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ARNI- New Frontier.pptx
- 3. 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
- 4. 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
- 5. 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
- 6. 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
- 7. 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
- 8. 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
- 9. 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. Hypertension. 2017;69:411-420.
- 10. 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: Hypertension. 2017;69:411-420. Hypertension. 2017;69:411-420.
- 11. 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 Hypertension. 2017;69:411-420.
- 12. 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 Hypertension Research (2022) 45:824–833
- 13. 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 Hypertension Research (2022) 45:824–833 Hypertension Research (2022) 45:824–833
- 14. 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 Hypertension Research (2022) 45:824–833 Hypertension Research (2022) 45:824–833
- 15. ARNI in Resistant hypertension with HFpEF
- 16. 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
- 17. 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: Jackson AM et al. European Heart Journal (2021) 42, 3741–3752 • 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 Jackson AM et al. European Heart Journal (2021) 42, 3741–3752
- 18. 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 Jackson AM et al. European Heart Journal (2021) 42, 3741–3752 Jackson AM et al. European Heart Journal (2021) 42, 3741–3752
- 19. Sacubitril–valsartan for apparent resistant hypertension in heart failure with preserved ejection fraction: Safety of ARNi vs Valsartan Jackson AM et al. European Heart Journal (2021) 42, 3741–3752 • 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: Jackson AM et al. European Heart Journal (2021) 42, 3741–3752
- 20. 24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan
- 21. 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
- 22. 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: Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 23. 24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan: 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: Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 24. 24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan: 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 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 25. 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: Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 26. 24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan: 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: Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 27. 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: 24-Hour BP Reduction of Sacubitril/Valsartan vs. Olmesartan: Blood pressure control rate at week 8 in patients with a dipper or nondipper profile of nocturnal blood pressure. Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612 Kazuomi Kario et al. J Am Heart Assoc. 2023;12:e027612
- 28. Recent ongoing Study with ARNI in Hypertension
- 29. 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
- 30. Role of ARNi in HFpEF?
- 31. NT-Pro BNP Trajectory with ARNI in PARAGON HF J Am Coll Cardiol HF. 2020;8 (5) 372–381
- 32. Treatment Effect Across Left Ventricular Ejection Fraction: PARADIGM HF and PARAGON HF Solomon et al. Circulation. 2020;141:352–361 Ejection Fraction (%)
- 34. 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
- 35. 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
- 36. Role of ARNi in Hypertensive HF?
- 37. Hypertension present in >50% of HF patients: Heart failure registries Clinical Hypertension (2020) 26:1
- 38. Sacubitril–valsartan as a treatment for apparent resistant hypertension in patients with HFpEF European Heart Journal (2021) 42, 3741–3752
- 39. 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.
- 40. Thank you….
Editor's Notes
- —Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mmHg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mmHg; mean seated pulse pressure, 69.7 mmHg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) were added-on for patients not achieving blood pressure target (
- Study Objective: Investigate the efficacy of sacubitril/valsartan vs. olmesartan in treating systolic hypertension in elderly patients. Study Design: Multicenter, double-blind, randomized controlled trial. Elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mmHg. Patient Characteristics: 454 patients, mean age 67.7 years, mean seated systolic blood pressure 158.6 mmHg, mean seated pulse pressure 69.7 mmHg. Treatment Regimens: Randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg. Force titrated to double initial doses after 4 weeks. Primary Assessment: At week 12, sacubitril/valsartan reduced central aortic systolic pressure greater than olmesartan by -3.7 mmHg (P=0.010). Secondary Assessments at Week 12: Central aortic pulse pressure: -2.4 mmHg (P<0.012). 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). Sleep Effect: Pronounced differences in 24-hour ambulatory pressures observed during sleep. Long-Term Results: After 52 weeks, blood pressure parameters similar between treatments (P<0.002). More patients needed add-on antihypertensive therapy with olmesartan (47%) vs. sacubitril/valsartan (32%; P<0.002). Tolerability and Safety: Both treatments equally well tolerated. Study Name: PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly). Significant Findings: Demonstrated the superiority of sacubitril/valsartan over olmesartan in reducing central aortic and brachial pressures in elderly patients with systolic hypertension and arterial stiffness.
- Study Objective: Investigate the efficacy of sacubitril/valsartan vs. olmesartan in treating systolic hypertension in elderly patients. Study Design: Multicenter, double-blind, randomized controlled trial. Elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mmHg. Patient Characteristics: 454 patients, mean age 67.7 years, mean seated systolic blood pressure 158.6 mmHg, mean seated pulse pressure 69.7 mmHg. Treatment Regimens: Randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg. Force titrated to double initial doses after 4 weeks. Primary Assessment: At week 12, sacubitril/valsartan reduced central aortic systolic pressure greater than olmesartan by -3.7 mmHg (P=0.010). Secondary Assessments at Week 12: Central aortic pulse pressure: -2.4 mmHg (P<0.012). 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). Sleep Effect: Pronounced differences in 24-hour ambulatory pressures observed during sleep. Long-Term Results: After 52 weeks, blood pressure parameters similar between treatments (P<0.002). More patients needed add-on antihypertensive therapy with olmesartan (47%) vs. sacubitril/valsartan (32%; P<0.002). Tolerability and Safety: Both treatments equally well tolerated. Study Name: PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly). Significant Findings: Demonstrated the superiority of sacubitril/valsartan over olmesartan in reducing central aortic and brachial pressures in elderly patients with systolic hypertension and arterial stiffness.
- Study Overview: Efficacy and Safety of Sacubitril/Valsartan vs. Olmesartan Phase III study evaluating sacubitril/valsartan's efficacy and safety in Japanese patients with essential hypertension. Patients (n = 1161) aged ≥20 years with mild to moderate hypertension (mean sitting systolic blood pressure [msSBP] ≥150 to <180 mmHg). Randomized into three groups: Sacubitril/valsartan 200 mg (n = 387) Sacubitril/valsartan 400 mg (n = 385) Olmesartan 20 mg (n = 389) Treatment duration: Once daily for 8 weeks. Primary and Secondary Assessments: Primary assessment: Reduction in msSBP from baseline with sacubitril/valsartan 200 mg vs. olmesartan 20 mg at Week 8. Sacubitril/valsartan 200 mg achieved significantly greater msSBP reduction vs. olmesartan at Week 8: Between-treatment difference: -5.01 mmHg (95% CI: -6.95 to -3.06 mmHg, P < 0.001 for noninferiority and superiority). Secondary assessments: Greater msSBP reduction with sacubitril/valsartan 400 mg vs. olmesartan at Week 8. Reductions in msDBP and msPP with both sacubitril/valsartan doses vs. olmesartan (P < 0.05 for all). Higher overall blood pressure (BP) control rate with sacubitril/valsartan treatment. Safety and Tolerability: Sacubitril/valsartan safety and tolerability profiles generally comparable to olmesartan. Adverse event rate with sacubitril/valsartan not dose-dependent. Conclusion: Sacubitril/valsartan more effective in achieving superior BP reduction and higher proportion of patients reaching target BP goals compared to olmesartan. Effective and well-tolerated treatment option for Japanese patients with mild to moderate essential hypertension.
- Week 8: More patients achieved overall BP control with both sacubitril/valsartan doses than olmesartan (Fig. 3). Higher percentage of patients in sacubitril/valsartan groups achieved SBP response (msSBP < 140 mmHg or ≥20 mmHg reduction) compared to olmesartan. Similarly, greater percentage of patients in sacubitril/valsartan groups achieved DBP response (msDBP < 90 mmHg or ≥10 mmHg reduction) compared to olmesartan.
- Aims Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on ‘apparent resistant hypertension’ in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril–valsartan with valsartan. ................................................................................................................................................................................................... Methods and results In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). ‘Apparent resistant hypertension’ was defined as systolic blood pressure >_140 mmHg (>_135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. ‘Apparent mineralocorticoid receptor antagonist (MRA)-resistant’ hypertension was defined as systolic blood pressure >_140 mmHg (>_135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril–valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6–19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7–14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05–1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril–valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril–valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30–2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18–5.89). ................................................................................................................................................................................................... Conclusion Sacubitril–valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA
- Aims: Investigate the effect of neprilysin inhibition on "apparent resistant hypertension" in patients with heart failure and preserved ejection fraction (HFpEF) using data from the PARAGON-HF trial. Compare the effects of sacubitril–valsartan with valsartan in this context. Methods and Results: Categorized patients (n = 4795) based on systolic blood pressure after valsartan run-in. Defined "apparent resistant hypertension" as systolic BP >140 mmHg (>135 mmHg if diabetes) despite valsartan, calcium channel blocker, and diuretic treatment. Defined "apparent MRA-resistant hypertension" as systolic BP >140 mmHg (>135 mmHg if diabetes) despite above treatments and a mineralocorticoid receptor antagonist (MRA). Primary outcome: Composite of heart failure hospitalizations and cardiovascular death. Explored clinical endpoints, safety of sacubitril–valsartan, and BP reductions according to hypertension category. 15.2% (731 patients) had apparent resistant hypertension; 2.8% (135 patients) had apparent MRA-resistant hypertension. Primary outcome rate higher in apparent resistant hypertension patients (17.3) vs. controlled BP patients (13.4) per 100 person-years, adjusted rate ratio of 1.28. Systolic BP reductions with sacubitril–valsartan vs. valsartan: Apparent resistant hypertension: -4.8 mmHg (Week 4), 3.9 mmHg (Week 16) Apparent MRA-resistant hypertension: -8.8 mmHg (Week 4), -6.3 mmHg (Week 16) Proportion achieving controlled systolic BP by Week 16: Apparent resistant hypertension: 47.9% (sacubitril–valsartan), 34.3% (valsartan), adjusted odds ratio 1.78. Apparent MRA-resistant hypertension: 43.6% (sacubitril–valsartan), 28.4% (valsartan), adjusted odds ratio 2.63. Conclusion: Sacubitril–valsartan may be effective in treating apparent resistant hypertension in HFpEF patients. Beneficial even for those with persistently elevated BP despite four antihypertensive drug classes, including an MRA.
- Aims: Study the impact of neprilysin inhibition on "apparent resistant hypertension" in HFpEF patients using PARAGON-HF trial data. Compare sacubitril–valsartan with valsartan. Methods and Results: Categorized patients (n = 4795) by systolic BP after valsartan run-in. "Apparent resistant hypertension" defined as BP >140 mmHg (>135 mmHg if diabetes) despite treatment. "Apparent MRA-resistant hypertension" defined similarly. Primary outcome: Heart failure hospitalizations and cardiovascular death. 15.2% (731 patients) had apparent resistant hypertension; 2.8% (135 patients) had apparent MRA-resistant hypertension. Higher primary outcome rate in apparent resistant hypertension (17.3) vs. controlled BP (13.4) per 100 person-years, adjusted rate ratio 1.28. Systolic BP reductions with sacubitril–valsartan vs. valsartan: Apparent resistant hypertension: -4.8 mmHg (Week 4), 3.9 mmHg (Week 16) Apparent MRA-resistant hypertension: -8.8 mmHg (Week 4), -6.3 mmHg (Week 16) Proportion achieving controlled systolic BP by Week 16: Apparent resistant hypertension: 47.9% (sacubitril–valsartan), 34.3% (valsartan), adjusted odds ratio 1.78. Apparent MRA-resistant hypertension: 43.6% (sacubitril–valsartan), 28.4% (valsartan), adjusted odds ratio 2.63. Conclusion: Sacubitril–valsartan effective for apparent resistant hypertension in HFpEF patients. Useful for patients with persistently elevated BP despite multiple antihypertensive drugs, including an MRA.
- BACKGROUND: Nighttime blood pressure (BP) and an abnormal nocturnal BP dipping profile are important cardiovascular risk factors in patients with hypertension. This post hoc analysis investigated the effects of sacubitril/valsartan on 24-hour BP in patients with mild-to-moderate hypertension and in patient subgroups based on nocturnal BP dipping status. METHODS AND RESULTS: Data from a randomized clinical trial comparing the BP-lowering effects of 8weeks of treatment with sacubitril/valsartan (200 or 400mg/d) and olmesartan (20mg/d) in Japanese patients with mild-to-moderate hypertension were analyzed. The primary end point was change in 24-hour, daytime, and nighttime BP in patient subgroups based on nocturnal BP dipping status (dipper, nondipper). Six hundred thirty-two patients with baseline and follow-up ambulatory BP data were included. Both sacubitril/valsartan dosages reduced 24-hour, daytime, and nighttime systolic BP, and 24-hour and daytime diastolic BP, to a significantly greater extent than olmesartan in the dipper and nondipper groups. However, between-group differences in nighttime systolic BP were more significant in the nondipper group (difference [95% CI] for sacubitril/valsartan 200 and 400mg/d versus olmesartan 20mg/d: –4.6 [95% CI, −7.3 to −1.8] and −6.8 [95% CI, −9.5 to −4.1] mmHg, respectively; P
- Background: Nocturnal blood pressure (BP) and abnormal dipping profile are cardiovascular risks in hypertension. Study investigates sacubitril/valsartan effects on 24-hour BP in mild-to-moderate hypertension. Focus on patient subgroups by nocturnal BP dipping status. Methods and Results: Randomized trial analyzed BP effects of sacubitril/valsartan (200/400mg/d) and olmesartan (20mg/d). Japanese patients with mild-to-moderate hypertension over 8 weeks. Primary goal: Change in 24-hour, daytime, nighttime BP in dipper/nondipper subgroups. 632 patients' baseline/follow-up BP data studied. Both sacubitril/valsartan doses lowered BP more than olmesartan in dipper/nondipper groups. Significant reduction in 24-hour, daytime, nighttime systolic BP. Also lowered 24-hour, daytime diastolic BP. Nighttime systolic BP reduction more significant in nondipper group: Sacubitril/valsartan 200mg/d: -4.6 mmHg Sacubitril/valsartan 400mg/d: -6.8 mmHg Between-group differences: P<0.01 and P<0.001. Greatest between-group differences in BP control rate in nondipper subgroup: Sacubitril/valsartan 200mg/d: 34.4% Sacubitril/valsartan 400mg/d: 42.6% Olmesartan 20mg/d: 23.1% Conclusions: Sacubitril/valsartan valuable for nondipper profile patients' nocturnal BP. Confirms potent 24-hour BP lowering in Japanese hypertension patients. Highlights therapeutic potential of sacubitril/valsartan in hypertensive populations.
- Sacubitril/Valsartan Effectiveness and Patient Subgroups: Significantly more effective than olmesartan in lowering 24-hour ambulatory systolic blood pressure (SBP). Exception: No significant difference in patients with diabetes (Figure S3). Gender and Body Mass Index Impact on Effectiveness: 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). Dosage and Patient Characteristics: 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).
- Response Rates and BP Control: Over 30% of patients on sacubitril/valsartan achieved BP control (24-hour SBP <130mmHg, 24-hour DBP <80mmHg) by week 8 on average. BP control rates at week 8 higher with both sacubitril/valsartan doses than with olmesartan in the nondipper subgroup. Differences between sacubitril/valsartan and olmesartan less pronounced in the dipper subgroup (Figure 4). Nocturnal BP Dipping Status Change: No difference in the proportion of patients with a change in nocturnal BP dipping status between treatment groups during the study.
- Sacubitril/ Valsartan versus Valsartan in regressing myocardial fibrosis in hypertension