William R Hiatt

University of Colorado Hospital, Denver, Colorado, United States

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Publications (241)1688.05 Total impact

  • William R Hiatt, R Kevin Rogers, Eric P Brass
    Circulation 07/2014; 130(1):69-78. · 15.20 Impact Factor
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    ABSTRACT: Tirasemtiv (CK-2017357), a novel small-molecule activator of the fast skeletal muscle troponin complex, slows the rate of calcium release from troponin, thus sensitizing fast skeletal muscle fibers to calcium. In preclinical studies, tirasemtiv increased muscle force and delayed the onset and reduced the extent of muscle fatigue during hypoxia in vitro and muscle ischemia in situ. This study evaluated the effect of single doses of tirasemtiv on measures of skeletal muscle function and fatigability in patients with stable calf claudication due to peripheral artery disease (PAD). Sixty-one patients with an ankle-brachial index ≤0.90 in the leg with claudication received single double-blind doses of tirasemtiv 375 mg and 750 mg and matching placebo in random order about 1 week apart. After 33 patients were treated, the 750 mg dose was decreased to 500 mg due to adverse events and these dose groups were combined for analysis. On each study day, bilateral heel-raise testing was performed before and at 3 and 6 hours after dosing; a 6-minute walk test was performed at 4 hours after dosing. Claudicating calf muscle performance was increased at the highest dose and plasma concentration of tirasemtiv; however, the 6-minute walk distance decreased with both the dose and plasma concentration of tirasemtiv, possibly due to dose-related adverse events, particularly dizziness, that could impede walking ability. In conclusion, the mechanism of fast skeletal muscle troponin activation improved muscle function but not 6-minute walking distance in patients with claudication due to PAD. CLINICALTRIALSGOV IDENTIFIER NCT01131013:
    Vascular medicine (London, England). 05/2014;
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    ABSTRACT: To determine the effect of ticagrelor compared to clopidogrel in patients with peripheral artery disease (PAD) and acute coronary syndromes (ACS). PLATO (n = 18,624) was a multicentre, double-blind, randomized trial in ACS, that showed a 16% reduction in cardiovascular death (CV-death), myocardial infarction (MI) and stroke with ticagrelor compared with clopidogrel, without significant increase in overall major bleeding. We performed a post-hoc analysis of cardiovascular and bleeding outcomes in PLATO according to reported PAD status at baseline. At one year, CV death, MI or stroke occurred in 19.3% of patients with PAD (n = 1144) compared to 10.2% in patients without PAD (p < 0.001). The Kaplan-Meier one year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs 20.6% (HR: 0.85 95% CI 0.64-1.11; for PAD status by treatment interaction, p = 0.99) and for death from any cause 8.7% vs 11.9%, (HR: 0.74 95% CI 0.50-1.08; interaction p = 0.73). PLATO-defined major bleeding event rates at one year were 14.8% for ticagrelor compared to 17.9% for clopidogrel, (HR: 0.81 95% CI 0.59-1.10; interaction p = 0.09). PAD patients have a high rate of ischaemic and bleeding events post ACS. The reduction of CV death, MI or stroke with ticagrelor compared with clopidogrel in PAD patients was consistent with the overall trial result although it did not reach statistical significance. Overall major bleeding was similar between the therapies.
    European journal of preventive cardiology. 05/2014;
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    ABSTRACT: Critical limb ischemia (CLI) represents the most severe clinical manifestation of peripheral arterial disease (PAD) and is the major cause of ischemic amputation in the United States. Risk factors and the associated incidence and prevalence of CLI have not been well described in the general population. This study describes the risk factors for PAD progression to CLI and estimates the annual incidence and prevalence of CLI in a representative United States patient cohort. This was a retrospective cohort analysis of adults with commercial, Medicare supplemental, or Medicaid health insurance who had at least one PAD or CLI health care claim from January 1, 2003, through December 31, 2008, and 12 months of continuous coverage. Two subgroups of CLI presentation were identified: primary CLI (patients without any prior PAD or subsequent PAD diagnostic code >30 days after CLI diagnostic code) and secondary CLI (patients with prior PAD or subsequent PAD diagnostic codes ≤30 days of a CLI diagnostic code). Patterns of presentation, annual incidence, and prevalence of CLI were stratified by health care plan. Risk factors for progression to CLI were compared by presentation type. From 2003 to 2008, the mean annual incidence of PAD was 2.35% (95% confidence interval [CI], 2.34%-2.36%) and the incidence of CLI was 0.35% (95% CI, 0.34%-0.35%) of the eligible study population, with primary and secondary presentations occurring at similar rates. The mean annualized prevalence of PAD was 10.69% (95% CI, 10.67%10.70%) and the mean annualized prevalence of CLI was 1.33% (95% CI, 1.32%-1.34%) of the eligible study population, and two-thirds of the cases presented as secondary CLI. CLI developed in 11.08% (95% CI, 11.30%-11.13%) of patients with PAD. A multivariable model demonstrated that diabetes, heart failure, stroke, and renal failure were stronger predictors of primary rather than secondary CLI presentation. These data establish new national estimates of the incidence and prevalence of CLI and define key risk factors that contribute to primary or secondary presentations of CLI within a very large contemporary insured population cohort in the United States.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 05/2014; · 3.52 Impact Factor
  • William R Hiatt, Robert J Smith
    New England Journal of Medicine 01/2014; 370(5):396-9. · 51.66 Impact Factor
  • Source
    L. Norgren, W.R. Hiatt, M.R. Jaff
    European Journal of Vascular and Endovascular Surgery. 01/2014;
  • William R. Hiatt
    JACC: Heart Failure. 01/2014;
  • Journal of the American College of Cardiology 01/2014; 63(14):1457–1458. · 14.09 Impact Factor
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    ABSTRACT: Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in PAD patients, have limitations. Cells identified usingcytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) to assess the safety and efficacy of autologous bone marrow–derived ALDHbr cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index <0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary endpoints are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance (MR) imaging at 6 months compared to baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based endpoints that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDHbr cells in patients with claudication and provide valuable insight into the utility of advanced MR imaging endpoints.
    American Heart Journal. 01/2014;
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    ABSTRACT: Nitrite stores decrease after exercise in patients with peripheral artery disease (PAD) and diabetes represents decreased nitric oxide (NO) bioavailability that may contribute to endothelial dysfunction and limit exercise duration. The primary objective of this placebo-controlled study was the safety and tolerability of multiple doses of oral sodium nitrite in patients with PAD, predominantly with diabetes, over a period of 10 weeks. The primary efficacy endpoint was endothelial flow-mediated dilatation (FMD) and secondary efficacy endpoints included a 6-minute walk test and quality of life assessment. Of the 55 subjects, the most common side effects attributed to sodium nitrite were a composite of headache and dizziness occurring in 21% with the 40 mg dose and 44% with the 80 mg dose. There was no clinically significant elevation of methemoglobin. FMD non-significantly worsened in the placebo and 40 mg groups, but was stable in the 80 mg group. Diabetic patients receiving 80 mg had significantly higher FMD compared with the placebo and 40 mg groups. There was no significant change in 6-minute walk test or quality of life parameters over time compared to placebo. In conclusion, sodium nitrite therapy is well tolerated in patients with PAD. The possible clinical benefit of sodium nitrite should be studied in a larger and fully powered trial.
    Vascular Medicine 12/2013; · 1.62 Impact Factor
  • Journal of the American College of Cardiology 11/2013; · 14.09 Impact Factor
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    ABSTRACT: Supervised walking programs offered at medical facilities for patients with peripheral artery disease (PAD) and intermittent claudication (IC), although effective, are often not used due to barriers, including lack of reimbursement and the need to travel to specialized locations for the training intervention. Walking programs for PAD patients that occur in community settings, such as those outside of supervised settings, may be a viable treatment option because they are convenient and potentially bypass the need for supervised walking. This review evaluated the various methods and outcomes of community walking programs for PAD. A literature review using appropriate search terms was conducted within PubMed/MEDLINE and the Cochrane databases to identify studies in the English language that used community walking programs to treat PAD patients with IC. Search results were reviewed, and relevant articles were identified that form the basis of this review. The primary outcome was peak walking performance on the treadmill. Ten randomized controlled trials examining peak walking outcomes in 558 PAD patients demonstrated that supervised exercise programs were more effective than community walking studies that consisted of general recommendations for patients with IC to walk at home. Recent community trials that incorporated more advice and feedback for PAD patients in general resulted in similar outcomes, with no differences in peak walking time compared with supervised walking exercise groups. Unstructured recommendations for patients with symptomatic PAD to exercise in the community are not efficacious. Community walking programs with more feedback and monitoring offer improvements in walking performance for patients with claudication and may bypass some obstacles associated with facility-based exercise programs.
    Journal of Vascular Surgery 10/2013; · 2.88 Impact Factor
  • William R Hiatt, Sanjay Kaul, Robert J Smith
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    ABSTRACT: The management of type 2 diabetes has been challenged by uncertainty about possible cardiovascular effects related to treatment intensity and choice of drug. Although the Food and Drug Administration (FDA) considers a decrease in glycated hemoglobin an approvable end point, very intensive glycemic control is associated with increased cardiovascular and all-cause mortality.(1) The safety of specific drugs for type 2 diabetes - particularly the thiazolidinediones - has also been questioned. After rosiglitazone had been approved in the United States in 1999 and in Europe in 2000, a highly publicized meta-analysis in 2007 reported a 43% increase in myocardial infarction (P=0.03) . . .
    New England Journal of Medicine 09/2013; · 51.66 Impact Factor
  • Journal of the American College of Cardiology 08/2013; · 14.09 Impact Factor
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    ABSTRACT: Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e., decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and bleeding harm. We suggest a bivariate endpoint as a general approach to the assessment of "net clinical benefit" in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1), and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT). This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 06/2013; · 6.08 Impact Factor
  • Journal of the American College of Cardiology 05/2013; · 14.09 Impact Factor
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    ABSTRACT: BACKGROUND: Patients with claudication secondary to peripheral artery disease have a substantial impairment in walking capacity. This study evaluated factors suspected to be correlated with treadmill walking performance in an effort to gain insights into the pathophysiology of the impairment. METHODS: A multivariate model was developed to define the associations between clinical and laboratory biomarkers with treadmill peak walking time (PWT) in patients enrolled in three clinical trials. The model was initially developed in a cohort of 385 patients from one trial using 23 candidate-independent variables and then tested in the combined data from the other two trials (351 patients). RESULTS: The final model was built from 14 variables that met the predefined univariate criteria of P < .15. Main effects remaining in the model were age, resting ankle-brachial index, smoking status, hypertension, statin use, country (United States vs non-United States countries), and high-sensitivity C-reactive protein. The model was highly statistically significant (P < .0001) but explained only a limited portion of the population heterogeneity (r(2) = 0.173). The main effects plus interaction terms had an r(2) = 0.2178. The main effects model was tested in an independent cohort of 351 patients from two other clinical trials in peripheral arterial disease that did not include high-sensitivity C-reactive protein. The model successfully fit the data set, based on prospectively defined root mean squared error and was statistically significant (P = .0005) but had lower overall explanatory power than in the index cohort (r(2) = 0.0687). CONCLUSIONS: As expected, age and ankle-brachial index contributed to exercise limitation among patients with PAD. The association of C-reactive protein, hypertension, and smoking with PWT is consistent with a role for inflammation or oxidative stress in determining treadmill walking performance. In contrast to previous reports from smaller and more homogenous populations, clinical attributes and biomarkers explain only a small portion of PWT heterogeneity.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 05/2013; · 3.52 Impact Factor
  • Robert J Smith, William R Hiatt
    JAMA Internal Medicine 05/2013; · 10.58 Impact Factor
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    ABSTRACT: BACKGROUND: Non-valvular atrial fibrillation is associated with an increase in thromboembolism, i.e. stroke, and atherosclerotic events, i.e. myocardial infarction. Vitamin E possesses anti-coagulant as well as anti-atherosclerotic properties. Our aim was to assess whether vitamin E is associated with cardiovascular events in patients with non-valvular atrial fibrillation. METHODS: Serum levels of cholesterol-adjusted vitamin E were measured in 1012 patients with non-valvular atrial fibrillation. Patients were followed for a mean time of 27.0months, and cardiovascular events, such as cardiovascular death and fatal and nonfatal stroke or myocardial infarction, were recorded. RESULTS: During the follow-up period, cardiovascular events occurred in 109 (11%) patients (18 fatal and 14 nonfatal myocardial infarction; 13 fatal and 19 nonfatal ischemic strokes; 45 cardiovascular deaths). Lower vitamin E serum levels were found in patients who experienced cardiovascular events compared to those who did not (3.8±1.2 vs. 4.4±1.8μmol/mmol cholesterol; p<0.001). Using a Cox proportional hazard model, age, diabetes, history of stroke and myocardial infarction and vitamin E serum levels (HR 0.77; 95% CI: 0.67-0.89; p=0.001) independently predicted cardiovascular events. Patients with vitamin E<4.2μmol/mmol cholesterol (median values) had an increased risk of cardiovascular events (HR 1.87; 95% CI: 1.25-2.80: p=0.002). CONCLUSIONS: Low vitamin E serum levels are associated with an increased risk of cardiovascular events in patients with non-valvular atrial fibrillation.
    International Journal of Cardiology 05/2013; · 6.18 Impact Factor
  • William R Hiatt
    Nature Reviews Cardiology 04/2013; · 10.40 Impact Factor

Publication Stats

10k Citations
1,688.05 Total Impact Points

Institutions

  • 2001–2014
    • University of Colorado Hospital
      • Department of Medicine
      Denver, Colorado, United States
    • University of Minnesota Twin Cities
      Minneapolis, Minnesota, United States
  • 2012–2013
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1988–2013
    • University of Colorado
      • • Department of Medicine
      • • Division of Cardiology
      • • Division of Geriatric Medicine
      • • Colorado Prevention Center (CPC)
      • • Section of Vascular Surgery and EndoVascular Therapy
      • • Department of Physical Medicine and Rehabilitation
      • • Department of Neurology
      • • Division of General Internal Medicine
      • • Division of Clinical Pharmacology and Toxicology
      Denver, Colorado, United States
  • 2007–2012
    • Duke University Medical Center
      • Division of Cardiology
      Durham, NC, United States
  • 2003–2012
    • Hospital of the University of Pennsylvania
      • • Department of Medicine
      • • Division of Cardiovascular Medicine
      Philadelphia, Pennsylvania, United States
  • 2011
    • Rhode Island Hospital
      Providence, Rhode Island, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
    • The Chinese University of Hong Kong
      • Department of Medicine and Therapeutics
      Hong Kong, Hong Kong
  • 2008–2011
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
    • University of California, San Diego
      • Department of Family and Preventive Medicine
      San Diego, CA, United States
    • Wake Forest School of Medicine
      • Department of Biostatistical Sciences
      Winston-Salem, NC, United States
  • 2006–2011
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, California, United States
    • Regis University
      Denver, Colorado, United States
    • University of Missouri - Kansas City
      Kansas City, Missouri, United States
  • 2009
    • Children's Hospital Colorado
      • Department of Pediatrics
      Aurora, CO, United States
    • Massachusetts General Hospital
      • Vascular Center
      Boston, MA, United States
    • University of Pennsylvania
      • Division of Cardiovascular Medicine
      Philadelphia, PA, United States
  • 1998–2007
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2004
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
  • 2002
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
    • Uniformed Services University of the Health Sciences
      Maryland, United States
  • 1999
    • Texas Tech University Health Sciences Center
      • Department of Surgery
      Lubbock, TX, United States
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1995
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Neurology
      New Orleans, LA, United States
  • 1994
    • Case Western Reserve University
      • Department of Medicine (University Hospitals Case Medical Center)
      Cleveland, OH, United States