Document Number-IN-11027

Saving Lives: Comprehensive HF Protocol Approved Date-16/1/2023

Expiration Date-10/1/2025

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 HF is a growing public health problem, with high morbidity and mortality

BURDEN HOSPITALIZATION MORTALITY

HF is the number The 5-year mortality

one cause of rate for patients with
HF affects hospitalization
in people >65 years2,a
HF is ~50%4

~64 million
people
worldwide1 hHF is projected to Mortality significantly
rise by ~50% over increases after each
the next 25 years3 HF readmission5

a
In developed countries.
1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789-1858; 2. Cowie MR et al. ESC Heart Fail. 2014;1(2):110-145;
3. Groenewegen A et al. Eur J Heart Fail. 2020;22(8):1342-1356; 55; 4. Jones NR et al. Eur J Heart Fail. 2019;21(11):1306-1325; 5. Setoguchi S et al. Am Heart J.
2 2007;154(2):260-266.
 An insidious disease that starts before the first symptoms

Prevention of HF Treatment of HF

NYHA class Progression o

f remodeling
I
Worsening symptoms

IIs

IIm

III ACS Exacerbation

(attack)
IV Stage A Stage B Stage C Stage D
Structural heart disease Signs & symptoms Refractory heart failure
At high risk but w/o Refractory HF
Structural heart disease but w/o signs or Structural heart disease
structural heart requiring specialized
symptoms with prior or current symptoms.
disease or symptoms interventions.

ACS = acute coronary syndrome; HF = heart failure; NYHA = New York Heart Association; w/o = without.
Kato M. The concept of heart failure: chronic diseases accompanied by an attack of acute exacerbation. In: Sato N, eds. Therapeutic Strategies for Heart Failure. Tokyo,
Japan: Springer: 2018:1-15. © AstraZeneca 2019
 Despite poor prognosis, there is a lack of urgency for early identification
and initiation of GDMT

Over 40% have HF

symptoms up to 5 years
GDMT for HF is suboptimal
for the majority of patients3
!
prior to diagnosis1
~75% are diagnosed Over 30% mortality rate
with HF following 1 year after hHF2,b
an unplanned hHF1,2,a

a
Based on data from 2010-20131 and 20172; bBased on patients diagnosed with HF during hHF from 2012-2015.
1. Bottle A et al. Heart. 2018;104(7):600-605; 2. Lawson CA et al. Article and supplementary appendix. Lancet Public Health. 2019;4(8):e406-e420; 3. Ghazi L et al. J Am Coll
4 Cardiol. 2022;79(22):2203-2213. © AstraZeneca 2019
 DAPA-HF: The first and only SGLT2 inhibitor to significantly reduce
CV mortality in HFrEF patients, with and without T2D1,2

Primary endpoint1 Baseline characteristics3

1
Composite of CV death
or worsening HF (hHF
N=4744 or an urgent HF visit)
• LVEF ≤40%
• Elevated NT-proBNP
1437 pg/mL 31%
• eGFR ≥30 mL/min/1.73 m2 Median Average
Secondary endpoints 1
NT-proBNP LVEF
• CV death or hHF
• Total number of hHF (first and
1:1 randomization recurrent) and CV death
• Change in KCCQ-TSS from
baseline to 8 months 55% 41%
DAPA 10 mg Placebo • ≥50% sustained decline in eGFR, Without With an eGFR
ESKD or renal death T2D <60 mL/min/1.73 m2
• All-cause mortality
Median follow-up: 18.2 months

1. McMurray JJV et al. N Engl J Med. 2019;381(21):1995-2008; 2. Packer M et al. N Engl J Med. 2020;383(15):1413-1423; 3. McMurray JJV et al. Eur J Heart Fail.
5 2019;21:1402-1411.
 Dapagliflozin significantly reduced the risk of CV death and
worsening HFa in patients with HFrEF1,2

CV Death or
Primary Endpoint Worsening HFa
Composite of CV Death or Worsening HFa

26 %
30

RRR All-cause
HR: 0.74 (95% CI: 0.65-0.85)
25 mortality was
Placebo
4.9% ARR also reduced in
Cumulative Incidence (%)

the dapagliflozin
20 Statistically p=0.00001 group
significant DAPA 10 mg
as early as
All-cause
15 CV death Worsening HFa
Day 28 3,b
mortality

10 18 RRR %
30 RRR %
17 RRR%

1.9% ARR 3.7% ARR 2.3% ARR

5 NNT=21 p=0.029 p=0.00003 p=0.022c

0
0 3 6 9 12 15 18 21 24 Consistent benefit in the primary
Months from Randomization endpoint across key subgroups

a
hHF or an urgent HF visit; bPost-hoc analysis; cNominal p-value.
1. McMurray JJV et al. N Engl J Med. 2019;381(21):1995-2008; 2. McMurray J. Presented at: ESC Congress; August 31-September 4, 2019; Paris, France; 3. Berg DD et al.
6 JAMA Cardiol. 2021;6(5):499-507.
 Dapa HF: 21% RRR in Composite of Ventricular arrhythmia,
resuscitated cardiac arrest or sudden death

Placebo - 175/2371
21% Dapagliflozin - 140/2373
RRR

HR 0.79 (95%CI 0.63-0.99), p=0.037

James Curtain et al. European Heart Journal (2021) 00, 1–12

 Diabetes
Diabetes Status
Status

Dapagliflozin Significantly Reduced the Primary Endpoint,

Regardless of Diabetes Status and HbA1c in the No T2D Group 1

CV Death or hHF or Urgent HF Visit

Dapagliflozin 10 mg, Placebo, Interaction

Outcome n/N (%) n/N (%) HR (95% CI) p-valueb
Total population 386/2373 (16.3) 502/2371 (21.2) 0.74 (0.65-0.85)

T2Da 215/1075 (20.0) 271/1064 (25.5) 0.75 (0.63-0.90)

0.80
No T2D 171/1298 (13.2) 231/1307 (17.7) 0.73 (0.60-0.88)

Normo-glycemic (HbA1c <5.7%) 53/438 (12.1) 71/419 (16.9) 0.67 (0.47-0.96)

0.72
Pre-diabetes (HbA1c ≥5.7-<6.5%) 118/860 (13.7) 160/888 (18.0) 0.74 (0.59-0.94)

0.4 0.6 0.8 1.0 1.2 1.4

Dapagliflozin 10 mg Better Placebo Better

a
Includes 1983 patients with a pre-existing diagnosis of diabetes and 156 patients with previously undiagnosed diabetes (HbA1c ≥6.5% at Visits 1 and 2); bA non-significant
result for an interaction test can be interpreted as consistency of effect across the subgroup.2
CV = cardiovascular; HbA1c = glycated hemoglobin; HF = heart failure; hHF = hospitalization for heart failure; HR = hazard ratio; T2D = type 2 diabetes.
8 1. Petrie MC et al. JAMA. 2020;323:1353-1368; 2. Alosh M et al. J Biopharm Stat. 2015;25:1161-1178.
 Dapagliflozin Was Well Tolerated in the Group Without T2D1,a
T2Db No T2D
Dapagliflozin Dapagliflozin
10 mg Placebo 10 mg Placebo Interaction
Event, % n=1075 n=1064 n=1298 n=1307 p-valuec
Any serious AEd 41.7 48.3 34.6 36.9 0.16
AE leading to treatment discontinuation 4.0 5.4 5.3 4.5 0.09
AE of interest
Volume depletion 7.8 7.8 7.3 6.1 0.40
Kidney AE 8.5 8.7 4.8 6.0 0.36
Fracture 2.1 2.4 2.1 1.9 0.58
Amputation 1.1 0.8 0.1 0.2 0.24
Major hypoglycemiae 0.4 0.4 0 0 NA
Diabetic ketoacidosisf 0.3 0 0 0 NA

a
Safety population included all patients who had undergone randomization and received at least one dose of dapagliflozin (n=2368) or placebo (n=2368); bIncludes 1983 patients with a pre-existing
diagnosis of diabetes and 156 patients with previously undiagnosed diabetes (HbA1c ≥6.5% at Visits 1 and 2); cA non-significant result for an interaction test can be interpreted as consistency of
effect across the subgroup2; dIncluding death; eDefined as hypoglycemia requiring the assistance of another person to actively administer carbohydrates or glucagon or to take other corrective action;
f
All cases of diabetic ketoacidosis occurred in patients with diabetes at baseline and were adjudicated as definite or probable.
AE = adverse event; HbA1c = glycated hemoglobin; NA = not applicable; T2D = type 2 diabetes.
9 1. Petrie MC et al. JAMA. 2020;323:1353-1368; 2. Alosh M et al. J Biopharm Stat. 2015;25:1161-1178.
 EMPEROR-Reduced reinforced SGLT2i benefits irrespective of T2D however
lacks mortality benefits in HFrEF patients

• 3730 patients with HFrEF (LVEF ≤40%, NYHA Class II-IV) receiving recommended therapy
• Patients enrolled based on varying thresholds for LVEF and NT-proBNP
• 50% of the population did not have T2D

• Results: HR or Absolute Difference

Outcome (95% CI)
Primary: composite of CV death or hHF 0.75 (0.65-0.86)
CV death 0.92 (0.75-1.12)
hHF 0.69 (0.59-0.81)
First secondary: total hHF 0.70 (0.58-0.85)
Second secondary: mean slope of change in eGFR 1.73a (1.10-2.37)
All-cause death 0.92 (0.77-1.10)
Composite of Ventricular Arrhythmia, Resuscitated Cardiac Data not available
Arrest or Sudden Death

• Safety results were similar to the known safety profile of empagliflozin.

a
Absolute difference reported as mL/min/1.73 m2.
CV = cardiovascular; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; HR = hazard ratio; LVEF = left ventricular
ejection fraction; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; SGLT2 = sodium-glucose cotransporter 2; T2D = type 2 diabetes.
10 Packer M et al. N Engl J Med. 2020;383:1413-1424.
 Dapagliflozin: In treatment of Cardio-renal complications

Focus on Treatment of Chronic Kidney Diseases

11
 Close Association Between Cardiac and Kidney Pathophysiology1,2

Cardiorenal RAAS Activation

Connectors
Oxidative Stress

Inflammation

SNS Activation
Chronic Heart Failure Kidney Disease
• Genetic predisposition Normal kidney
• Environmental risk factors function
Chronic hypoperfusion,
Apoptosis
• Low cardiac output
• Inflammation Initiation of
• Arterial calcification kidney damage
• Endothelial calcification
Sclerosis - Fibrosis

• Chronic hypoperfusion
• Increased venous pressure Progression
• Increased venous resistance to CKD

Anemia, Metabolic Abnormalities, Volume Overload

CKD = chronic kidney disease; CV = cardiovascular; RAAS = renin-angiotensin aldosterone system; SNS = sympathetic nervous system.
1. Adapted from Raina R et al. Cardiol Res. 2020;11:76-88; 2. Adapted from Yogasundaram H et al. Can J Cardiol. 2019;35:1208-1219; 3. Damman K et al. J Am Coll
12 Cardiol. 2014;63:853-871; 4. Metra M et al. Eur Heart J. 2012;33:2135-2143. © AstraZeneca 2021
 CKD and HF Are Interconnected: CKD Is Associated With Increased
Risk of HF and Conversely HF Is Associated With Risk of eGFR Decline
Incidences of HF are higher in those with CKD than those without 1 HF is associated with rapid
decline in eGFR2,a
HFrEF HFpEF
6 6 25
CKD HFrEF CKD HFpEF 22.0
Cumulative incidence

Cumulative incidence

Prevalence of rapid eGFR

No CKD HFrEF No CKD HFpEF 20
4 4
of HF (%)

of HF (%)

decline (%)
15

10 8.6
2 2

0 0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12 HF No HF
Time (years) Time (years)

HF is associated with the risk

CKD is associated with incident HF
of kidney function decline

a
Rapid rate of eGFR decline was defined as slopes steeper than −5 mL/min/1.73 m2/year.
CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with
reduced ejection fraction.
13 1. Nayor M et al. Eur J Heart Fail. 2017;19:615-623; 2. George LK et al. Circ Heart Fail. 2017;10:e003825. © AstraZeneca 2021
Evidence for expanding the role of Dapagliflozin to fill
the vacuum in CKD Management
 DAPA-CKD enrolled a diverse population of patients with CKD, including
various etiologies

eGFR range2,b Cause of kidney disease2

25-75 mL/min/1.73 m2
The first trial to study
• eGFR ≥45: 41%
• eGFR <45: 59% 12%
the cardiorenal effects
of an SGLT2 inhibitor 5%
in patients with CKD, 3
%
with and without
T2D1,a
UACR range1 6%
≥200 to ≤5000 mg/g
N=4304 58%

1:1 randomization 16%

DAPA therapy could
continue following
DAPA 10 mg Placebo dialysis initiation3,4,c Diabetic nephropathy FSGS
Ischemic/ hypertensive nephropathy Unknown cause
IgA nephropathy Otherd
Median follow-up time: 2.4 years
a
All patients were required to be on a stable dose of an ACE inhibitor or ARB for at least 4 weeks before screening, if not medically contraindicated. Patients with T1D, polycystic kidney
disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis were excluded; bPatients were permitted to continue with dapagliflozin therapy if eGFR fell to
<25 mL/min/1.73 m2 over the course of the study; cAt the investigators discretion; d‘Other’ included patients with chronic pyelonephritis, chronic interstitial nephritis, and other causes.
1. Heerspink HJL et al. N Engl J Med. 2020:383(15):1436-1446; 2. Wheeler DC et al. Nephrol Dial Transplant. 2020;35(10):1700-1711; 3. Heerspink HJL et al. Nephrol Dial Transplant.
15
15 2020;35(2):274-282; 4. Heerspink HJL et al. Eur Heart J. 2021;42(13):1216-1227. © AstraZeneca 2021
DAPA-CKD was the first dedicated CKD trial to demonstrate robust
cardiorenal and mortality benefits

Primary composite Composite of

All-cause mortality1,b
outcome1,a CV death or hHF1,b

39% 31% 29%

RRR RRR RRR

NNT=19
p<0.001 p=0.004 p=0.009

The FIRST dedicated CKD trial to

reduce all-cause mortality risk2

a
Sustained ≥50% eGFR decline, ESKD, kidney or CV death; bSecondary endpoint.
1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436-1446; 2. Garcia Sanchez JJ et al. Adv Ther. 2022;39(1):193-220. © AstraZeneca 2021
 Cardiorenal and mortality benefits in DAPA-CKD were consistent, regardless
of T2D status

Primary composite Composite of

All-cause mortality1,c,d
outcome1,a,b CV death or hHF1,c,e

Patients 36% 26% 30%

with T2D RRR RRR RRR

Patients 50%
without T2D RRR

The FIRST dedicated CKD trial

to reduce all-cause mortality risk2
a
Sustained ≥50% eGFR decline, ESKD, kidney or CV death; bp interaction=0.24; cSecondary endpoint; dp interaction=0.25; ep interaction=0.78.
17 1. Wheeler DC et al. Lancet Diabetes Endocrinol. 2021;9(1):22-31; 2. Garcia Sanchez JJ et al. Adv Ther. 2022;39(1):193-220. © AstraZeneca 2021
 The cardiorenal and mortality benefits observed in DAPA-CKD were
consistent across early and late CKD stages

Primary composite Composite of

All-cause mortality1,c,d
outcome1,a,b CV death or hHF1,c,e

CKD 42% 31% 31%

stage 2/3 RRR RRR RRR

CKD 27%
stage 4 RRR

The FIRST dedicated CKD trial

to reduce all-cause mortality risk2
a
Sustained ≥50% eGFR decline, ESKD, kidney or CV death; bp interaction=0.22; cSecondary endpoint; dp interaction=0.95; ep interaction=0.63.
18 1. Chertow GM et al. J Am Soc Nephrol. 2021;32(9):2352-2361; 2. Garcia Sanchez JJ et al. Adv Ther. 2022;39(1):193-220. © AstraZeneca 2021
 Dapagliflozin was well-tolerated in patients with CKD, regardless of disease
etiology

Safety outcomes1,2,a (%) DAPA 10 mg Placebo

Discontinuation due to AE 5.5 5.7

Any serious AE 29.5 33.9
AEs of interest
AKIb 2.9 4.2
Kidney-related adverse eventc 7.2 8.7
DKAd 0 <0.1
Major hypoglycemiae 0.7 1.3
Volume depletionc 5.9 4.2

The safety profile of dapagliflozin

CKD Baseline
was generally consistent, T2D status3
regardless of… etiology3–5,f CKD stage6
a
Included 4304 patients with CKD, with or without T2D; bAbrupt decline in kidney function defined as doubling of serum creatinine since last central laboratory result; cBased on predefined
list of preferred terms; dDefinite or probable; eAE with the following criteria confirmed by the investigator: i) symptoms of severe impairment in consciousness or behavior, ii) need of
external assistance, iii) intervention to treat hypoglycemia, iv) prompt recovery of acute symptoms following the intervention; fAEs of interest were not assessed and interaction p-value
suggested the proportions of patients who discontinued due to AEs varied by etiology.
1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436-1446; 2. Heerspink HJL et al. Kidney Int. 2022;101(1):174-184; 3. Wheeler DC et al. Lancet Diabetes Endocrinol. 2021;9(1):22-
31; 4. Wheeler DC et al. Kidney Int. 2021;100(1):215-224; 5. Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2021; 6. Chertow GM et al. J Am Soc Nephrol.
19 2021;32(9):2352-2361. © AstraZeneca 2021
 Empa Kidney reinforced SGLT2i benefits irrespective of T2D
however lacks mortality benefits in CKD patients
DAPA-CKD1a EMPA-Kidney2b
Outcome (N=4304) (N=6609)
Dapagliflozin Empagliflozin
Primary Endpoint
DAPA-CKD EMPA-Kidney
Composite of ≥50% sustained
Composite of ≥40% sustained
eGFR decline, ESKD (dialysis/
eGFR decline, ESKD (dialysis/ 39%​RRR 28%​RRR
transplantation/sustained eGFR
transplantation/sustained eGFR
decline to <15), renal or CV death
decline to <10), renal or CV death NNT = 19 NNT = 27

Key Secondary Endpoints

All-cause death
31%​RRR 13%​RRR

Composite of CV death or hHF

29%​RRR 16%​RRR

This chart does not imply comparable or superior efficacy/safety profiles. Each study was PBO-controlled and no direct
comparisons to the other SGLT2 inhibitor were included. Please refer to study publications for additional information.
Note: Green check indicates the endpoint met statistical significance. Red X indicates the endpoint did not reach statistical significance.
a
Median follow-up of 2.4 years; bMedian follow-up of 2.0 years.
CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; hHF = hospitalization for heart failure; NNT = number needed to treat; PBO = placebo; RRR = relative risk reduction;
SGLT2 = sodium-glucose cotransporter 2.
20 1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436-1446; 2. Herrington WG et al. Online ahead of print. N Engl J Med. 2022. © AstraZeneca 2022
What are Guidelines recommending?

© AstraZeneca 2019
 Major guidelines recommend SGLT2 inhibitors across HFrEF, HFmrEF, and
HFpEF to reduce hHF and CV mortality1,2

a HF type COR LOE

HFrEF (LVEF ≤40%) I A

HF type COR LOE

HFrEF (LVEF ≤40%) 1 A
HFmrEF (LVEF 41-49%) 2a B-R
HFpEF (LVEF ≥50%) 2a B-R

GDMT use, including SGLT2 inhibitors, is suboptimal 3

a
2021 ESC HF guidelines recommend dapagliflozin or empagliflozin in patients with HFrEF to reduce the risk of hHF and death. These guidelines were released before full results of
SGLT2 inhibitor trials in patients with HFmrEF or HFpEF, with or without T2D, were available.1,4-6
1. McDonagh TA et al. Eur Heart J. 2021;42(36):3599-3726; 2. Heidenreich PA et al. J Am Coll Cardiol. 2022;79(17):e263-e421; 3. Ghazi L et al. J Am Coll Cardiol.
2022;79(22):2203-2213; 4. Anker SD et al. N Engl J Med. 2021;385:1451-1461; 5. Nassif ME et al. Nat Med. 2021;27:1954-1960; 6. Solomon SD et al. N Engl J Med.
22 2022;387(12):1089-1098. © AstraZeneca 2019
Do Adding Therapies to HFrEF Treatment Regime Help?
If Yes, How Should They be Sequenced ??
 Combining Foundational Therapies Can Extend The Lives of
Patients With HF By 6 Years
Estimated survival in patients over 65 years receiving Comprehensive
comprehensive therapy versus placeboa,b therapy:
Projected mean event-free survival
ARNI, BB, MRA and
100
Comprehensive therapy 13.0 years (11.5, 14.6) SGLT2i
Conventional therapy 6.7 years (5.8, 7.5)
80 Difference (95% CI) 6.3 years (4.8, 7.9) Conventional
Event-free survival (%)
therapy:
60
ACEi/ARB+ BB

40

20

0
65 70 75 80 85 90
Age (years)
a
Comprehensive therapy was defined as treatment with angiotensin receptor neprilysin inhibitor, BB, mineralocorticoid receptor antagonist, and sodium–glucose co-transporter 2 inhibitor, whereas
conventional therapy was defined as treatment with angiotensin-converting enzyme inhibitor / angiotensin receptor blocker + BB; bIn this cross-trial analysis, the investigators estimated the treatment effects of
comprehensive therapy versus conventional therapy in patients with heart failure with reduced ejection fraction by making indirect comparisons with the EMPHASIS-HF, DAPA-HF and PARADIGM-HF trials
BB, β blocker; CI, confidence interval; HF, heart failure
Vaduganathan M, et al. Lancet 2020;396:121–128
 Limitations of Traditional HFrEF Therapy Sequencing 1

• The conventional sequence for initiating HFrEF therapy is

Step 1: ACEI/ARB
by order in which they were tested in clinical trials.
Time period of 6 months or more

Prescribers are advised to titrate each drug to the target

dose used in clinical trials before adding another therapy.
Step 2: Beta-blocker
• This conventional approach has many limitations:
• Delay in starting therapies demonstrated to reduce
Step 3: MRA morbidity and mortality within the first 30 days of
treatment initiation
Step 4a: ARNI • Assumes that the most effective and well-tolerated
treatments were developed first
• Assumes that foundational treatments are effective only
Step 5: SGLT2 inhibitor when titrated to target doses

a
Conversion from ACEI/ARB to ARNI.2,3
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin-receptor neprilysin inhibitor; HFrEF = heart failure with reduced ejection fraction; MRA
= mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose cotransporter 2.
25 1. McMurray JJV et al. Online ahead of print. Circulation. 2020; 2. Yancy CW et al. J Am Coll Cardiol. 2017;70:776-803; 3. Ponikowski P et al. Eur Heart J. 2016;37:2129-2200. © AstraZeneca 2023
 New Expert Proposal for Sequencing of HFrEF Foundational Therapy
Completed in 4 Weeks
Rationale for New Sequencinga of HFrEF Therapy:
• Treatment with all 4 foundational therapies should occur within 4 weeks since much of the benefit is seen within 30 days of initiation
• Addition of a new drug class yields greater benefits than dose titration of existing agents
• Morbidity and mortality reduced even with low starting doses
• Magnitude of treatment benefit of each drug class independent of background HFrEF therapy
• Improvement in safety and tolerability

Step 1 Step 2 Step 3

Simultaneous initiation Within 1-2 weeks of Step 1 Within 1-2 weeks of Step 2

Beta- SGLT2
ARNIb MRAc
blocker inhibitor

4 weeks
a
Sequence for a patient with clinical euvolemia from diuretics; bIf SBP <100 mm Hg, it may be appropriate to evaluate tolerance by prescribing an ARB first before switching to an ARNI; cIf serum
potassium is normal and renal function is not severely impaired. MRA may be Step 2 in a patient with hypotension.
ARB = angiotensin-receptor blocker; ARNI = angiotensin-receptor neprilysin inhibitor; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; SBP = systolic
blood pressure; SGLT2 = sodium-glucose cotransporter 2.
26 McMurray JJV et al. Online ahead of print. Circulation. 2020. © AstraZeneca 2023
 Patient Profiling
In Heart Failure
For Tailoring
Medical Therapy

27 Rosano et al. European Journal of Heart Failure (2021) 23, 872–881

 2021 ESC/HFA Consensus Recommends Starting SGLT2 Inhibitors as a
Component of Foundational Therapy for All HFrEF Patient Phenotypes

Give black drugs

Reduce/suspend red drugs
Add blue drugs

In patients with predominant chronic coronary syndrome, BP threshold is 120/80 mmHg.

a
28 Rosano GMC et al. Eur J Heart Fail. 2021;23:872-881. © AstraZeneca 2019
 Are all Dapagliflozins same as Forxiga?

© AstraZeneca 2019
29
 Bioequivalence and Therapeutic equivalence are not similar 1

≠
Pharmaceutical Equivalence Bioequivalence
(Blood Concentration of Drug in Healthy
(Stability & Dissolution Testing)
Volunteers)

Bioequivalence ≠ Therapeutic Equivalence

(Outcome in Actual Patients)

1. A mere bio-equivalent Generic may not necessarily lead to the same therapeutic effect as the Innovator.

2. Without an outcome based Clinical Trial Therapeutic equivalence cannot be established by a generic.

1. Vandana Roy, Indian J Med Res. 2018 May; 147(5): 442–444.

30 2. Chow SC. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312.

Bioequivalent Drug May Not Be Therapeutically Equivalent
To Original Drug

80-125% Range is allowed to

conclude Bio-equivalent drug

Generics’ bioavailability may range from

-20% to +25%
ORIGINAL GENERICS (COPY)

Reference(s): Guidelines for Bioavailability and Bioequivalence, CDSCO, 2005. Available from
https://dineshthakur.com/wp-content/uploads/2016/06/be-guidelines-draft-ver10-march-16-05.pdf. Last accessed 28th Nov, 2022
 Why to take a chance in a patient suffering with complex
Cardio-Renal Metabolic disease and not achieving its Goals?

HF: Heart Failure; HFrEF: Heart Failure with a reduced Ejection Fraction; CKD: Chronic Kidney Diease; RCT: Randomised Control Trial
References: 1. Forxiga India Specific Prescribing Information Version 20 dated 10/08/2021; 2. Wiviott SD et al. N Engl J Med. 2019;380(4):347-357.; 3. McMurray JJV et al. N Engl J Med. 2019;381(21):1995-2008.; 4. Heerspink HJL et al.
Epub 2020 Sep 24. PMID: 32970396.; 5. Sonesson C, et al. Cardiovascular
diabetology. 2016 Dec;15(1):1-2.; 6. CDSCO-guidelines for BA/BE studies.
32
 Many datapoints consistently spotting the differences
between the original and the generic drugs

© AstraZeneca 2019
33
 Case 1: Compared to Innovator Generic statins had higher CVE
events

Higher probability of
• 31% suffering a Cardio
Vascular event for
generics compare to
innovator statin

CVE: Cardio-Vascular Event

34 Sicras-Mainar et al. Lipids in Health and Disease (2018) 17:277 Image used only for educational purposes . AstraZeneca is not responsible for copyright
 Case 2 : A >2-fold increase in Stent Thrombosis (ST) coincident with
generic OAPs

• A study from Mount Sinai Medical Center revealed that during

generic clopidogrel administration, 1054 PCIs were performed,
giving a definite 30-day ST incidence of 0.38% (4 of 1054)
• By comparison, 3-year historic data indicated a definite 30-day ST
incidence of 0.14% (20 of 14 432)
• Representing a 2.7-fold increase in definite 30-day ST with
generic clopidogrel use (P = .076).

• After exclusion of 3 historic controls with a defined reason for ST (noncompliance, marked
thrombocytosis) : 3.2-fold increase in 30-day ST with generic clopidogrel (P = .050).

• Kovacic JC, Mehran R, Sweeny J, Li JR, Moreno P, Baber U, Krishnan P, Badimon JJ, Hulot JS, Kini A, Sharma SK. Clustering of acute and subacute stent
thrombosis related to the introduction of generic clopidogrel. J Cardiovasc Pharmacol Ther. 2014 Mar;19(2):201-8.
35
 Summary: Dapagliflozin Transform Patient Outcomes

SGLT2 inhibitors, including Dapagliflozin demonstrated A mere bio-equivalent

dapagliflozin, recommended significant benefits in Primary Generic may not necessarily
in patients with HFrEF as composite outcome across the lead to the same therapeutic
well as CKD with eGFR >25 subgroups effect as the Innovator.
ml/min/1.72m2 Only Dapagliflozin in SGLT2i
proved reduction in CV and All Bioequivalence =
Cause Death in HF Patients Therapeutic Equivalence.
GDMT use, includes
Generic drug may not reach to
Dapagliflozin Only Dapagliflozin in SGLT2i
the patient’s target goal
demonstrated 31% RRR in All
Cause Death in CKD patients

1. Heidenreich PA et al. J Am Coll Cardiol. 2022;79(17):e263-e421; 2. Ghazi L et al. J Am Coll Cardiol. 2022;79(22):2203-2213; 3. McMurray JJV et al. N Engl J Med.
2019;381(21):1995-2008; 4. Solomon SD et al. Online ahead of print. N Engl J Med. 2022; 5. Jhund PS et al. Online ahead of print. Nat Med. 2022; 6. Butler J et al. Eur
36 Heart J. 2022;43(5):416-426; 7. Bhatt DL et al. N Engl J Med. 2021;384(2):117-128.
HF Protocol for Treatment of Heart Failure
 Check List of A Patient Coming With
Symptoms of Suspected HF for the First Time
(Non Acute Setting)
 Check List
A. Assessment of HF Probability • Heart Murmur
1. Clinical History • Jugular Venous Dilation
• History of coronary artery disease (CAD) • Laterally Displaced/Broadened Apical
Beat
• History of arterial hypertension • TMT as and When required
• Exposition to cardiotoxic drug/radiation 3. ECG
• Use of diuretic use • Any Abnormality
• Orthopnoea, Paroxysmal Nocturnal 4. Investigations (if ≥ 1 of above is present)
dyspnoea • NT- Pro BNP/BNP
2. Physical Examination • Transthoracic echocardiography
• Blood Pressure
• Rales
• Bilateral Ankle Edema
 Other tests for initial assessment once a patient with newly diagnosed HF in
order to evaluate the patient’s suitability for particular therapies

• Haemoglobin • UACR • Chest radiography (X-ray)

is recommended in
• TLC & DLC • TSAT (transferrin saturation)
patients with HF to
& TIBC (total iron-binding
• Serum sodium detect/exclude alternative
capacity)
• Serum Potassium pulmonary or other
• Natriuretic peptides diseases, which may
• Serum Urea contribute to dyspnoea
• A 12-lead ECG is
• Serum Creatinine recommended in all patients • Kidney Sonography
• eGFR with HF in order to determine
heart rhythm, heart rate, QRS
• Liver function tests morphology, and QRS
(bilirubin, AST, ALT, duration, and to detect other
GGTP) relevant abnormalities.
• Glucose, HbA1c • Exercise testing
• TSH
40
 Check List of a patient coming
for follow up

-Follow-up frequency-
* Initially once every two weeks till adequate dose
is established
* Subsequently once every three months

Modified based on the clinical expertise & routine practice

 Check List
Clinical History Investigations
• Use of diuretic use • NT- Pro BNP/BNP
• Symptoms of Orthopnoea, Paroxysmal • If there is change in symptom status
Nocturnal dyspnoea • LFT Once in six months
Physical Examination • Transthoracic echocardiography
• Rales • If there is change in symptom status

• Bilateral Ankle Edema • Once every 6 months for one year after hHF
Once a year subsequently.
• Heart Murmur
• Serum sodium
• Jugular Venous Dilation
• Serum Potassium
• Laterally Displaced/Broadened Apical
Beat • Serum Urea
• Blood Pressure • Serum Creatinine
ECG • Glucose, HbA1c
• Any Abnormality • Postural hypotension
• eGFR
Treatment Checklist
CLASS OF MOLECULE NAME OF DRUG DOSE DURATION

Lifestyle Modification Weight, Diet, Exercise and Quitting Tobacco

ACE – Inhibitors/
Angiotensin receptor
blockers

Beta blockers
SGLT2 Inhibitors
Sacubitril/Valsartan

Aldosterone antagonist

Loop Diuretics
Ivabradine
Other therapy
 ESC 2021 Heart Failure Guidelines:

Management of patients with HFrEF

• ACEI/ARNIa
• Beta-blocker
• MRA
• Dapagliflozin/Empagliflozin
• Loop diuretic for fluid retention
(Class I)

LVEF ≤35% and QRS <130 ms and LVEF >35% or device therapy not SR and
where appropriate indicated or appropriate LVEF ≤35% and QRS ≥130 ms

ICD CRT-Db/-P
Non-ischemic Ischemic QRS 130-149 ms QRS ≥150 ms
(Class IIa) (Class I) (Class IIa) (Class I)

Class of Recommendation
If symptoms persist, consider therapies with Class II recommendations Class I
As a replacement for ACEI; bWhere appropriate.
a
Class IIa
McDonagh TA et al. Online ahead of print. Eur Heart J. 2021.
45 © AstraZeneca 2019
Heart Failure with CKD Considerations
• The level of care for heart failure offered to people with CKD should be the same as is offered to
those without CKD.
• In people with CKD and heart failure, any escalation in therapy and/or clinical deterioration
should prompt monitoring of eGFR and serum potassium concentration
• In people with GFR <60 ml/min/1.73 m2 (GFR categories G3a-G5), it is recommend that serum
concentrations of BNP/NT-proBNP be interpreted with caution and in relation to GFR with
respect to diagnosis of heart failure and assessment of volume status.

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease,
Kidney International Supplements (2013) 3, 91–111
 SGLT2i Score better in HF with CKD Patients

Black—drugs that should be

given to patients;
Red—drugs that should be
reduced or discontinued;
Blue—drugs that should be
added.

Rosano et al. European Journal of Heart Failure (2021) 23, 872–881

European Heart Journal, ehab368, https://doi.org/10.1093/eurheartj/ehab368 Published: 27 August 2021
 pharmacological treatments indicated in patients with (NYHA Class II-IV) heart failure with
reduced ejection fraction
Recommendations Class Level

ARB
An ARB is recommended to reduce the risk of HF hospitalization and CV I B
death in symptomatic patients unable to tolerate an ACE-I or ARNI (patients
should also receive a beta-blocker and an MRA)

An ARB may be considered to reduce the risk of HF hospitalization and death IIb C
in patients who are symptomatic despite treatment with a beta-blocker who
are unable to tolerate an MRA.
Diuretics
Diuretics are recommended in patients with HFrEF with signs and/or I C
symptoms of congestion to alleviate HF symptoms, improve exercise
capacity, and reduce HF hospitalizations.

European Heart Journal, ehab368, https://doi.org/10.1093/eurheartj/ehab368 Published: 27 August 2021

pharmacological treatments indicated in patients with (NYHA Class II-IV) heart failure with
reduced ejection fraction
Recommendations Class Level

If-channel inhibitor
Ivabradine should be considered in symptomatic patients with LVEF <_35%, in SR IIa B
and a resting heart rate >_70 b.p.m. despite treatment with an evidence-based
dose of beta-blocker (or maximum tolerated dose below that), ACE-I/(or ARNI),
and an MRA, to reduce the risk of HF hospitalization and CV death.
Ivabradine should be considered in symptomatic patients with LVEF <_35%, in SR IIa C
and a resting heart rate >_70 b.p.m. who are unable to tolerate or have
contraindications for a beta-blocker to reduce the risk of HF hospitalization and CV
death. Patients should also receive an ACE-I (or ARNI) and an MRA
Soluble guanylate cyclase receptor stimulator
Vericiguat may be considered in patients in NYHA class IIIV who have had IIb B
worsening HF
despite treatment with an ACE-I (or ARNI), a beta-blocker and an MRA to reduce
the risk of
CV mortality or HF hospitalization
European Heart Journal, ehab368, https://doi.org/10.1093/eurheartj/ehab368 Published: 27 August 2021
pharmacological treatments indicated in patients with (NYHA Class II-IV) heart failure with reduced
ejection fraction

Recommendations Class Level

HYDRALAZINE AND ISOSORBIDE DINITRATE
Hydralazine and isosorbide dinitrate should be considered in self-identified black IIa B
patients with LVEF <_35% or with an LVEF <45% combined with a dilated left ventricle
in NYHA class IIIIV despite treatment with an ACE-I (or ARNI), a beta-blocker and an
MRA to reduce the risk of HF hospitalization and death.142
Hydralazine and isosorbide dinitrate may be considered in patients with symptomatic IIb B
HFrEF who cannot tolerate any of an ACE-I, an ARB, or ARNI (or they are
contraindicated) to reduce the risk of death.
DIGOXIN
Digoxin may be considered in patients with symptomatic HFrEF in sinus rhythm IIb B
despite treatment with an ACE-I (or ARNI), a betablocker and an MRA, to reduce the
risk of hospitalization (both all-cause and HF hospitalizations)
N-3 PUFA
An n-3 PUFA preparation may be considered in symptomatic HF patients to reduce IIb B
the risk of cardiovascular hospitalization and cardiovascular death

European Heart Journal, ehab368, https://doi.org/10.1093/eurheartj/ehab368 Published: 27 August 2021

Check-list of medications & their recommended doses

European Heart Journal, ehab368, https://doi.org/10.1093/eurheartj/ehab368 Published: 27

August 2021
Rx
Dapagliflozin Tablets
Forxiga® 5mg & 10 mg
FORXIGA® is available as a film-coated tablet for oral administration.
Composition: Each film coated tablet contains: Dapagliflozin propanediol monohydrate equivalent to Dapagliflozin 5 mg or 10 mg, Excipients: Q.S., Titanium Dioxide IP & Iron oxide yellow Ph.Eur.
Mechanism of action: Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to
urinary excretion of excess glucose (glucuresis). FORXIGA® is orally available and requires once-daily dosing.
INDICATIONS AND USAGE:
Type 2 diabetes mellitus
In adults aged 18 years and older with type II diabetic mellitus to improve glycemic control.
As mono-therapy when diet and exercise alone do not provide adequate glycemic control in patients for whom use of metformin is considered in appropriate due to intolerance.
As add on combination therapy in combination with other glucose–lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycemic control.
For study results with respect to combination of therapies, effects on glycemic control and cardiovascular events and the population studied (for Forxiga 10mg).
Heart Failure (For Forxiga10mg)
Forxiga is indicated in adults for the treatment of heart failure with reduced ejection fraction.
Chronic kidney disease (For Forxiga 10mg)
Forxiga is indicated in adults for the treatment of patients of Chronic Kidney Disease (CKD) up to Stage III (eGFR of greater than or equal to 30ml/min/1.73m2).
Chronic kidney disease (For Forxiga 10mg)
To reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
Forxiga is indicated in adults for the treatment of patients of Chronic Kidney Disease (CKD) up to eGFR of greater than or equal to 25 ml/min/1.73m2. Below this, initiation is not recommended, however patients may continue 10 mg orally once daily to
reduce the risk of eGFR decline, ESKD, CV death and hHF
FORXIGA® is not indicated for use in patients with type 1 diabetes.
FORXIGA® should not be used for the treatment of diabetic ketoacidosis
For Heart failure patients FORXIGA® can be used in patients with eGFR ≥ 25 mL/min/1.73 m2. Patients with eGFR ≤ 25 ml/min/1.73m2 were excluded from clinical study.
DOSAGE AND ADMINISTRATION: The recommended dose of FORXIGA® is 10 mg taken once daily at any time of the day regardless of meals.
Monotherapy and Add-On Combination Therapy
The recommended dose of FORXIGA® is 10 mg once daily as monotherapy or as add-on to combination therapy with metformin (with or without SU), a thiazolidinedione, a sulfonylurea, a DPP4-inhibitor (with or without metformin), or insulin (with or
without oral antidiabetic therapy, either metformin plus insulin dual therapy or metformin plus sulfonylurea plus insulin triple therapy).
Cardiovascular and renal outcomes (DECLARE)
Heart failure or cardiovascular death
Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite of hospitalization for heart failure or cardiovascular death. The difference in treatment effect was driven by hospitalization for heart failure , with no difference in
cardiovascular death.
Major adverse cardiovascular events (MACE)
Dapagliflozin 10mg demonstrated non-inferiority versus placebo for the composite of cardiovascular death, myocardial infarction or ischemic stroke (one-sided p <0.001).
Nephropathy
Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, end-stage renal disease, renal or cardiovascular death.
Heart Failure
Forxiga 10 mg was superior to placebo in preventing CV death and worsening heart failure, with consistent treatment effect on primary and secondary endpoints. Forxiga also reduced the total number of events of hospitalizations for heart failure (first
and recurrent) and cardiovascular death.
Chronic Kidney Disease
Forxiga 10mg was superior to placebo in reducing the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, reaching ESKD, CV or renal death (HR 0.61 [95% CI 0.51, 0.72]; p<0.0001).
Special warnings and special precautions for use
Renal Impairment
There is a limited experience with initiating treatment with Forxiga in patients with eGFR<25mL/min/1.73m2. The glucose lowering efficacy of Dapagliflozin is dependent on renal function and is reduced in patients where eGFR is <45mL/min/1.73m2.
Ketoacidosis in patients with diabetes mellitus
Patients treated with FORXIGA® who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are
below 14 mmol/l (250 mg/dl). If ketoacidosis is suspected, discontinuation or temporary interruption of FORXIGA should be considered and the patient should be promptly evaluated.
Use with medications known to cause hypoglycemia
Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with FORXIGA in patients with
type 2 diabetes mellitus
CONTRAINDICATIONS: FORXIGA® is contraindicated in patients with a history of any serious hypersensitivity reaction to the active substance or to any of the excipients.
PREGNANCY and LACTATION: FORXIGA must not be used in the second and third trimesters of pregnancy. When pregnancy is detected, FORXIGA should be discontinued. FORXIGA must not be used by a nursing woman
ADVERSE REACTIONS: The common adverse reactions in patients treated with FORXIGA 10 mg in clinical trials and postmarketing are Genital infection, Urinary tract infection, Diabetic ketoacidosis, Back pain, Pollakiuria and polyuria.
Incompatibilities: Not applicable. Shelf life: refer outer pack.
Storage: Do not store above 30°C. Pack size: refer to outer carton
FORXIGA® is a Registered Trademark of the AstraZeneca group of companies.
For Further Information Contact:
AstraZeneca Pharma India Limited, Block N1, 12th Floor, Manyata Embassy Business Park, Outer Ring Road, Bangalore-560045
For more information refer full Prescribing Information Version 21 dated 29/06/2022