Lights, Cam era, ( Vaso) Action! Vasoactive Agents for Catecholam - PowerPoint PPT Presentation

Lights, Cam era, ( Vaso) Action! Vasoactive Agents for Catecholam ine Refractory Septic Shock Gregory Kelly, Pharm.D. PGY2 Emergency Medicine Pharmacy Resident University of Rochester Medical Center October 28, 2017

Conflicts of I nterest 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 deficiency in First case report in severe shock septic shock 1 9 6 0 -8 0 ’s 1 9 5 4 1 9 5 7 1 9 9 7 2 0 0 3 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 I ntervention 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 .0 1 units/ m in Titrate by 0 .0 0 5 units/ m in Every 1 0 m inutes to reach m ax of 0 .0 3 units/ m in MAP ≥65 -7 0 m m Hg MAP < 6 5 -7 0 m m Hg Decrease I ncrease norepinephrine by norepinephrine 1 -2 m cg/ m in every 5 -1 0 m inutes Russell JA, et al. New Engl J Med. 2008; 358: 877-87.

Norepinephrine Requirem ents Norepinephrine Vasopressin Russell JA, et al. New Engl J Med. 2008; 358: 877-87.

Mortality 4 5 0 Day 2 8 Day 9 0 4 0 0 P = 0 .2 7 P = 0 .1 0 3 5 0 Patients Alive 3 0 0 2 5 0 2 0 0 1 5 0 1 0 0 5 0 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 Days Since Drug I nitiation Vasopressin Norepinephrine Russell JA, et al. New Engl J Med. 2008; 358: 877-87.

Subgroup Analyses More Severe Septic Shock Less Severe Septic Shock 1 0 0 1 0 0 9 0 9 0 Percent Patients Alive Percent Patients Alive 8 0 8 0 7 0 7 0 6 0 6 0 5 0 5 0 4 0 4 0 3 0 3 0 2 0 2 0 1 0 1 0 0 0 0 2 8 9 0 0 2 8 9 0 Days Since Drug I nitiation Days Since Drug I nitiation Vasopressin Norepinephrine Vasopressin Norepinephrine Russell JA, et al. New Engl J Med. 2008; 358: 877-87.

Secondary Outcom es Organ Dysfunction Vasopressor free days Ventilator free days No significant Renal replacement free days differences Organ failure free days SIRS free days Adverse Effects Acute myocardial infarction Cardiac arrest No significant Life-threatening arrhythmia differences Digital ischemia 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 I ntervention With placebo With placebo With hydrocortisone With hydrocortisone Gordon AC, et al. JAMA. 2016; 316: 509-518.

Prim ary Outcom e Renal Failure-Free Patients Renal Failure-Free Days 7 0 1 4 Percent of Patients 6 0 1 2 Num ber of Days 5 0 1 0 4 0 8 3 0 6 2 0 4 1 0 2 0 0 Vasopressin Norepinephrine Vasopressin Norepinephrine Gordon AC, et al. JAMA. 2016; 316: 509-518.

Renal Replacem ent Therapy ( RRT) Rate of RRT Duration of RRT 4 0 3 .5 AR ( 9 5 % CI ) : -9 .9 ( -1 9 .3 to -0 .6 ) 3 5 Percent of Patients 3 Num ber of Days 3 0 2 .5 2 5 2 2 0 1 .5 1 5 1 1 0 0 .5 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 2 0 1 4 Average wholesale price (AWP): $ 8 .6 7 / day April 2014 Vasopressin rebranded with indication for catecholamine refractory vasodilatory shock 0.04 unit/ min IV infusion April 2 0 1 4 -present Average wholesale price (AWP): $ 4 1 5 .8 0 / day Curtis N, et al. Am J Health-Syst Pharm. 2017; 74: 105-6.

Take Hom e 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 & VANI SH 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 I I

Angiotensin I I : A History ATII Phase First animal study III Trial Isolated of ATII (ATHOS III) case reports 2 0 1 4 2 0 1 7 1 9 5 7 1 9 5 8 1 9 6 1 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 I ntervention ATII vs. Norepinephrine alone ATII: Angiotensin II Chawla LS, et al. Crit Care. 2014; 18: 534.

Drug Titration ATI I * start at 2 0 ng/ kg/ m in for 1 hour Norepinephrine Norepinephrine Norepinephrine > 1 0 m cg/ m in 5 -1 0 m cg/ m in < 5 m cg/ m in No change I ncrease ATI I by Decrease ATI I by 1 0 ng/ kg/ m in 1 0 ng/ kg/ m in ( Max 4 0 ng/ kg/ m in) ( Min 1 0 ng/ kg/ m in) 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.

Prim ary Outcom e Chawla LS, et al. Crit Care. 2014; 18: 534.

Secondary Outcom es Urine Output Mean Arterial Pressure 5 0 7 8 Urine Output Per Hour ( m L) 4 5 7 6 4 0 7 4 3 5 7 2 3 0 MAP 2 5 7 0 2 0 6 8 1 5 6 6 1 0 6 4 5 0 6 2 -2 -1 0 1 2 3 4 5 6 7 8 -2 -1 0 1 2 3 4 5 6 7 8 Hour Hour ATI I Placebo ATI I 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 I ntervention ATII vs. Norepinephrine alone Khanna A, et al. New Engl J Med. 2017; 377: 419-30.

Prim ary Outcom e MAP response at 3 hours: Mean change in norepinephrine dose at 3 hours: OR 7.95 (95% CI 4.76-13.3), p < 0 .0 0 1 -0.03 vs. 0.03, p < 0 .0 0 1 Khanna A, et al. New Engl J Med. 2017; 377: 419-30.

ATHOS 3 : Secondary Outcom es Mortality 6 0 P = 0 .1 2 Percent Mortality ( % ) 5 0 P = 0 .2 2 4 0 3 0 2 0 1 0 0 7 -day m ortality 2 8 -day m ortality HR 0 .7 8 ( 0 .5 3 -1 .1 6 ) HR 0 .7 8 ( 0 .5 7 -1 .0 7 ) ATI I Placebo Khanna A, et al. New Engl J Med. 2017; 377: 419-30.

SOFA Scores Change in SOFA Score at 4 8 hours Cardiovascular SOFA Scoring 1 .5 P = 0 .4 9 Score Characteristic 1 MAP ≥ 70mmHg Change in SOFA Score 0 0 .5 Cardiovascular SOFA 0 1 MAP < 7 0 m m Hg SOFA -0 .5 Dopam ine 2 ≤ 5 mcg/kg/min -1 Norepinephrine 3 -1 .5 ≤ 0.1 mcg/kg/min P = 0 .0 1 -2 Norepinephrine 4 ATI I Placebo > 0 .1 m cg/ kg/ m in SOFA: Sequential Organ Failure Assessment Score Khanna A, et al. New Engl J Med. 2017; 377: 419-30.

Adverse Events 6 Percent ( % ) Occurrence 5 4 3 2 1 0 Cardiac arrest Acute coronary Ventricular Peripheral Mesenteric syndrom e fibrillation ischem ia ischem ia ATI I Placebo Khanna A, et al. New Engl J Med. 2017; 377: 419-30.

Conflicts of I nterest

Take Hom e 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 I I Case series showing ability to increase blood pressure in septic shock. Vasopressin ATI I 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.