Lights, Camera, (Vaso)Action! Vasoactive Agents for Catecholamine Refractory Septic Shock Gregory Kelly, Pharm.D. PGY2 Emergency Medicine Pharmacy Resident University of Rochester Medical Center October 28, 2017 Conflicts of Interest I have no conflicts of interest to disclose Presentation Objectives 1. Discuss the currently available literature evaluating angiotensin II as a treatment modality for septic shock. 2. Interpret the results of the ATHOS-3 trial and its applicability to the management of patients with septic shock. Vasopressin Vasopressin: A History Case series of vasopressin First case report deficiency in in severe shock septic shock 1960-80’s 1954 1957 1997 2003 Vasopressin Use of First RCT first vasopressin for suggesting synthesized GI superiority of hemorrhage, vasopressin + diabetes norepinephrine to insipidus and norepinephrine ileus alone Matis-Gradwohl I, et al. Crit Care. 2013;17:1002. VAAST Trial: design VASST Trial Design Mutlicenter, international, randomized, double-blind trial • n = 778 Population • Refractory septic shock Intervention Vasopressin 0.01-0.03 units/min vs. Norepinephrine alone Russell JA, et al. New Engl J Med. 2008;358:877-87. Drug Titration Vasopressin start at 0.01 units/min Titrate by 0.005 units/min Every 10 minutes to reach max of 0.03 units/min MAP ≥65-70mmHg MAP <65-70mmHg Decrease Increase norepinephrine by norepinephrine 1-2 mcg/min every 5-10 minutes Russell JA, et al. New Engl J Med. 2008;358:877-87. Norepinephrine Requirements Norepinephrine Vasopressin Russell JA, et al. New Engl J Med. 2008;358:877-87. Mortality 450 Day 28 Day 90 400 P = 0.27 P = 0.10 350 300 250 200 150 Patients Alive Patients 100 50 0 0 10 20 30 40 50 60 70 80 90 Days Since Drug Initiation Vasopressin Norepinephrine Russell JA, et al. New Engl J Med. 2008;358:877-87. Subgroup Analyses More Severe Septic Shock Less Severe Septic Shock 100 100 90 90 80 80 Alive 70 Alive 70 60 60 50 50 40 40 30 30 20 20 Percent Patients PercentPatients 10 10 0 0 0 28 90 0 28 90 Days Since Drug Initiation Days Since Drug Initiation Vasopressin Norepinephrine Vasopressin Norepinephrine Russell JA, et al. New Engl J Med. 2008;358:877-87. Secondary Outcomes Organ Dysfunction Vasopressor free days Ventilator free days No significant Renal replacement free days Organ failure free days differences SIRS free days Adverse Effects Acute myocardial infarction Cardiac arrest No significant Life-threatening arrhythmia Digital ischemia differences Cerebrovascular accident Russell JA, et al. New Engl J Med. 2008;358:877-87. 2x2 factorial, multicenter, double-blind, randomized Design controlled trial • n = 409 Population • Refractory septic shock Vasopressin titrated up to Norepinephrine 0.06 units/min Intervention With placebo With placebo With hydrocortisone With hydrocortisone Gordon AC, et al. JAMA. 2016;316:509-518. Primary Outcome Renal Failure-Free Patients Renal Failure-Free Days 70 14 60 12 50 10 40 8 30 6 20 4 Number of Days Percent of Patients 10 2 0 0 Vasopressin Norepinephrine Vasopressin Norepinephrine Gordon AC, et al. JAMA. 2016;316:509-518. Renal Replacement Therapy (RRT) Rate of RRT Duration of RRT 40 3.5 AR (95% CI): -9.9 (-19.3 to -0.6) 35 3 30 2.5 25 2 20 1.5 15 1 10 Number of Days Percent of Patients 5 0.5 0 0 Vasopressin Norepinephrine Survivors Nonsurvivors Vasopressin Norepinephrine Gordon AC, et al. JAMA. 2016;316:509-518. Cost Considerations 0.04 unit/min IV infusion Pre-April 2014 Average wholesale price (AWP): $8.67/day April 2014 Vasopressin rebranded with indication for catecholamine refractory vasodilatory shock 0.04 unit/min IV infusion April 2014-present Average wholesale price (AWP): $415.80/day Curtis N, et al. Am J Health-Syst Pharm. 2017;74:105-6. Take Home Points •Early Scientific Data •Observed decreased secretion of vasopressin in patients with septic shock •Suggested potential for vasopressin to reduce catecholamine dose requirements and improve outcomes in patients with septic shock •VASST & VANISH Trials •No improvement in mortality with addition of vasopressin to catecholamine therapy •No reduction in adverse effects or outcomes with addition of vasopressin to catecholamine therapy •Bottom Line •No strong evidence to support benefit of adding vasopressin to catecholamine therapy Angiotensin II Angiotensin II: A History ATII Phase First animal study III Trial Isolated of ATII (ATHOS III) case reports 1957 1958 1961 2014 2017 ATII first First human First synthesized case series randomized in septic controlled shock trial (ATHOS) Khanna A, et al. New Engl J Med. 2017;377:419-30. The Three Musketeers D’artagnan: Impetuous, hotheaded Epinephrine Porthos: Muscular, boisterous, vain Norepinephrine Aramis: Sophisticated, pensive Vasopressin Athos: Leader of the musketeers, Angiotensin mysterious, secretive II Bellomo R, et al. Crit Care Resusc. 2017;19:3-4. Design Randomized controlled trial • n = 20 Population • Refractory septic shock Intervention ATII vs. Norepinephrine alone ATII: Angiotensin II Chawla LS, et al. Crit Care. 2014;18:534. Drug Titration ATII* start at 20 ng/kg/min for 1 hour Norepinephrine Norepinephrine Norepinephrine >10 mcg/min 5-10 mcg/min <5 mcg/min Increase ATII by No change Decrease ATII by 10 ng/kg/min 10 ng/kg/min (Max 40ng/kg/min) (Min 10ng/kg/min) Infusions co-titrated to maintain mean arterial pressure (MAP) of 65 Assessments repeated every hour for 6 hours Chawla LS, et al. Crit Care. 2014;18:534. Primary Outcome Chawla LS, et al. Crit Care. 2014;18:534. Secondary Outcomes Urine Output Mean Arterial Pressure 50 78 45 76 40 74 35 30 72 25 70 MAP 20 68 15 66 10 5 64 0 62 UrineOutput Per Hour(mL) -2 -1 0 1 2 3 4 5 6 7 8 -2 -1 0 1 2 3 4 5 6 7 8 Hour Hour ATII Placebo ATII Placebo Chawla LS, et al. Crit Care. 2014;18:534. ATHOS-3 Trial Phase III, international, multicenter, randomized, placebo- Design controlled trial • n = 321 Population • Refractory septic shock Intervention ATII vs. Norepinephrine alone Khanna A, et al. New Engl J Med. 2017;377:419-30. Primary Outcome MAP response at 3 hours: Mean change in norepinephrine dose at 3 hours: OR 7.95 (95% CI 4.76-13.3), p <0.001 -0.03 vs. 0.03, p <0.001 Khanna A, et al. New Engl J Med. 2017;377:419-30. ATHOS 3: Secondary Outcomes Mortality 60 P = 0.12 50 P = 0.22 40 30 20 10 PercentMortality (%) 0 7-day mortality 28-day mortality HR 0.78 (0.53-1.16) HR 0.78 (0.57-1.07) ATII Placebo Khanna A, et al. New Engl J Med. 2017;377:419-30. SOFA Scores Change in SOFA Score at 48 hours Cardiovascular SOFA Scoring 1.5 P = 0.49 Score 1 Characteristic 0.5 MAP ≥ 70mmHg 0 Cardiovascular SOFA 0 SOFA MAP < 70mmHg 1 -0.5 Dopamine 2 ≤ 5 mcg/kg/min -1 Change Change SOFA in Score Norepinephrine -1.5 3 ≤ 0.1 mcg/kg/min P = 0.01 -2 Norepinephrine ATII Placebo 4 > 0.1 mcg/kg/min SOFA: Sequential Organ Failure Assessment Score Khanna A, et al. New Engl J Med. 2017;377:419-30. Adverse Events 6 5 4 3 2 1 Percent(%) Occurrence 0 Cardiac arrest Acute coronary Ventricular Peripheral Mesenteric syndrome fibrillation ischemia ischemia ATII Placebo Khanna A, et al. New Engl J Med. 2017;377:419-30. Conflicts of Interest Take Home Points •ATHOS & ATHOS 3 trials •ATII increases MAP and decreases norepinephrine dose requirements •No significant differences in clinically significant outcomes •Clinical Application •ATII represents an option to increase MAP in catecholamine refractory patients with vasodilatory shock •Evidence to support clinical benefits of using ATII at this time are lacking •Areas for Future Research •Larger studies powered to investigate clinically significant outcomes •Subgroup analyses to determine patient populations in which ATII may be preferable to standard of care Vasopressin versus Angiotensin II Case series showing ability to increase blood pressure in septic shock. Vasopressin ATII Dunser et al. Ability to decrease catecholamine requirements ATHOS-3 2003 VASST Impact on mortality TBD VANISH Impact on morbidity and mortality TBD Conclusions Morbidity and mortality in septic shock remain high despite current standard of care Vasopressin and angiotensin II represent options to assist in hemodynamic maintenance in catecholamine refractory septic shock. Current evidence does not support the use of vasopressin to reduce morbidity or mortality in catecholamine refractory septic shock. Angiotensin II has not yet been demonstrated to improve morbidity or mortality, however further evidence is needed to determine a potential role in therapy. Questions? Gregory Kelly, Pharm.D. PGY2 Emergency Medicine Pharmacy Resident September 27, 2017 [email protected] Sepsis: Current Management Design Randomized controlled trial In Hospital Mortality 60 56.8 • n = 263 50 46.5 • Patients presenting to ED with severe 42.3 sepsis or septic shock 40 Population • 2 of 4 SIRS criteria 30.5 30 • SBP <90 mmHg (after fluid 30 Control resuscitation*) EGDT 20 • Lactate >4 mmol/L 14.9 10 Intervention Early goal-directed therapy or standard care Percentage (%)of Patients 0 All patients* Severe Septic sepsis* shock* Outcomes Primary: In-hospital mortality *Denotes statistical significance ED: Emergency department; EGDT: Early goal-directed therapy; SIRS: Systemic inflammatory response syndrome; SBP: Systolic blood pressure Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. New Engl J Med 2001;345(19)1368-77. 34 Early Goal Directed Therapy Goal Therapy to Achieve CVP 8-12 mmHg 500 mL bolus of crystalloid given every 30 minutes MAP >65 mmHg Vasopressors • PRBC to achieve Hct ≥ 30% SCVO2 >70% • Dobutamine if Hct ≥ 30% and SCVO2 <70% CVP: Central venous pressure; Hct: Hematocrit MAP: Mean arterial pressure; PRBC: Packed red blood cells; SCVO2: Central venous oxygen saturation Rivers E, Nguyen B, Havstad S, et al.