10/1/2013. I have no actual or potential conflict of interest with today s presentation

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1 I have no actual or potential conflict of interest with today s presentation Kimberly C. Berger, PharmD, BCPS Clinical Specialist Critical Care Rush University Medical Center October 2, 2013 Review the indications and mechanisms of action for the new oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban Discuss the safety and controversy surrounding the new oral anticoagulants particularly in the emergency setting Describe the pharmacokinetics and the differences in effect on coagulation markers of the oral anticoagulants Review the literature evaluating the options for reversal of the new oral anticoagulants Summarize the risks and benefits associated with each reversal option for the new oral anticoagulants Identify new drugs used for the prevention/treatment of venous thromboembolism or stroke prevention Review the indications and mechanisms of action for the new oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban. Discuss the safety and controversy surrounding the new oral anticoagulants particularly in the emergency setting Recall agents used for the emergent reversal of anticoagulants Background Timeline Anticoagulant Drugs Estimated 2 million people in US suffer from venous thromboembolism (VTE) each year Risk of ischemic stroke in patients with atrial fibrillation (AF) is ~5% Anticoagulation Effective in reducing risk of thromboembolism Effective in treating thromboembolism Significant bleeding risks 1

Options were limited for thromboembolic disease and stroke prevention Warfarin Heparin Low

used oral anticoagulant Limitations INR monitoring Variable dosing Drug-drug interactions

Pipeline Betrixaban Eribaxaban ATI-5923 Indication: nonvalvular AF to prevent stroke and

thrombin-bound fibrin Indications Reduce risk of stroke and systemic embolism in patients

Prophylaxis of DVT which may lead to PE in patients undergoing knee or hip replacement

2 Options were limited for thromboembolic disease and stroke prevention Warfarin Heparin Low molecular weight heparins (LMWH) Anti-Xa inhibitors Direct thrombin inhibitors Most widely used oral anticoagulant Limitations INR monitoring Variable dosing Drug-drug interactions Drug-diet interactions Genetics New FDA approvals Dabigatran Rivaroxaban Apixaban Drugs in Pipeline Betrixaban Eribaxaban ATI-5923 Indication: nonvalvular AF to prevent stroke and systemic embolism Mechanism of action Direct thrombin inhibitor Inhibits free and thrombin-bound fibrin Indications Reduce risk of stroke and systemic embolism in patients with nonvalvular AF Treatment of VTE and for reduction in risk of recurrence of DVT and PE Prophylaxis of DVT which may lead to PE in patients undergoing knee or hip replacement surgery Mechanism of action Anti-Xa inhibitor Selective and reversible inhibitor Fibrinogen Fibrin (clot) 2

Indication: reduce the risk of stroke and systemic embolism in nonvalvular AF Mechanism of action Anti-Xa inhibitor Selective and reversible inhibitor Study Groups Design Results RE-LY (n=18,113)

warfarin Double blind, placebo controlled, non-inferiority Double blind, placebo controlled, non-inferiority Double blind, randomized, controlled Double blind, randomized, controlled Stroke/systemic

001 Stroke/systemic embolus: Apixaban 1.6%/year ASA 3.7%/year HR 0.45 [0.32-0.62], p<0.001 Stroke/systemic embolus: Apixaban 1.27%/year Warfarin 1.6%/year HR 0.79 [0.66-0.95], p=0.

and Embolism Trial in Atrial Fibrillation; AVERROES: Apixaban Vs Acetylsalicylic Acid to prevent Stroke in AF patients who have failed or are unsuitable for Vitamin K Antagonist Treatment; ARISTOTLE:

2: THA (n=2,509) RECORD 3: TKA (n=2,531) RECORD 4:TKA (n=3,148 Rivaroxaban vs. LMWH/VKA Rivaroxaban 10mg daily vs.

3 Indication: reduce the risk of stroke and systemic embolism in nonvalvular AF Mechanism of action Anti-Xa inhibitor Selective and reversible inhibitor Study Groups Design Results RE-LY (n=18,113) ROCKET-AF (n=14,264) AVERROES (n=5,599) ARISTOTLE (n=18,201) Dabigatran vs. warfarin Rivaroxaban vs. warfarin Apixaban vs. ASA Apixaban vs. warfarin Double blind, placebo controlled, non-inferiority Double blind, placebo controlled, non-inferiority Double blind, randomized, controlled Double blind, randomized, controlled Stroke/systemic embolus: Dabigatran %/year Warfarin 1.69%/year HR 0.66 [ ], p<0.001 Stroke/systemic embolus: Rivaroxaban 1.7%/year Warfarin 2.2%/year HR 0.79 [ ], p<0.001 Stroke/systemic embolus: Apixaban 1.6%/year ASA 3.7%/year HR 0.45 [ ], p<0.001 Stroke/systemic embolus: Apixaban 1.27%/year Warfarin 1.6%/year HR 0.79 [ ], p=0.01 RE-LY: Randomized Evaluation of Long term anticoagulation therapy; ROCKET-AF: Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; AVERROES: Apixaban Vs Acetylsalicylic Acid to prevent Stroke in AF patients who have failed or are unsuitable for Vitamin K Antagonist Treatment; ARISTOTLE: Apixaban for Reduction In STroke and Other ThromboemboLic events in atrial fibrillation; HR: hazard ratio Study Groups Design Results EINSTEIN investigators (n=3,349) RECORD 1: THA (n=4,451) RECORD 2: THA (n=2,509) RECORD 3: TKA (n=2,531) RECORD 4:TKA (n=3,148 Rivaroxaban vs. LMWH/VKA Rivaroxaban 10mg daily vs. enoxaparin 40mg daily Open label, randomized, event driven, non-inferiority, paralleled with superiority study Randomized, double blind, double dummy Recurrent VTE: Rivaroxaban 2.1%/year LMWH/warfarin 3%/year HR 0.68 [ ], p<0.001 DVT/PE or death from any cause Rivaroxaban 1.1% Enoxaparin 3.7%, p<0.001 DVT/PE or death from any cause Rivaroxaban 2% Enoxaparin 9.3%, p<0.001 DVT/PE or death from any cause Rivaroxaban 9.6% Enoxaparin 18.9%, p<0.001 DVT/PE or death from any cause Rivaroxaban 6.9% Enoxaparin 10.1%, p<0.012 LMWH: low molecular weight heparin; VKA: vitamin K antagonist THA: total hip arthroplasty; TKA: total knee arthroplasty; RECORD: REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism; DVT: deep vein thrombosis; PE: pulmonary embolism Increased bleeding risks Risk factors Age Trauma Surgery Overdose Drug Study Observed Bleeding Rate Major Bleeding Intracranial bleeding Warfarin Various Up to 20% 7.2% Up to 2.5% UFH/LMWH Various Up to 16% Up to 4% 0.8% Dabigatran RE-LY 16.42% 3.11% 0.3% Rivaroxaban Apixaban ROCKET-AF 14.9% 3.6% 0.5% EINSTEIN 8.1% 0.7% NR RECORD % < % NR AVERROES 10.8% 1.4% 0.4% ARISTOTLE 18.1% 2.13% 0.33% UFH: unfractionated heparin; LMWH: low molecular weight heparin; NR: not reported 3

Which of the following agents does not inhibit factor Xa in the clotting cascade? A. Rivaroxaban B. Apixaban C. Dabigatran D. Warfarin E.

Rivaroxaban B. Apixaban C. Dabigatran D. All of the above E.

None of the above Monitoring Reversal Options VTE prophylaxis for joint replacement surgery Dabigatran: RE-MOBILIZE, RE-MODEL, RE-NOVATE Apixaban: ADVANCE 1-3 Treatment

4 Which of the following agents does not inhibit factor Xa in the clotting cascade? A. Rivaroxaban B. Apixaban C. Dabigatran D. Warfarin E. None of the above Which of the following agents does not inhibit factor Xa in the clotting cascade? A. Rivaroxaban B. Apixaban C. Dabigatran D. Warfarin E. None of the above Which of the following medication is approved for the treatment of VTE and for reduction in risk of recurrence of DVT and PE? A. Rivaroxaban B. Apixaban C. Dabigatran D. All of the above E. None of the above Which of the following medication is approved for the treatment of VTE and for reduction in risk of recurrence of DVT and PE? A. Rivaroxaban B. Apixaban C. Dabigatran D. All of the above E. None of the above Monitoring Reversal Options VTE prophylaxis for joint replacement surgery Dabigatran: RE-MOBILIZE, RE-MODEL, RE-NOVATE Apixaban: ADVANCE 1-3 Treatment of VTE Dabigatran: RE-COVER Apixaban: AMPLIFY, AMPLIFY-EXT Acute Coronary Syndromes Rivaroxaban: ATLAS-ACS TIMI-51 Apixaban: APPRAISE 1 & 2 4

5 High mortality rate associated with cerebral hemorrhage and anticoagulation use Emergency setting Lack of commercially available reversal options Lack of monitoring Costs associated with reversal options Effects on coagulation markers not fully understood Activated partial thromboplastin time (aptt) Thrombin time (TT) Ecarin clotting time (ECT) Prothrombin time (PT) International normalized ratio (INR) Anti-Xa Drug aptt TT ECT PT/INR Anti-Xa Warfarin Yes --- UFH Yes LMWH Yes Dabigatran Yes Yes Yes +/- --- Rivaroxaban +/ Yes Apixaban +/ Yes UFH: unfractionated heparin; LMWH: low molecular weight heparin; aptt: activated partial thromboplastin time; PT: prothrombin time; INR: international normalized ratio 68 YOM presents to ED s/p fall PMH: AF, coronary artery disease, diabetes Home medications: Metoprolol 50mg PO BID Dabigatran 150mg PO BID Lisinopril 10mg PO daily Insulin GCS=9 VS: 95/ % 2L NC CT head: marked intracerebral hemorrhage Laboratory values Hemoglobin 7.2 g/dl aptt 69 seconds PT seconds INR 1.1 SCr=0.7 mg/dl Drug Commercially Available Product Warfarin Vitamin K UFH Protamine LMWH Protamine Dabigatran??? Rivaroxaban??? Immediately the ED physician want to know how to reverse the patient s anticoagulation. Apixaban??? 5

6 T/F: The novel oral anticoagulants are completely safe in comparison to the old anticoagulants. Data on warfarin reversal Data on reversal of new anticoagulants Drug Peak Action Halflife (h) Elimination Dialyzable Warfarin 3-5 d Liver/Renal No UFH Immediate 1-2 RES No Blood Products Fresh Frozen Plasma Recombinant Factor VIIa (NovoSeven ) Prothrombin Complex Concentrates (PCC) LMWH 3-5 h 5-7 Renal>80% No Dabigatran 1-3 h Renal 80% Yes Rivaroxaban 2-3 h 5-9 Renal 36% No Apixaban h 8-15 Renal 25% No Clinical management of major bleeding associated with new oral anticoagulants Stop drug administration Early volume and packed red blood cell replacement Local measures to stop bleeding Plasma separated from whole blood Contains factors II, VII, IX, and X Indications Active bleeding with elevated INR Urgent reversal of warfarin 6

7 Study Design Results Limitations Makris M et al. (n=41) Goldstein JN et al. (n=69) Prospective, -12 patients observational received FFP for emergent -INR decreased reversal of 10.2 to 2.3 INR Retrospective chart review for emergent reversal in patients with ICH -Mean 4 to achieve reversal in 24 hours -Shorter time to administration of FFP -Sample size -Showed that clotting factor concentrates provided better reversal -Cut-off was 24 hours -Retrospective -No difference in mortality FFP for reversal of new oral anticoagulants No human studies exist FFP is unlikely to influence effects of dabigatran No direct evidence in humans to support the efficacy of FFP or other transfusions Only to be administered in setting of documented dilutional coagulopathy Derived from human plasma Contains factors II, VII, IX and X Multiple formulations 3-factor II, IX, and X 4-factor II, VII, IX, and X Product Name Factor II Factor VII Factor IX Factor X Bebulin VH 120 (13) Beriplex Cofact KCentra Profilnine SD 148 (11) *Factor concentrations are presented in international. Product also contains Protein C and S. Anti-inhibitor coagulant complex Factor VIII inhibitor bypassing activity Contains non-activated factors II, IX and X Contains activated factor VII Recombinant factor VIIa only Activates extrinsic pathway of the coagulation cascade 7

8 Intrinsic Pathway Vascular changes XII XIIa XI XIa IX IXa Extrinsic Pathway Tissue thromboplastin VII VIIa Study Design Results Limitations Pabinger I et al. (n=43) Prospective, multinational single arm using 4- factor product 30 minute post infusion INR<1.3: 93% INR 1.4: 7% -Other coumarin products -Utilized 4- factor product Common Pathway VIII X II Xa Thrombin (IIa) Tran H et al. (n=50) Prospective, cohort study using 3- factor product INR<1.4: -91% (baseline 3.5) INR : -93% (baseline 5.6) -Small sample size -No comparator group Fibrinogen Fibrin Perzborn E et al. Reversal of rivaroxaban in rats Partially reversed PT prolongation Reversed inhibition of thrombin formation Shortened bleeding time Godier et al. Reversal of rivaroxaban in rabbit model Decreased aptt (97.3 to 62.1) No effect on bleeding Eerenberg ES et al. Randomized, placebo-controlled crossover study Healthy volunteers received rivaroxaban or dabigatran 50 /kg PCC administered after anticoagulant 11 day washout period Rivaroxaban Baseline PT: 15.8 ± 1.3 seconds Post PCC: 12.8 ± 1.0 seconds Dabigatran Baseline aptt: 59.4 ± 15.8 seconds Post PCC: no effect Baseline ECT: 69 ± 26 seconds Post PCC: no effect PCC immediately and completely reverses anticoagulant effect of rivaroxaban in healthy subjects No influence on the anticoagulant action of dabigatran 8

9 Strengths Evaluated rivaroxaban and dabigatran Crossover design Appropriate outcomes Limitations Study population Sample size Study Design Results Limitations Brody DL et al. (n=12) Freeman WD et al. (n=7) Retrospective, cohort of patients on warfarin with ICH Retrospective, observational of patients on warfarin with ICH Median time of presentation to INR<1.3: -rfviia group: 9h -Control group: 32h INR<1.5 reduced in 5 patients within 5 hours -No outcomes -Sample size -Small sample size -No comparator group -6 patients received vitamin K Godier et al. Rivaroxaban reversal in rabbit model Reduced aptt (97.3 to 63.1 seconds, p<0.02) Reduced bleeding time (140 to 92 seconds, p<.02) No effect on total blood loss Studies evaluating dabigatran reversal limited. However, appears to be ineffective. Limitations Study populations Sample sizes Evaluation of coagulation markers No benefit on bleeding noted Which of the following is NOT a reversal option for either rivaroxaban or dabigatran? A. Fresh Frozen Plasma B. Prothrombin Complex Concentrates C. Recombinant factor VIIa D. Vitamin K E. All of the above Which of the following is NOT a reversal option for either rivaroxaban or dabigatran? A. Fresh Frozen Plasma B. Prothrombin Complex Concentrates C. Recombinant factor VIIa D. Vitamin K E. All of the above 9

FFP PCC rfviia ABO typing Yes No No What reversal options should we be using in the emergency setting?

Infusion volume 1-3L <300mL <300mL Clotting factor concentration Low High VII only FFP 3-4 reported in literature to reduce INR Weight based dosing: 10-15mL/kg PCC INR

Package Size FFP 0.20 15mL/kg 1250mL 250 1 unit=250ml Bebulin VH 1.14 60/kg 6156 5400 500, 1000, 1500 Profilnine SD 119 1.19 60/kg 5400 500, 1000, 1500 6426 FEIBA 1.

12 1000mcg 1000mcg 2120 1,2,5,8mg A 71yom presents with ICH who reportedly takes dabigatran at home.

10 FFP PCC rfviia ABO typing Yes No No What reversal options should we be using in the emergency setting? Administration time Slow (thawing time) Rapid Rapid INR correction Slow Rapid Intermediate Thromboembolism risk Slight Yes Yes Infection Risk Yes Minimal Minimal Infusion volume 1-3L <300mL <300mL Clotting factor concentration Low High VII only FFP 3-4 reported in literature to reduce INR Weight based dosing: 10-15mL/kg PCC INR based dosing: /kg Weight based dosing: /kg Factor VIIa Standard dose: 1000mcg x 1 Weight based dosing: 15-90mcg/kg Product $/unit Dose Total Cost Dose ($) Package Size FFP mL/kg 1250mL unit=250ml Bebulin VH /kg , 1000, 1500 Profilnine SD /kg , 1000, FEIBA /kg , 1000, Kcentra /kg NovoSeven mcg 1000mcg ,2,5,8mg A 71yom presents with ICH who reportedly takes dabigatran at home. Patient weight=90kg FFP for mild to moderate bleeding PCCs should be considered in severe bleeding The role of factor VIIa in new anticoagulant reversal is limited Develop institutional standards d for dosing recommendations Which of the following is NOT a benefit of PCCs for anticoagulant reversal? A. Rapid administration time B. Minimal infection risk C. Low volume D. Cost E. All of the above 10

11 Which of the following is NOT a benefit of PCCs for anticoagulant reversal? A. Rapid administration time B. Minimal infection risk C. Low volume D. Cost E. All of the above 1. United States Department of Health. Available at: Accessed: August You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. CHEST 2012;141(2):e531S-75S. 3. Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012;87:S Galanis T, Thomson L, Palladino M, Merli, GJ. New oral anticoagulants. J Thromb Thrombolysis 2011;31: Warfarin [package insert]. Barr Laboratories: Pomona, NY. Updated Garcia D, Libby E, Crowther MA. Blood 2010;115: Dabigatran etexilate t (Pradaxa ). Boehringer Ingelheim Pharmaceuticals, Inc: Rigelfield, ld CT. Updated Rivaroxaban (Xarelto ). Janssen Pharmaceuticals: Gurabo, PR. Updated Apixaban (Eliquis ). Bristol-Myers Squibb Company: Princeton, NJ. Updated Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364: Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;36: EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358: Eriksson BI, Kakkar AK, Turpie AG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip replacement. J Bone Join Surg 2009;91: Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD-3). N Engl J Med 2008;358: Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD-4): a randomized trial. Lancet 2009;373: Agnelli G, Becattini C, Franco L. New oral anticoagulants for the treatment of venous thromboembolism. Best Practice & Research Clinical Hematology 2013; Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol 2013;35: Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis 2010;29(2): Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-based clinical practice guidelines. CHEST 2012;141(2):e44S-88S. 23. Reiss RF. Hemostatic defects in massive transfusion: rapid diagnosis and management. Am J Crit Care 2000;9(3): Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997;77(3): Goldstein Jn, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006;37: Lexi-Drugs Online. Hudson (OH) : Lexi-Comp, Inc. 27. Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates evaluation of safety and thrombogenecity. Crit Care 2011;15(1): FEIBA [package insert]. Baxter Healthcare: Deerfield, IL. Updated Hilgartner MW, Knatterud GL. The use of factor eight inhibitor bypassing activity product for treatment of bleeding episodes in hemophiliacs with inhibitors. Blood 1983;61(1): Recombinant factor VIIa (NovoSeven ). Novo Nordisk: Princeton, NJ. Updated Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008;6(4): Tran H, Collecutt M, Whitehead S, Salem H. Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation. Intern Med J 2011;41(4): Perzborn E et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. J Thromb Haemost 2009;7(S2):379 [abstract]. 34. Godier A, Miclot A, LeBonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012;116(1): Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. Circulation 2011;124: Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of recombinant factor VIIa in patients with warfarin associated intracranial hemorrhage. Neurocrit Care 2005;2: Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004;79(12): Kimberly C. Berger, PharmD, BCPS Clinical Specialist Critical Care Rush University Medical Center Contact: Kimberly_Berger@rush.edu 11

12 New Drugs, New Problems: Reversal Options for New Anticoagulants Self Assessment Questions 1. Which of the following agents does not inhibit factor Xa in the clotting cascade? A. Rivaroxaban B. Apixaban C. Dabigatran D. Warfarin E. None of the above 2. Which of the following medication is approved for the treatment of VTE and for reduction in risk of recurrence of DVT and PE? A. Rivaroxaban B. Apixaban C. Dabigatran D. All of the above E. None of the above 3. T/F: The novel oral anticoagulants are completely safe in comparison to the old anticoagulants. 4. Which of the following is NOT a reversal option for either rivaroxaban or dabigatran? A. Fresh Frozen Plasma B. Prothrombin Complex Concentrates C. Recombinant factor VIIa D. Vitamin K E. All of the above 5. Which of the following is NOT a benefit of PCCs for anticoagulant reversal? A. Rapid administration time B. Minimal infection risk C. Low volume D. Cost E. All of the above

3/19/2012. What is the indication for anticoagulation? Has the patient previously been on warfarin? If so, what % of the time was the INR therapeutic?

3/19/2012. What is the indication for anticoagulation? Has the patient previously been on warfarin? If so, what % of the time was the INR therapeutic? Abigail E. Miller, PharmD, BCPS Clinical Specialist, Cardiology University of North Carolina Hospitals I have no personal financial relationships with the manufacturers of the products to disclose. Boehringer