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Pharmacology – What’s New in Anticoagulation Medications

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1 Pharmacology – What’s New in Anticoagulation Medications
James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health Sciences Clinical Assistant Professor of Medicine, UNC Clinical Pharmacy Specialist-Anticoagulation Cone Health, Greensboro, NC

2 Faculty Disclosure The speaker reported the following financial relationships or relationships to products or devices he or his spouse has with commercial interests related to the content of this CME activity: James B. Groce III, PharmD, CACP Fees for non-CME services received directly from a commercial interest or their agents: Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Eisai Pharmaceuticals, Inc. Janssen Pharmaceuticals, Inc. Sanofi-aventis Stago-Diagnostica The Joint Commission

3 Objectives Review the cardiology focused indications of the new anticoagulant medications. Discuss the benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator. Identify key opportunities in the management of patients using the new anticoagulants.

4 Atrial Fibrillation and Anticoagulation
An estimated 2.6 million Americans have AF Prevalence of AF is increasing—estimated to be 12 million patients by 2050 AF is responsible for 15-20% of all strokes Untreated stroke risk with AF is approximately 5% AF strokes are severe: causing death and disability Anticoagulation therapy Effectively lowers the incidence and severity of AF stroke Fewer than 60% of eligible patients with AF have received anticoagulation with warfarin Many patients with AF have INRs below the recommended therapeutic range AF=atrial fibrillation. INR=international normalized ratio. Ogilvie IM, et al. Am J Med. 2010;123: Hylek E et al. N Engl J Med. 2003; 349:

5 ACCF/AHA/HRS Focus Update 2011 Guidelines for Antithrombotic Therapy to Prevent Stroke
Risk Category Recommended Therapy No risk factors aspirin, mg daily One moderate-risk factor (Age ≥75 yrs, HTN, CHF, LVEF ≤35%, and diabetes) aspirin, mg daily, or warfarin (INR , target 2.5), or dabigatran† Any high-risk factor or more than 1 moderate-risk factor (Previous stroke, TIA or embolism, mitral stenosis, and Prosthetic heart valve*) warfarin (INR 2.0 to 3.0, target 2.5),* or dabigatran † * If mechanical valve, target INR >2.5. † dabigatran is useful as an alternative to warfarin in patients with AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure, or advanced liver disease. Fuster V, et al. J Am Coll Cardiol. 2006;48:e149-e246. Wann SL, et al. Heart Rhythm. 2011;8:e1-e8. HTN=hypertension. INR=international normalized ratio. CHF=congestive heart failure. LVEF=left ventricular ejection fraction. 5

6 Therapies to Prevent Thrombotic Stroke
Anticoagulants Antiplatelet Agents Non-antithrombotic Drugs Vitamin K Antagonist New Anticoagulants aspirin +/- clopidogrel Anti-hypertensive Statin Anti-arrhythmic Left Atrial Appendage Occlusion or Excision Umbrella device External clip Surgical excision warfarin Non-warfarin Vitamin K Antagonists tecarfarin Direct Thrombin Inhibitors ximelagatran dabigatran AZD 0837 Factor Xa Inhibitors apixaban rivaroxaban idraparinux edoxaban YM150 betrixaban LY517717

7 Characteristics of an Ideal Anticoagulant
Predictable dose response (no need for monitoring) High efficacy-to-safety index Hirsh, 2005, p454, c2, table 1 Parenteral and oral administration Rapid onset of action Antidote As shown with the schematic, characteristics of an ideal anticoagulant include a high efficacy-to-safety index, predictable dose response (no need for monitoring), availability of parenteral and oral dosage routes, rapid onset of action, antidote, minimal nonanticoagulant side effects, and minimal drug-drug interactions. Hirsh, 2005, p454, c2, table 1 Minimal non-anticoagulant side effects Minimal drug-drug interactions Hirsh J et al. Blood. 2005;105(2): Hirsh J, O’Donnel M, Weitz JI. New anticoagulants. Blood. 2005;105(2):

8 Newer Oral Anticoagulants
dabigatran1,4* rivaroxaban2 apixaban3 Manufacturer Boehringer Ingelheim Bayer with Ortho-McNeil Bristol-Myers Squibb with Pfizer Brand Name Pradaxa® Xarelto® Eliquis® Approval Status Approved in U.S Approved in U.S. 2011 Approved in the EU 2011 Indication Stroke prevention in patients with AF Thromboembolism in adult patients undergoing elective hip or knee replacement surgery Not approved in US EU indication: Prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery Dosage Recommendation 150mg bid (Clcr > 30mL/min) 75mg bid (Clcr 15 – 30mL/min) 75mg bid (Clcr 30 – 50mL/min)* 10mg qd Ortho 20mg qd Afib Clcr > 50mL/min 15mg qd Afib (Clcr 15-50mL/min) 5 mg bid Mechanism of Action Direct factor IIa inhibitor Direct factor Xa inhibitor dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc apixaban European Union summary of product characteristics. Pfizer and Bristol-Myers Squibb rivaroxaban prescribing information. Janssen Pharmaceuticals, Inc *dronedarone, systemic ketoconazole

9 Pharmacokinetic Properties of the New Oral Anticoagulants
dabigatran rivaroxaban apixaban T1/2 12-14 hours 5-9 hours 8-15 hours Metabolism Conjugation (esterase catalyzed hydrolysis in liver or plasma) Oxidation (mainly via CYP3A4) and hydrolysis 70% unchanged 30% Inactive metabolites Renal Excretion 80% 36% 30% Substrate for p-glycoprotein Yes Metabolized by CYP3A4 No Wittkowsky AK. J Thromb Thrombolysis. 2010;29: Ufer M. Thrombosis and Haemostasis. 2010;103:

10 Differences Between New Oral Anticoagulants and Warfarin
Parameter Oral Anticoagulants Warfarin Onset/Offset of action Rapid Slow Dose–anticoagulant effect relationship Linear Predictable Food–drug interactions Low probability of interaction Moderate probability of interaction Monitoring for anticoagulant effect Not required Not available Required POCT and PST Available POCT=point-of-care testing PST=patient self-testing

11 AF Stroke Risk

12 Stroke Risk Stratification in AF
CHADS2 CHA2DS2-VASc Risk Factor Score Cardiac Failure 1 HTN Age ≥75 y Diabetes Stroke 2 Risk Factor Score Cardiac Failure 1 HTN Age ≥75 y 2 Diabetes Stroke Vascular Disease (MI, PAD, Aortic Atherosclerosis) Age y Sex Category (Female) Total Score Annual Risk of Stroke (%)     CHADS2 CHA2DS2-VASc HTN=hypertension. MI=myocardial infarction. PAD=peripheral artery disease. Lip GY, Halperin JL. Am J Med. 2010;123(6): Camm AJ, et al. Eur Heart J. 2010;31(19): 12

13 RE-LY: Study Design R Atrial fibrillation ≥1 Risk Factor
Absence of contra-indications 951 centers in 44 countries 10 efficacy outcome=stroke or systemic embolism 10 safety outcome=major bleeding Non-inferiority margin=1.46 Performed December 2005-March 2009 Median follow-up: 2.0 years Follow-up 99.9% complete Mean TTR=64% (patients on warfarin) R Open Blinded warfarin (INR ) n=6000 dabigatran etexilate 110 mg bid n=6000 dabigatran etexilate 150 mg bid n=6000 bid=twice daily. INR=international normalized ratio. RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy. Connolly SJ, et al. N Engl J Med. 2009;361:

14 RE-LY Trial: Primary Efficacy & Safety Outcomes
dabigatran 150 mg better warfarin better Stroke/systemic embolism1 0.65 ( ) 0.90 ( ) Efficacy Outcomes Myocardial Infarction1 1.27 ( ) 1.29 ( ) Vascular death1 0.85 ( ) 0.90 ( ) Intracranial Hemorrhage (ICH)1 0.41 ( ) 0.30 ( ) Major GI bleeding2 1.47 ( ) 1.06 ( ) Safety Outcomes Major bleeding1 0.93 ( ) 0.80 ( ) Total bleeding1 0.91 ( ) 0.78 ( ) 0.0 0.5 1.0 1.5 2.0 Relative risk dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. March 2011. Connolly SJ, et al. N Engl J Med. 2009;361: RE-LY=Randomized Evaluation of Long-term Anticoagulation Therapy.

15 ROCKET AF Study Design NVAF rivaroxaban 20 mg/d
CHADS2 Risk Factors Prior stroke, TIA, or non-CNS systemic embolus – OR – CHF or LVEF ≤35% Hypertension Age ≥75 years Diabetes At least 2 required Randomized double-blind/ double-dummy (N=14,264) rivaroxaban 20 mg/d (15 mg/d for CrCl 30 to <50 mL/min) warfarin INR target: 2.0 to 3.0 inclusive Monthly assessments* warfarin management was determined by clinician Enrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10% Abbreviations: CHADS2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CrCl = creatinine clearance; INR = international normalized ratio. *Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter. 1. Patel MR et al. N Engl J Med. 2011;365(10): ROCKET AF Study Investigators. Am Heart J ;159(3): 15

16 Rocket-AF Primary Efficacy Outcome Stroke and Non–CNS Embolism
6 rivaroxaban warfarin Rate/100 PTY 2.12 2.42 5 4 Cumulative Event Rate (%) 3 rivaroxaban warfarin 2 1 HR (95% CI): 0.88 ( ) Noninferiority P value <.001 120 240 360 480 600 720 840 960 1080 No. at risk Rivaroxaban 7081 6879 6683 6470 5264 4105 2951 1785 768 155 Warfarin 7090 6871 6656 6440 5225 4087 2944 1783 776 154 Days From Randomization *Included all randomized subjects followed for events both on and off study drug until end of study site notification (N=14171). Patel MR et al. N Engl J Med. 2011;365(10):

17 Rocket-AF Primary Safety Outcomes
Events, No. (Rate/100 PTY) rivaroxaban (n=7061)* warfarin (n=7082)* HR (95% CI) P value Major bleeding (any) 395 (3.60) 386 (3.45) 1.04 ( ) .576 Bleeding causing death 27 (0.24) 55 (0.48) 0.50 ( ) .003 Critical organ bleeding† 91 (0.82) 133 (1.18) 0.69 ( ) .007 Hgb drop ≥2 g/dL 305 (2.77) 254 (2.26) 1.22 ( ) .019 Transfusion (>2 units) 183 (1.65) 149 (1.32) 1.25 ( ) .044 Bleeding site Intracranial hemorrhage‡ 55 (0.49) 84 (0.74) 0.67 ( ) GI bleeding§ 224 (---) 154 (---) --- .001 Note that ICH is a component of critical organ bleeding in notes. Abbreviations: GI, gastrointestinal; hgb, hemoglobin. *Safety population on-treatment. †Critical bleeding sites included intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal. ‡Intracranial hemorrhage included intraparenchymal, intraventricular, subarachnoid, subdural hematoma, and epidural hematoma. §GI hemorrhage included upper GI, lower GI, and rectal bleeds. Patel MR et al. N Engl J Med. 2011;365(10):

18 ARISTOTLE: Study Design
Inclusion risk factors Age ≥ 75 years Prior stroke, TIA or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) warfarin (target INR 2-3) warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa

19 ARISTOTLE Main Trial Results
Stroke or systemic embolism ISTH major bleeding 21% RRR 31% RRR apixaban 212 patients, 1.27% per year warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P=0.011 apixaban 327 patients, 2.13% per year warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001 Median TTR 66% Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa

20 What Is the Impact of Time in Target Range (TTR)?

21 Time in Target Range (TTR)
What is the TTR for the patient below?

22 3 Methods for Calculating TTR: Percentage of Visits in Range
For an individual patient, the number of visits “in range” is divided by the number of visits 3 Patient Visits with INR in range = 60% TTR 5 Total Patient Visits

23 3 Methods for Calculating TTR: Cross Section of Patients In Range
For a group of patients, a date is selected and all patients are evaluated on the last reading prior to that date. Sept 30, 2011 is selected to assess TTR for 100 patients Patients are evaluated using last INR readings prior to Sept 30, 2011 Out of 100 patients, 71 had readings in therapeutic range 71 Patient with INR in range 71% TTR As of Sept 30, 2011 = 100 Total Patients

24 3 Methods for Calculating TTR: % Days in Range (Rosendaal Method)
More complicated methodology which looks at the amount of time between visits to determine how long the patient might have been within their therapeutic range Between measurements on May 1 and May 31, it is assumed that the patient slowly moved from 2.5 to 3.5 over 30 days On May 15th, the patient was probably over 3.0 15 days In range 15 days Out of range Patient was in range 50% of the time

25 Phase 3 Trials in Atrial Fibrillation: TTR and warfarin Efficacy
Study Mean TTR (%) Mean CHADS2 Score CHADS2 ≥3 Patients (%) Primary Efficacy Rate (warfarin Arm)* Overall CHADS2 2 CHADS2 ≥3 ROCKET AF1 55 3.5 87.0 2.2 1.3 2.3 RE-LY2 64 2.1 32.5 1.7 1.4 2.7 ARISTOTLE3 62 30.2 1.6 2.8 ROCKET AF enrolled a population of patients with AF at higher risk of stroke The overall event rate for the warfarin arm in ROCKET AF was higher than those reported in RE-LY and ARISTOTLE This difference may have been driven by the greater proportion of CHADS2 ≥3 patients enrolled in ROCKET AF/ *Rate per 100 patient-years. 1. Patel MR et al. N Engl J Med. 2011;365(10): 2. Connolly SJ, et al. N Engl J Med. 2009;361: doi: /NEJMoa 3. Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa

26 Benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator.

27 New oral anticoagulants
Benefits and shortcomings of the currently available anticoagulant therapies. New oral anticoagulants No coagulation testing Less time and travel No finger stick or venipuncture Fixed dose: no dose finding Primary Care or Cardiology Simplifies responsibility Fewer strengths Possible decease in dosing errors Diet Less effect

28 Benefits and shortcomings of the currently available anticoagulant therapies.
Given the challenges associated with warfarin, an oral anticoagulant is especially attractive Features of oral anticoagulants that may be associated with greater adherence include Do not require monitoring Fewer adverse effects, drug-drug, and drug-food interactions Improved adherence may reduce the risk of subtherapeutic INR and may lead to better treatment outcomes and possibly lower costs Kirsch B. Manag Care. 2011;20(2):33-36.

29 Identify key opportunities in the management of patients using the new anticoagulants

30 Key opportunities in the management of patients
Review appropriateness prior to dispensing CBC q72h while inpatient Recommend CBC 7-10 days post discharge Discharge counseling CBC=complete blood count. Moses Cone Health System Pharmacy & Therapeutics Formulary Review. January Approved. 

31 Key opportunities in the management of patients
Creatinine Clearance Recommended Dose of Dabigatran >30 mL/min 150 mg twice daily* 15 – 30 mL/min 30 – 50 mL/min 75 mg twice daily† 75mg twice daily‡ <15 mL/min Dosing recommendations cannot be provided * With or without food. † Based upon pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. ‡For patients on P-gp inhibitors (dronedarone or systemic ketoconazole) dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc

32 Key opportunities in the management of patients
Converting from warfarin to dabigatran Discontinue warfarin Start with dabigatran when INR <2.0 Converting from dabigatran to warfarin Creatinine Clearance Recommended Starting Time of Warfarin >50 mL/min 3 days before discontinuing dabigatran 31-50 mL/min 2 days before discontinuing dabigatran 15-30 mL/min 1 day before discontinuing dabigatran <15 mL/min No recommendations can be made INR=international normalized ratio. dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc

33 Key opportunities in the management of patients
Administration of Parenteral Anticoagulant Recommended Starting Time of Dabigatran Intermittent dosing 0-2 hours before time of next dose Continuous infusion At time of discontinuation dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc

34 Key opportunities in the management of patients
Creatinine Clearance Recommended Starting Time of Parenteral Anticoagulant CrCl ≥30 mL/min 12 hours after last dose of dabigatran CrCl ≤30 mL/min 24 hours after last dose of dabigatran CrCl=creatinine clearance. dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc

35 Key opportunities in the management of patients
warfarin rivaroxaban rivaroxaban  warfarin There are no clinical trial data to guide converting from rivaroxaban to warfarin Rivaroxaban may affect INR, so INR measurements made during coadministration of rivaroxaban with warfarin may not be useful One approach is to discontnue rivaroxaban and begin both a parenteral anticoagulant and warfarin when the next rivaroxaban dose would have been taken* Discontinue warfarin Initiate rivaroxaban when the INR is below 3.0 to avoid inadequate anticoagulation There are recommendations for switching patients from warfarin to rivaroxaban to help support continued anticoagulation For patients who are currently receiving warfarin, warfarin should be discontinued and the INR of the patient should be monitored. rivaroxaban should be initiated once the INR of the patient falls below 3.0 to avoid periods of inadequate anticoagulation This is the same methodology used in the ROCKET AF study to transition patients from warfarin to study drug1 No clinical trial data are available to guide converting patients from rivaroxaban® to warfarin. rivaroxaban® affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach, based on published guidelines, is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban® would have been taken The recommendation to use a parenteral anticoagulant together with warfarin after discontinuing rivaroxaban is analogous to the bridging protocol recommended for starting moderate- to high-risk patients on warfarin2 Reference: 1. Data on file. Janssen Pharmaceuticals, Inc., Raritan, NJ. 2. Fuster V, Rydén LE, Cannom DS, et al ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-e198. *The recommendation to use a parenteral anticoagulant together with warfarin after discontinuing rivaroxaban is analogous to the bridging protocol recommended for starting moderate- to high-risk patients on warfarin.1 Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198.

36 Key opportunities in the management of patients
Anticoagulation after discontinuation was not stipulated in ROCKET AF Warfarin patients who completed the study were generally maintained on warfarin Rivaroxaban patients were generally switched to warfarin There was no coadministration of warfarin and rivaroxaban This resulted in inadequate anticoagulation after stopping rivaroxaban until attaining a therapeutic INR No. of Strokes Although more strokes occurred in patients discontinuing rivaroxaban than warfarin at study completion, this imbalance was likely due to inadequate anticoagulation During the 28 days following the end of the study, there were 22 strokes in the patients taking rivaroxaban compared with 6 in the 4691 patients taking warfarin The ROCKET AF protocol did not stipulate anticoagulation after study drug discontinuation. In general, however, patients who were randomized to warfarin were maintained on warfarin while those randomized to rivaroxaban were switched to warfarin without a period of coadministration of rivaroxaban and warfarin. As a result, these latter patients were not adequately anticoagulated during the period between stopping rivaroxaban and achieving a therapeutic INR. This was likely responsible for the imbalance of events between the two treatment arms rivaroxaban (n=4637) warfarin (n=4691) Patel MR et al. N Engl J Med. 2011;365(10):

37 Key opportunities in the management of patients
Short half-life of oral anticoagulants makes adherence important Reduced monitoring may deny the physician the opportunity for patient education and the earlier detection of problems Denies the practitioner the opportunity to tailor the intensity of anticoagulant therapy for patient-specific factors Acquisition costs associated with oral anticoagulants will be greater than for warfarin Payers may erect barriers to access Cost-sharing may decrease adherence Ansell J. Hematology. 2010;

38 Key opportunities in the management of patients
Protocol development for use and management Short half-life of oral anticoagulants makes adherence important Protocol development for use and management of life-threatening/catastrophic bleed(s) No validated tests to measure anticoagulation effect No antidote for most agents Assessment of compliance more difficult than with vitamin K antagonists Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35: 38

39 Key opportunities in the management of patients
The successful use of (anticoagulation) depends on an “essential triad” which includes a Vigilant clinician Cooperative (well educated) patient Readily available and reliable laboratory If these factors are present, continuous use of anticoagulation is practical...and effective; if not, the use of the drug is dangerous… Foley WT, Wright IS. Am J Med Sci. 1949;217: Aske JM, Cherry CB. J Am Med Assoc. 1950;144:

40 Key opportunities in the management of patients
Availability of new oral anticoagulants will impact the way we think about care delivery and management for patients with atrial fibrillation We must STOP focusing upon INRs—and instead, as practitioners—focus upon assuring: The impact these new drugs have upon reduction of stroke and intracranial hemorrhage! Compliance, patient education—regarding their disease state as well as their drug therapies Continuing to deliver a “systematic means of oversight” for drug therapies and disease states—for which at their extremes—patients may either bleed to death—or clot to death: Baseline and periodic assessment of renal function Evaluation of drug-drug/drug-disease interactions

41 Key opportunities in the management of patients
Anticoagulation therapy lowers the incidence and severity of AF stroke Less than 60% of eligible AF patients have received anticoagulation therapy Newer oral anticoagulants exhibit a rapid onset of action, linear kinetics, low probability of drug and food interactions, and do not require monitoring—and, relative to warfarin—have further reduced the liklihood of stroke in the setting of non-valvular atrial fibrillation

42 Summary Current cardiology indications of the new anticoagulant medications include prevention of stroke in setting of NVAF. Benefits and shortcomings New oral agents eliminate a requirement of traditional monitoring and reduce stroke—when compared to warfarin—but lack a means of reversal Key opportunities for practitioner involvement in the management of patients: Will remain: provision of a systematic means of oversight Appropriateness of drug relative to the approved indication(s) Focus upon renal function and Rx-Rx interaction prevention for new agents

43 Pharmacology – What’s New in Anticoagulation Medications
James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health Sciences Clinical Assistant Professor of Medicine, UNC Clinical Pharmacy Specialist-Anticoagulation Cone Health, Greensboro, NC


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