ARNI- New Frontier.pptx

Blood-pressure reduction study using
LCZ696(ARNi), a novel dual-acting inhibitor.
Involved individuals with uncomplicated mild-to-moderate essential hypertension.
For patients following an antihypertensive washout, mean sitting diastolic blood pressure needed to be in
the range of 90–109 mm Hg.
Untreated patients had to exhibit a mean sitting diastolic blood pressure of 95–109 mm Hg to be considered
eligible.
Lancet 2010; 375: 1255–66
Lancet 2010; 375: 1255–66

Change in 24-hr ambulatory blood pressure
during the 8-week treatment period
• Blood-pressure lowering effects with LCZ696
• Remained consistent throughout the entire 24-hour dosing
period.
Sustained 24-hour Effect:
• Comparison of 24-Hour Mean Ambulatory Diastolic Blood
Pressure (duration 8 weeks)
• Minimal Differences and non- significant: LCZ696 vs.
Valsartan Doses
Ambulatory Diastolic Blood Pressure:
• Significantly lower 24-hour mean ambulatory systolic blood
pressure with 200 mg LCZ696 vs. 160 mg valsartan: -3.23
(95% CI -5.70 to -0.75).
Ambulatory Systolic Blood Pressure:
Lancet 2010; 375: 1255–66
Study Completion:
1215 patients successfully completed the 8-week treatment period.
Lancet 2010; 375: 1255–66

Change in placebo-subtracted sitting pulse pressure
during the 8-week treatment period:
Significant decreases in sitting pulse pressure
• Observed with 200 mg LCZ696 compared to 160 mg
valsartan (–2.25, 95% CI –4.45 to –0.06).
Significant decreases in sitting pulse
pressure
• A reduction of –3.32 (–5.51 to –1.13) in sitting pulse
pressure
A more pronounced effect seen with 400
mg LCZ696 compared to 320 mg valsartan,
with
Lancet 2010; 375: 1255–66
Change in placebo-subtracted sitting (A) pulse pressure
during the 8-week treatment period
Study Completion:
1215 patients successfully completed the 8-week treatment period.c
Lancet 2010; 375: 1255–66

Decreases in ambulatory pulse pressure
• Significantly different for 200 mg LCZ696 vs. 160 mg
valsartan (–2.48, –4.80 to –0.17).
Similarly, decreases in ambulatory pulse
pressure were
• A reduction of–3.95 (–6.28 to –1.62) in ambulatory pulse
pressure.
A more pronounced effect seen with 400
mg LCZ696 compared to 320 mg valsartan,
with
Study Completion:
1215 patients successfully completed the 8-week treatment period.
Lancet 2010; 375: 1255–66
Lancet 2010; 375: 1255–66

Blood pressure changes vs. placebo over 8-week treatment
Mean sitting systolic and diastolic blood pressure
• Complementary and fully additive reduction of blood
pressure
• Suggests that the drug holds promise for treatment of
hypertension and cardiovascular disease.
Compared with valsartan, dual-acting LCZ696 provides
LCZ696 demonstrated significantly greater reduction in
mean sitting diastolic blood pressure compared to
valsartan.
Average reduction with LCZ696: -2.17 mm Hg (95% CI -
3.28 to -1.06, p<0.0001).
Lancet 2010; 375: 1255–66
Change in placebo-subtracted mean sitting systolic blood pressure during the 8-week treatment
period
Change in placebo-subtracted mean sitting diastolic blood pressure during the 8-week treatment
period
Lancet 2010; 375: 1255–66

Blood-pressure reduction study using LCZ696(ARNi), a
novel dual-acting inhibitor:
Safety and Tolerance
Safety and Tolerance:
•LCZ696 was well tolerated.
•No cases of angio-edema reported.
•Only three serious adverse events during the treatment period, with none related to the study drug.
•No patient deaths occurred.
Lancet 2010; 375: 1255–66
Lancet 2010; 375: 1255–66

Study 4: PARAMETER STUDY
PARAMETER study
(Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With
Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly).
Hypertension. 2017;69:411-420.

PARAMETER STUDY
Central aortic systolic pressure (CASP) and pulse pressure from
baseline at wk 12 and 52 wk in elderly
• Sacubitril/valsartan reduced central aortic systolic
pressure greater than olmesartan by -3.7 mmHg
(P=0.010).
Primary Assessment at week 12:
• Central aortic pulse pressure: -2.4 mmHg
(P<0.012).
Secondary Assessments at Week 12:

PARAMETER STUDY
Peripheral and central 24-h mean ambulatory systolic blood
pressure (SBP) compare to olemesartan in elderly
• Mean 24-hour ambulatory brachial systolic blood
pressure: -4.1 mmHg (P<0.001).
• Mean 24-hour ambulatory central aortic systolic
pressure: -3.6 mmHg (P<0.001).
Secondary Assessments at Week 12:
• More patients needed add-on antihypertensive
therapy with olmesartan (47%) vs. sacubitril/valsartan
(32%; P<0.002).
Long-Term Results: After 52 weeks
Peripheral and central 24-h mean ambulatory systolic blood
pressure (SBP): at wk 12 (A) and wk 52 (B) end points

Efficacy and Safety of Sacubitril/Valsartan vs.
Olmesartan in essential hypertension
• Male or female Japanese patients ≥20 years old.
• Included both treated and untreated mild to moderate systolic hypertension.
• Approximately 30% of the study population comprised elderly patients (≥65 years).
Study Population Eligibility:
Hypertension Research (2022) 45:824–833

Efficacy of ARNi versus olmesartan in Japanese patients with
essential hypertension:
Change in mean sitting SBP, DBP and PP
• Sacubitril/Valsartan vs. Olmesartan (Week
8):
Superior BP Reductions -
• Superior mean systolic blood pressure
(msSBP) reduction over olmesartan.
• Between-treatment difference: -5.01 mmHg
(P < 0.001 for non-inferiority and superiority)
(Fig. 2).
Sacubitril/valsartan 200 mg:
• Greater msSBP reductions from baseline
compared to olmesartan at Week 8.
• Between-treatment difference: -6.97 mmHg
(P < 0.001) (Fig. 2).
Sacubitril/valsartan 400 mg:
Change from baseline in msSBP, msDBP, and msPP at Week 8

Efficacy of ARNi versus olmesartan in Japanese patients with
essential hypertension:
Proportion of patients who achieved control BP
Proportion of patients who achieved overall BP, systolic and diastolic blood
pressure control and response at the Week 8 endpoint
• More patients achieved BP control with
Sacubitril/Valsartan doses.
• Higher percentages of patients achieved systolic BP
response (msSBP < 140 mmHg or ≥20 mmHg
reduction) with Sacubitril/Valsartan compared to
olmesartan.
• Similarly, Sacubitril/Valsartan treatment showed
greater diastolic BP response (msDBP < 90 mmHg or
≥10 mmHg reduction) than olmesartan.
Sacubitril/Valsartan vs. Olmesartan

ARNI in Resistant hypertension
with HFpEF

Sacubitril–valsartan for apparent resistant hypertension in
heart failure with preserved ejection fraction.
• Examined systolic blood pressure changes in different hypertension categories.
Study Focus:
• Week -2: End of valsartan 80 mg twice daily open run-in.
• Week 0: End of sacubitril–valsartan 49/51 mg open run-in.
• Followed by double-blind treatment: valsartan 160 mg twice daily or sacubitril–valsartan 97/103
Treatment Phases:
Jackson AM et al. European Heart Journal (2021) 42, 3741–3752

Sacubitril–valsartan for apparent resistant hypertension in
heart failure with preserved ejection fraction:
Significant reduction in systolic blood pressure
• Controlled blood pressure
• 'Non-resistant' hypertension
• 'Apparent resistant' hypertension
• 'Apparent mineralocorticoid receptor
antagonist-resistant' hypertension
Hypertension Categories
Analyzed:
• Almost one in six patients with heart failure and
preserved ejection fraction had apparent
resistant hypertension in PARAGON-HF and this
was associated with worse clinical outcomes;
• Neprilysin inhibition reduced systolic blood
pressure significantly in these patients

Sacubitril–valsartan for apparent resistant hypertension in heart
failure with preserved ejection fraction:
Efficacy of ARNi vs Valsartan: Changes in systolic blood pressure
• Sacubitril–Valsartan vs. Valsartan
• More apparent resistant hypertension patients
achieved controlled systolic BP by Week 16 with
sacubitril–valsartan (47.9%) compared to
valsartan (34.3%).
• OR: 1.78 (95% CI 1.30–2.43).
Controlled Systolic BP Achievement
• Sacubitril–Valsartan vs. Valsartan
• Stronger response observed in apparent MRA-
resistant hypertension patients with sacubitril–
valsartan (43.6%) compared to valsartan
(28.4%).
• OR: 2.63 (95% CI 1.18–5.89).
Enhanced Response in MRA-Resistant
Hypertension Patients

Sacubitril–valsartan for apparent resistant hypertension in heart
failure with preserved ejection fraction:
Safety of ARNi vs Valsartan
• Similar trends in alternative apparent resistant hypertension definition.
• Remains true for apparent mineralocorticoid receptor antagonist-resistant hypertension.
Consistent Adverse Events:
• More with sacubitril–valsartan than
valsartan.
• Slight increase in apparent resistant
hypertension.
Hypotension:
• Less elevated in sacubitril–valsartan for
apparent resistant hypertension.
Serum Creatinine &
Potassium:

24-Hour BP Reduction of
Sacubitril/Valsartan vs. Olmesartan

Study 10: 24-Hour BP Reduction of Sacubitril/Valsartan vs.
Olmesartan in Japanese Essential Hypertension Patients based
on Nocturnal BP Dipping.
• Recognizing the significance of nighttime BP and its abnormal nocturnal dipping pattern in
contributing to cardiovascular risk.
• Sacubitril/valsartan treatment addresses various mechanisms that have the potential to enhance
cardiovascular outcomes in hypertensive patients, given its influence on these factors.
Clinical Implications:
Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612

24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan:
Overall Change in Ambulatory BP
Data are least-squares mean change±standard error (repeated measures ANCOVA model).
Daytime: 6 am to 10 pm; nighttime: 10 pm to 6 am. ABP indicates ambulatory blood pressure; DBP,
diastolic blood pressure; and SBP, systolic blood pressure. *P
Change in ambulatory systolic blood pressure (A) and diastolic blood
pressure (B) from baseline to week 8
• More pronounced with both sacubitril/valsartan
dosages compared to olmesartan at week 8.
• Graphical representation in Figure 1.
Ambulatory BP Changes (24-hour,
Daytime, Nighttime):
• Sacubitril/valsartan 200 mg/d: 83%
• Sacubitril/valsartan 400 mg/d: 85%
• Olmesartan group: 58%
Proportion of Patients with ≥5 mm
Hg BP Reduction:

Change in ambulatory systolic blood pressure
Change in ambulatory systolic blood pressure (A and B) from baseline
to week 8
• Significant reductions from baseline to week 8 with
sacubitril/valsartan (200mg/d, 400mg/d) and olmesartan
(20mg/d) in both dipper and nondipper groups.
BP Reductions - All Groups (24-hour, Daytime,
Nighttime):
• Greatest reductions in the non-dipper groups.
• Sacubitril/valsartan achieved notably higher nighttime
SBP and DBP reduction compared to olmesartan
Nondipper Group Impact:

Change in ambulatory diastolic blood pressure
• Sacubitril/valsartan 200mg/d and 400mg/d: Greater
reduction in nighttime SBP (P=0.022, P<0.001) and
nighttime DBP (P=0.041, P<0.001) in nondippers
compared to dippers (Figure S2).
Nondipper vs. Dipper Comparisons (Nighttime):
• Sacubitril/valsartan 400mg/d achieved a larger reduction
in 24-hour SBP in nondippers (-16.4mmHg) than dippers
(-12.7mmHg).
• Between-group difference: -3.7mmHg (P=0.004)
Dose Comparison - Nondippers:
Change in ambulatory diastolic blood pressure (C and D) from baseline to week 8 in
patient subgroups based on nocturnal blood pressure dipping status

Study 10: 24-Hour BP Reduction of Sacubitril/Valsartan vs.
Olmesartan:
Overall 24-hour systolic ambulatory blood pressure of nocturnal blood pressure
Time course of changes in 24-hour systolic ambulatory blood pressure overall
• Significantly more effective than olmesartan in
lowering 24-hour ambulatory systolic blood
pressure (SBP).
• Exception: No significant difference in patients
with diabetes
Sacubitril/Valsartan Effectiveness
and Patient Subgroups:

Dipper and Non dipper ambulatory blood pressureof nocturnal blood pressure
Time course of changes in patients with a dipper (B) or nondipper (C)
profile of nocturnal blood pressure
• With sacubitril/valsartan 200mg/d:
• Greater ambulatory BP reduction in women compared to men.
• Greater reduction in patients with body mass index ≥25kg/m² than
<25kg/m² (Figure S3).
Gender and Body Mass Index Impact on
Effectiveness:
• With sacubitril/valsartan 400mg/d:
• Greater ambulatory BP reduction in patients with nondipper vs. dipper
profile.
• Greater reduction in patients with baseline estimated glomerular
filtration rate <60 vs. ≥60mL/min per 1.73m².
• Greater reduction in men vs. women.
• Greater reduction in patients with body mass index <25kg/m² vs.
≥25kg/m² (Figure S3).
Dosage and Patient Characteristics:

Response to Therapy
• Over 30% of sacubitril/valsartan patients achieved BP control
(24-hour SBP <130mmHg, 24-hour DBP <80mmHg) by week 8
on average.
• Nondipper subgroup: Higher BP control rates at week 8 with both
sacubitril/valsartan doses compared to olmesartan.
• Dipper subgroup: Differences less prominent (Figure 4).
Response Rates and BP Control:
• No variation in the proportion of patients experiencing a change
in nocturnal BP dipping status among treatment groups
throughout the study.
Nocturnal BP Dipping Status Change:
Blood pressure control rate at week 8 in patients with a dipper or nondipper profile of
nocturnal blood pressure.

Recent ongoing Study with ARNI in
Hypertension

Sac/ Val versus Valsartan in regressing myocardial
fibrosis in hypertension
Front. Cardiovasc. Med. (Aug 2023)10:1248468. Once Daily
ARNI in
Hypertension
Sac/Val: Initial Dose 100-200mg OD, Max 400mg OD
Valsartan: Initial dose 80-160mg OD, Max 320 mg OD
Duration of Study:52 weeks
Group
1:1
Rando
mizatio
n
Singapore: 5 Centers: National Heart
Research Institute Singapore (NHRIS)
Primary endpoint:
• Change in CMR-derived diffuse
interstitial fibrosis volume
Secondary endpoint:
• CMR derived:
• LVM
• LVV
• BP Parameter:
• Office BP
• 24hr ambulatory BP
Health-related quality of life
assessment
• EuroQol EQ-5D-3L
questionnaire
Safety parameters:
• Serum potassium level
• Adverse Drug Reaction
Conclusion:
• REVERSE-LVH is the first trial that examines the anti-fibrotic potential of sacubitril/valsartan in a clinical population, guided by imaging.
• Myocardial fibrosis, a hallmark of HF, has shown regression on histology with lisinopril and losartan in HHD, torasemide in hypertensive
HF, and spironolactone in non-hypertensive HF

NT-Pro BNP Trajectory with ARNI in PARAGON HF
J Am Coll Cardiol HF. 2020;8 (5) 372–381

Treatment Effect Across Left Ventricular Ejection Fraction:
PARADIGM HF and PARAGON HF
Solomon et al. Circulation. 2020;141:352–361
Ejection Fraction (%)

ARNI-PRESERVED study: Safety & Effectiveness of
ARNI in Indian Patients with HFpEF (Ref.: Heart India 2021;9:179-83)
Comparison of vital parameters, laboratory results,
and ECHO parameters at the initial visit & 6-months
follow-up
• 154 HF patients with EF ≥ 50%,
• NYHA class II, III symptoms,
• NT-pro-BNP ≥600 pg/mL
• Yashoda Hospitals, Hyderabad,
Telangana

Eligibility for sacubitril/valsartan in HFmr/r EF (EF < 50%)
based on PARADIGM-HF/PARAGON-HF selection
criteria
Overall eligibility was 64%
in females vs. 62% in males
Journal of Internal Medicine, 2021, 289; 369–384

Role of ARNi in Hypertensive HF?

Hypertension present in >50% of HF patients:
Heart failure registries
Clinical Hypertension (2020) 26:1

Sacubitril–valsartan as a treatment for apparent
resistant hypertension in patients with HFpEF
European Heart Journal (2021) 42, 3741–3752

Effect of sacubitril/valsartan compared to olmesartan on
cardiovascular remodelling in subjects with essential hypertension
European Heart Journal (2017) 38, 3308–3317
Changes in least squares mean left ventricle
mass from baseline
Changes in least squares mean left ventricle
mass index from baseline.

ARNI- New Frontier.pptx

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