results: Of 611 proteins quantified based on differential stable isotope labeling, the levels of 116 (19%) were changed after 1 year of CEE (nominal P < 0.05), while 64 of these had estimated false discovery rates <0.05. Most of the changed proteins were not previously known to be affected by CEE and had relevance to processes that included coagulation, metabolism, osteogenesis, inflammation, and blood pressure maintenance. To validate quantitative proteomic data, 14 proteins were selected for ELISA. Findings for ten - IGF1, IGFBP4, IGFBP1, IGFBP2, F10, AHSG, GC, CP, MMP2, and PROZ - were confirmed in the initial set of 50 subjects and further validated in an independent set of 50 additional subjects who received CEE.

Conclusions: CEE affected a substantial fraction of the serum proteome, including proteins with relevance to findings from the WHI CEE trial related to cardiovascular disease and fracture.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00000611.
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http://dx.doi.org/10.1186/gm47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684668PMC
April 2009

Effects of rosuvastatin and atorvastatin on LDL and HDL particle concentrations in patients with metabolic syndrome: a randomized, double-blind, controlled study.

Diabetes Care 2009 Jun 5;32(6):1087-91. Epub 2009 Mar 5.

University of Michigan, Ann Arbor, Michigan, USA.

Objective: The purpose of this study was to examine the effects of statin therapy on lipoprotein particle concentrations in patients with the metabolic syndrome. Changes in lipoprotein particle concentration may predict the risk of coronary heart disease more accurately than lipoprotein cholesterol levels.

Research Design And Methods: Patients with dyslipidemia and the metabolic syndrome (n = 318) were randomly assigned in a double-blind study comparing 10 mg rosuvastatin (RSV), 10 mg atorvastatin, or placebo daily for 6 weeks. From weeks 6 to 12, patients in the RSV and placebo groups received 20 mg RSV, whereas the ATV group increased their dose to 20 mg daily. Lipoprotein particle concentrations were measured by nuclear magnetic resonance spectroscopy, LDL cholesterol was measured by beta-quantification, and other lipoproteins were measured by standard methods at baseline, 6 weeks, and 12 weeks. Lipoprotein levels were compared by analysis of covariance.

Results: Statins reduced LDL particle concentration less than LDL cholesterol (-30 to -38 vs. -38 to -51%). Reductions were greater with RSV than with ATV (P < 0.05 for LDL particle concentration and P < 0.001 for LDL cholesterol). Most patients attained LDL cholesterol <2.59 mmol/l (100 mg/dl) at 12 weeks (80% with RSV and 59% with ATV; P = 0.003), but only 27% of patients receiving RSV and 19% receiving ATV attained the goal of LDL particle concentration <1,000 nmol/l (P = 0.07).

Conclusions: In patients with the metabolic syndrome, statin-induced changes in LDL cholesterol do not accurately reflect changes in LDL particle concentration. Consequently, despite attainment of LDL cholesterol goals, these patients may retain considerable residual coronary heart disease risk.
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http://dx.doi.org/10.2337/dc08-1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681027PMC
June 2009

Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study.

BMJ 2009 Feb 3;338:b219. Epub 2009 Feb 3.

George Washington University, Washington, DC 20037, USA.

Objective: To evaluate resting heart rate as an independent predictor of cardiovascular risk in women.

Design: Prospective cohort study.

Setting: The Women's Health Initiative was undertaken at 40 research clinics in the United States.

Participants: 129 135 postmenopausal women.

Main Outcome Measure: Clinical cardiovascular events.

Results: During a mean of 7.8 (SD 1.6) years of follow up, 2281 women were identified with myocardial infarction or coronary death and 1877 with stroke. We evaluated associations between resting heart rate and cardiovascular events in Cox regression models adjusted for multiple covariates. Higher resting heart rate was independently associated with coronary events (hazard ratio 1.26, 95% confidence interval 1.11 to 1.42 for highest [>76 beats per minute] v lowest quintile [
Conclusion: Resting heart rate, a low tech and inexpensive measure of autonomic tone, independently predicts myocardial infarction or coronary death, but not stroke, in women.

Trial Registration: ClinicalTrials.gov NCT00000611.
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http://dx.doi.org/10.1136/bmj.b219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640113PMC
February 2009

Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women's health initiative trials of hormone therapy.

Arch Intern Med 2008 Nov;168(20):2245-53

Women's Health Initiative Branch, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Rockledge 2 Bldg, Ste 10018, Bethesda, MD 20892, USA.

Background: Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit.

Methods: This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus.

Results: In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events.

Conclusions: Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD.

Trial Registration: clinicaltrials.gov Identifier: NCT00000611.
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http://dx.doi.org/10.1001/archinte.168.20.2245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726792PMC
November 2008
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