1. ACCP Cardiology PRN Journal Club

2. 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

3. 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.

4. 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.

5. 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

6. Disclosure
I have no conflicts of interest to disclose.

7. 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.

8. 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.

9. 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:
N Engl J Med. 2006;355:

10. 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:
JAMA. 2007;297:

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

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

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

14. 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: /j.jacc [Epub ahead of print]

15. 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: /j.jacc [Epub ahead of print]

16. 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: /j.jacc [Epub ahead of print]

17. 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: /j.jacc [Epub ahead of print]

18. 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: /j.jacc [Epub ahead of print]

19. 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: /j.jacc [Epub ahead of print]

20. 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: /j.jacc [Epub ahead of print]

21. 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: /j.jacc [Epub ahead of print]

22. 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: /j.jacc [Epub ahead of print]

23. 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: /j.jacc [Epub ahead of print]

24. 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

25. 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:e

26. 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

27. 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

28. 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 the journal club at or
A PB Works Site has been created that houses our recorded calls, handouts, and Summary/Q&A documents. The link is