ACCP Cardiology PRN Journal Club

Announcements Thank you attending the ACCP Cardiology PRN Journal Club Please remain on mute during the presentation Thoughts, comments, and questions following the presentation are encouraged though! Type questions in the messaging box on the left and they will be addressed at the conclusion of the presentation

Dr. Laura Fuller Dr. Fuller received her Bachelor of Science degrees in Biology and Chemistry from the University of Memphis before completing her Doctor of Pharmacy degree from the University of Tennessee. She completed her PGY-1 Pharmacy Residency at Methodist University Hospital in Memphis, TN and is currently a PGY-2 Cardiology Resident at The Johns Hopkins Hospital in Baltimore, MD.

Dr. Brent Reed Dr. Brent Reed, is an assistant professor at the University of Maryland School of Pharmacy and a clinical pharmacy specialist at the University of Maryland Medical Center in Baltimore, MD, where he practices in the area of advanced heart failure. He also serves as the program director for the Postgraduate Year 2 Cardiology Pharmacy Residency Program at the University of Maryland. Dr. Reed received his Doctor of Pharmacy from the University of Tennessee College of Pharmacy in Memphis, TN, and subsequently completed a pharmacy practice residency and cardiology specialty residency at the University of North Carolina Hospitals in Chapel Hill, NC. Dr. Reed is a board-certified pharmacotherapy specialist with added qualifications in cardiology. In 2015, he co-founded the Applied Therapeutics, Research, and Instruction at the University of Maryland (ATRIUM) collaborative, which focuses on the advancement of cardiovascular care.

Brent Reed, PharmD, BCPS-AQ Cardiology Efficacy and Safety of Tolvaptan in Patients with Acute Heart Failure (TACTICS-HF) Laura A. Fuller, PharmD PGY2 Cardiology Pharmacy Resident The Johns Hopkins Hospital Presenter Brent Reed, PharmD, BCPS-AQ Cardiology Assistant Professor University of Maryland School of Pharmacy Mentor

Disclosure I have no conflicts of interest to disclose.

Vasopressin Fluid retention Arterial underfilling ↑ Vasopressin Hyponatremia ↑ SVR Vasopressin concentrations are known to be elevated in HF, correlate with its severity, and contribute to both fluid retention and hyponatremia, as well as increase systemic vascular resistance Naturally, as a mediator of ongoing neurohormonal activation in HF, vasopressin has become a pharmacotherapeutic target of interest However, the question remains whether excess vasopressin secretion and the hyponatremia that results is a truly a pharmacologic target or simply a surrogate marker for the severity of disease SVR: systemic vascular resistance Am J Health Syst Pharm. 2011;68:21-35.

Vasopressin Subtype Location Action Antagonist V1A Vascular smooth muscle Vasoconstriction Conivaptan V1B Anterior pituitary ACTH release V2 Renal cortical and medullary collecting duct Increases permeability of aquaporin-2 channel to water Tolvaptan Antagonism of V1A receptors located in the systemic vasculature results in vasodilation, whereas inhibiting the V2 receptor (specifically tolvaptan) in the kidneys, leads to an increase in free water clearance (aquaresis) and serum sodium level and a decrease in urine osmolality ACTH: adrenocorticotropic hormone Am J Health Syst Pharm. 2011;68:21-35.

Tolvaptan: Previous Data Associated with greater weight and fluid loss compared to standard therapy, but no improvements in long-term outcomes Effective at raising serum sodium levels in patients with hyponatremia Improvements in symptom-related patient self-assessments Not associated with worsening renal function or hypotension These changes did not generally lead to clinically important improvements such as prevention of hospitalizations or mortality; ACTIV in CHF post-hoc analysis: reduced 60-day mortality in patients with severe volume overload Reverted back to levels seen in patients receiving placebo indicating chronic use may be needed; recently published meta-analysis showed that patients with hyponatremia may have better mortality outcome with tolvaptan JAMA. 2004;291:1963-71. N Engl J Med. 2006;355:2099-112.

EVEREST Short-Term Trial Outcome Trial Design Prospective, randomized, double-blind, placebo-controlled trial Patient Population Chronic HF (EF <40%) hospitalized for worsening HF with signs and symptoms of congestion Intervention Tolvaptan 30 mg/day or matching placebo (standard therapy) within 48 hr of admission Same as short-term for a minimum of 60 days in addition to standard therapy Outcomes Composite of changes of global clinical status and body weight at day 7 or discharge All-cause mortality* and CV death or hospitalization for HF☨ Results Significantly greater improvements in primary outcome and dyspnea at day 1 No difference in all-cause mortality or CV death or hospitalization for HF Conclusions Tolvaptan, in addition to standard therapy, improves signs and symptoms of HF, but has no long-term effect on mortality or HF-related morbidity s/s of congestion: dyspnea, JVD, peripheral edema at rest or minimal exertion Significantly greater improvements is primary outcome primarily driven by changes in body weight All-cause mortality reached significance for noninferiority; no difference in CV mortality, CV death or hospitalization, or worsening HF; no difference in patient questionnaire at week 1 HF: heart failure; EF: ejection fraction; CV: cardiovascular *Tested for superiority and noninferiority ☨Tested for superiority only JAMA. 2007;297:1332-43. JAMA. 2007;297:1329-31.

TACTICS-HF Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Objective To address the acute use of tolvaptan to improve congestion in acute heart failure (AHF) J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Study Design Randomized, double-blind, placebo-controlled, multicenter clinical trial J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Patient Population No ejection fraction criterion Inclusion Criteria Exclusion Criteria Presented within the previous 24 hr with AHF Dyspnea at rest or with minimal exertion BNP >400 pg/mL or NT-proBNP >2000 pg/mL At least 1 additional sign or symptom of congestion: Orthopnea Edema Elevated jugular venous pressure Rales Congestion on chest radiograph Serum sodium  140 mEq/L Daily oral diuretic requirement of 40 mg furosemide (or equivalent) Systolic blood pressure <90 mmHg Serum creatinine >3.5 mg/dL or requiring renal replacement therapy Receiving IV vasoactive therapy (vasodilators or inotropes) Receiving ultrafiltration Patients could be enrolled whether they had HFrEF or HFpEF No ejection fraction criterion BNP: B-type natriuretic peptide NT-proBNP: N-terminal pro-B-type natriuretic peptide J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Randomization & Treatment Assignment AHF (dyspnea, elevated BNP/NT-proBNP, other signs/symptoms) <24 hr after presentation Fixed-dose furosemide☨ + tolvaptan 30 mg/day* x 48 hr Fixed-dose furosemide☨ + placebo daily* x 48 hr After 48 hr, rescue therapy could be given if indicated for worsening or persistent HF (additional loop diuretics, thiazide diuretics, IV vasodilators or inotropes, ultrafiltration, mechanical cardiac or respiratory support) IV furosemide: regimen mirrored the ”low-dose” arm in the DOSE study and was chosen to mitigate the potential risk of hypotension and over-diuresis from combining high-dose furosemide with tolvaptan Rescue therapy was at the discretion of the treating physician *3 doses given at 0, 24, and 48 hr ☨IV furosemide at 1x the patient’s outpatient dose given q12h, or 40 mg q12h, whichever was greater J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Endpoints 24 hr Primary endpoint: Percentage with at least moderate improvement in dyspnea by Likert scale both 8 and 24 hr without rescue therapy or death 48 hr Changes in renal function, changes in body weight and fluid loss, changes in dyspnea by Likert and 11-point numerical rating scale (NRS), and percent with worsening or persistent HF Day 7 or discharge Length of stay Moderate improvement= Rescue therapy= need for additional open label loop diuretics or the addition of a thiazide diuretic, IV vasoactive drug for HF, or mechanical circulatory or respiratory support 30 days Death, re-hospitalization, urgent clinic visit Total days deceased or hospitalized J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Statistical Analysis A sample size of 250 subjects would provide 80% power to detect a treatment effect of about 38% Dichotomous endpoints: Chi-square or Fisher exact Continuous endpoints: Wilcoxon rank-sum Intention-to-treat protocol for all analyses A p-value <0.05 considered statistically significant J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Results: Demographics Characteristic Placebo (n=128) Tolvaptan (n=129) All Patients (N=257) Age, yr, mean (SD) 63 (16) 66 (13) 65 (14) Female, % 33 34 African American, % 45 36 41 Baseline diuretic dose, mg/day, mean (SD) 72 (46) 71 (53) 71 (49) EF, %, mean (SD) 32 (17) 34 (17) 33 (17) EF  45% 25 ACEI or ARB, % 60 62 61 Beta-Blocker, % 88 92 90 Aldo antagonist, % 31 32 Sodium, mean (SD) 136 (4) 136 (3) Creatinine, mean (SD) 1.44 (0.6) 1.48 (0.7) 1.46 (0.6) EF- includes both HRrEF and HFpEF % pts on ACEI/ARB vs BB SD: standard deviation; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Results: Primary Endpoint No difference in dyspnea relief measured by Likert scale at 8 and 24 hr; need for rescue therapy also similar between groups at 24 hr Responders defined as moderate or marked improvement at all time points and no need for rescue therapy and no death J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Results: Symptomatic Endpoints Placebo (n=128) Tolvaptan (n=129) P-value % Moderate or better improvement in dyspnea (Likert scale) 48 hr 55% 65% NS 72 hr 60% 69% Dyspnea by numerical rating scale (0-10), mean (SD) Baseline 5.6 (2.3) 5.6 (2.4) -- 8 hr 4.3 (2.4) 4.2 (2.6) 24 hr 3.8 (2.3) 3.5 (2.5) 3.3 (2.2) 2.8 (2.4) 3.1 (2.2) 2.6 (2.4) % Responders 36% 45% 18% 30% 0.02 Whether assessed by the Likert scale or the numerical rating scale, dyspnea relief was not statistically different between patients randomized to tolvaptan or placebo Using the same definition of responders as the primary endpoint, patients randomized to tolvaptan were more likely to be classified as responders compared to placebo at 72 hr, and were less likely to need rescue therapy by 72 hr (39% tolvaptan vs 53% placebo, p=0.047) J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Results: Decongestion and Renal Function Placebo (n=128) Tolvaptan (n=129) P-value Change in weight (lbs), mean (SD) 24 hr -1.2 (13.2) -4.4 (6.6) 0.005 48 hr -3.5 (6.3) -6.1 (7.4) 0.004 72 hr -5.5 (7.0) -8.2 (9.7) NS Fluid loss (mL), mean (SD) 1541 (1525) 2182 (1844) 0.006 1419 (1379) 1948 (1636) 0.01 1401 (1387) 1757 (1670) Change in serum sodium (mEq/L), mean (SD) 0.2 (2.5) 3.2 (3.3) <0.001 -0.2 (2.8) 3.3 (3.7) -0.4 (2.9) 2.8 (3.9) Worsening renal function 27% 39% 0.037 Over diuresis 2% 5% Change in weight in lbs vs kg Significant differences in change in body weight and fluid loss at 24 and 28 hr, but no longer significant at 72 hrs compared to placebo (opposite to what was seen in dyspnea improvement significant improvement at 72 hr) Significant differences in serum sodium at all time points No differences in freedom in congestion (no JVP, rales, or orthopnea) or change in creatinine at any time point When worsening renal function was considered a dichotomous endpoint (defined as change in serum creatinine >/=0.3 mg/dL within 72 hr), this endpoint was more frequent in patients randomized to tolvaptan No significant differences in overdiuresis (defined as clinical evidence of volume depletion requiring intervention beyond holding diuretics) J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Results: Clinical Events and Safety Placebo (n=128) Tolvaptan (n=129) P-value Worsening HF 29.7% 23.3% NS IV loop diuretics 89.8% 91.8% Thiazides 27.1% 18.4% IV vasoactive treatment 23.7% 24.5% Mechanical circulatory or respiratory support 0% 4.1% Length of stay Mean days alive and outside of hospital through day 30 30-day rehospitalization or death Kaplan-Meier rate 30-day mortality 23 (18) 29% 6% 24 (19) 33% Median LOS 5 days in both groups IV loop diuretics majority of worsening HF events were treated with additional IV diuretics J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Conclusions In patients hospitalized for AHF, the addition of tolvaptan to diuretics did not improve the proportion of responders at 24 hr The use of tolvaptan resulted in greater fluid and weight loss, and trended towards greater dyspnea improvement at later time points No differences in clinical endpoints such as length of stay or post-discharge outcomes up to 30 days J Am Coll Cardiol. 2016; doi: 10.1016/j.jacc.2016.09.004. [Epub ahead of print]

Critique Strengths Weaknesses EF not an exclusion criterion Standardized loop diuretic dosing regimen Fixed-dose tolvaptan dosing Evaluated both surrogate and clinical endpoints Early enrollment (within 24 hr) Included patients with a broader spectrum of renal function EF not an exclusion criterion Standardized loop diuretic dosing regimen Fixed-dose tolvaptan dosing Lack of correlation between subjective and objective endpoints

Impact on Clinical Practice 2013 ACCF/AHA Heart Failure Guidelines: Tolvaptan may be used short-term in hospitalized patients with volume overload with persistent hyponatremia at risk for cognitive symptoms despite water restriction and optimization of GDMT (Class IIb: LOE B) Cost: ~$1200 for the 48-hr treatment in TACTICS-HF Further evaluation of tolvaptan hyponatremic hypervolemic HFrEF patients? The benefit of adding tolvaptan is outweighed by high cost secondary to the availability of less expensive alternatives with similar effects GDMT: guideline-directed medical therapy Circulation. 2013;128:e240-327.

Acknowledgements Journal Club Mentor: Program Director: Brent Reed, PharmD, BCPS-AQ Cardiology Program Director: John Lindsley, PharmD, BCPS-AQ Cardiology ACCP Cardiology PRN Journal Club Coordinators: Carrie S. Oliphant, PharmD, FCCP, BCPS-AQ Cardiology, AACC Ted Berei, PharmD, MBA Zachary Noel, PharmD, BCPS

Brent Reed, PharmD, BCPS-AQ Cardiology Efficacy and Safety of Tolvaptan in Patients with Acute Heart Failure (TACTICS-HF) Laura A. Fuller, PharmD PGY2 Cardiology Pharmacy Resident The Johns Hopkins Hospital Presenter Brent Reed, PharmD, BCPS-AQ Cardiology Assistant Professor University of Maryland School of Pharmacy Mentor

Thank you for attending! If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail.com or carrie.Oliphant@mlh.org A PB Works Site has been created that houses our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/