ESC HEART FAILURE ORIGINAL ARTICLE ESC Heart Failure 2022; 9: 2170–2180 Published online 19 May 2022 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13952 Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension Pau Codina1,2, Mar Domingo1, Elena Barceló1,3, Paloma Gastelurrutia3,4, Daniel Casquete1, Joan Vila5,6, Omar Abdul-Jawad Altisent1, Giosafat Spitaleri1, Germán Cediel1,7, Evelyn Santiago-Vacas1,7, Elisabet Zamora1,2,3,7, María Ruiz-Cueto1, Javier Santesmases1,2, Rafael de la Espriella8, Domingo A. Pascual-Figal7,9,10, Julio Nuñez7,8, Josep Lupón1,2,3,7 and Antoni Bayes-Genis1,2,3,7* 1 Heart Institute, University Hospital Germans Trias i Pujol, Badalona, Spain; 2Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; 3ICREC Research Program, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Barcelona, Spain; 4Institut d’Investigació Biomèdica de Bellvitge- IDIBELL, L’Hospitalet de Llobregat, Spain; 5REGICOR Research Group, Hospital del Mar Medical Research (IMIM), Barcelona, Spain; 6CIBER of Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; 7CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; 8Cardiology Department, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain; 9Cardiology Department, Hospital Virgen de la Arrixaca, University of Murcia, Murcia, Spain; and 10Centro Nacional de Investigaciones cardiovasculares (CNIC), Madrid, Spain Abstract Aims Prior studies have not fully characterized the haemodynamic effects of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan in heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF–PH). The aim of the Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS-HFpEF) study is to assess pulmonary artery pressure (PAP) dynamics by means of implanted PAP monitors in patients with HFpEF–PH treated with sacubitril/valsartan. Methods and results This single-arm, investigator-initiated, interventional study included 14 consecutive ambulatory symp- tomatic HFpEF–PH patients who underwent CardioMEMS implantation prior to enrolment [mean ejection fraction 60.4 ± 7.2%, baseline mean PAP (mPAP) 33.9 ± 7.6 mmHg]. Daily PAP values were examined during three periods: a 6 week period after CardioMEMS implantation and before sacubitril/valsartan treatment (pre-ARNI), a 6 week period with sacubitril/valsartan treatment (ARNI ON), and a 6 week period of sacubitril/valsartan withdrawal (ARNI OFF). The primary endpoint was change in mPAP with and without sacubitril/valsartan. Secondary endpoints included changes in 6 min walking distance, B-line sum in lung ultrasound, and quality of life (QoL). During the study period, 1717 mPAP measurements were recorded. Between pre-ARNI vs. ARNI ON, mPAP significantly declined by 4.99 mmHg [95% confidence interval (CI) 5.55 to 4.43]. Between ARNI ON vs. ARNI OFF, mPAP significantly increased by +2.84 mmHg [95% CI +2.26 to +3.42]. Between pre-ARNI vs. ARNI ON, we found an improvement in 6 min walking distance, B-lines, and QoL. Mean loop diuretic management did not differ be- tween periods. Conclusions Sacubitril/valsartan significantly reduced mPAP in patients with HFpEF–PH, independent of loop diuretic man- agement, together with improvement in functional capacity, lung congestion, and QoL. Sacubitril/valsartan may be a therapeu- tic alternative in HFpEF–PH. Keywords Heart failure; Preserved LVEF; Pulmonary hypertension; Pulmonary artery pressure; ARNI Received: 18 January 2022; Revised: 14 March 2022; Accepted: 13 April 2022 *Correspondence to: Antoni Bayes-Genis, MD, PhD, Head, Heart Institute, University Hospital Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autonoma de Barcelona, Carretera del Canyet s/n, 08916 Barcelona, Spain. Email: abayesgenis@gmail.com © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension 2171 Introduction with EF below the median (<57%) and among women. The FDA has recently approved the use of Sac/Val for patients Heart failure with preserved ejection fraction (HFpEF) is a with HFpEF and a below-normal left ventricular ejection frac- highly prevalent syndrome affecting approximately one-half tion (LVEF).11 of patients with heart failure (HF). The estimation of the prev- There is paucity of data regarding the haemodynamic ef- alence of pulmonary hypertension (PH) in HF is difficult be- fects of Sac/Val on PH in patients with HFpEF–PH. Recently, cause a reliable diagnosis of PH by echocardiography is not Burgdorf et al. described a significant reduction of PAP after possible in cross-section studies, and all invasive studies suf- transition to Sac/Val in a retrospective case series of 18 fer from a very substantial referral bias because the indica- patients with HFpEF and PH assessed during right heart tion for right heart catheterization in these patients most catheterization.12 In contrast, we conducted the likely was based on evidence of PH in the echocardiogram.1 ARNIMEMS-HFpEF prospective study (Treatment of PH With Using a non-invasive PH definition, up to 80% of patients with Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF develop PH. Patients with HFpEF and PH (HFpEF–PH) HFpEF Patients With CardioMEMS Device; NCT04753112) to have worse quality of life (QoL) and increased mortality than assess the effects of maximum tolerated doses of Sac/Val HFpEF patients without PH.2 on PAP dynamics measured using an implanted PAP monitor- Attempts to treat PH in HFpEF–PH have resulted in a suc- ing device. cession of failures, despite approaching this problem from different pathobiological angles. The endothelin receptor an- tagonist bosentan, which is effective in pulmonary arterial hy- pertension, has failed in HFpEF–PH.3 The potent phosphodi- Methods esterase type 5 inhibitor sildenafil increases cyclic guanosine monophosphate (cGMP) levels, causing endogenous nitric Study design oxide-mediated vasodilatation in both systemic and pulmo- nary vasculature. Despite the initial positive trial in the field The ARNIMEMS-HFpEF study is a non-randomized, single- reported by Guazzi et al.,4 other attempts have failed to show arm, investigator-initiated, interventional trial that enrolled a reduction in pulmonary artery pressure (PAP) or improve- consecutive ambulatory patients with symptomatic HFpEF ment in other haemodynamic parameters in HFpEF–PH.5,6 In- and an implanted haemodynamic monitor (CardioMEMS de- creased cGMP levels by oral soluble guanylate cyclase stimu- vice) for longitudinal PAP monitoring. Patients were lators also increase cGMP levels but do not affect PAP, instructed to upload their PAP data daily, and their adherence pulmonary vascular resistance, or transpulmonary pressure to daily PAP uploads and PAP data was visible to site staff. In- gradient.7 Lastly, direct NO donors were examined in the vestigators evaluated PAP twice weekly and guided case man- INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise agement based on the average diastolic PAP over the previ- Capacity in Heart Failure with Preserved Ejection Fraction) ous 3–4 days. trial but resulted in no benefit in terms of exercise capacity, In the present study, we examined daily PAP values during Kansas City Cardiomyopathy Questionnaire (KCCQ) score, three periods: a 6 week period after CardioMEMS implanta- New York Heart Association (NYHA) functional class, diastolic tion and before Sac/Val treatment (pre-ARNI), a 6 week pe- function, or N-terminal pro-brain natriuretic peptide (NT- riod following initiation of Sac/Val treatment (ARNI ON), proBNP) levels.8 and a 6 week period following Sac/Val withdrawal (ARNI The angiotensin receptor-neprilysin inhibitor (ARNI) sacu- OFF). During the pre-ARNI period (Weeks 6 to 0), baseline bitril/valsartan (Sac/Val) is a particulate guanylyl cyclase acti- treatment was maintained and adjusted according to mean vator that increases natriuretic peptides, which signal PAP (mPAP). Diuretics, beta-blockers, angiotensin-converting through cGMP and exert potent antimitogenic and vasodila- enzyme inhibitor (ACEI)/angiotensin II receptor blockers tory effects. Evidence regarding the effects of Sac/Val on PH (ARB), and/or mineralocorticoid-receptor antagonists were is mainly limited to experimental research. In a used based on systemic blood pressure (BP), heart rate, and well-characterized rat model of PH, 6 weeks of Sac/Val treat- right heart catheterization data. During the ARNI ON period ment led to PH reduction associated with decreased pulmo- (Weeks 1–6), Sac/Val was initiated, replacing ACEI/ARB when nary vascular remodelling.9 necessary, and was then up-titrated every 2 weeks to the Clinical evidence regarding Sac/Val in HFpEF has been de- maximum tolerated dose. During the ARNI OFF period rived from the PARAGON-HF trial, which included patients (Weeks 7–12), Sac/Val was withdrawn, and baseline therapy with HF and an ejection fraction (EF) ≥ 45%. The primary end- was restarted and maintained until the end-of-study visit. point fell just short of showing a statistically significant reduc- Pre-specified scheduled visits occurred at baseline (Week tion in HF-related hospitalizations and deaths (P = 0.06).10 No 6) and at Weeks 0, 2, 4, 6, and 12. All visits included clinical PH subanalyses were performed, yet the results suggested assessment. The visits at baseline and at 0, 6, and 12 weeks heterogeneity, with a possible benefit of Sac/Val in patients included the 6 min walking test (6MWT), KCCQ-12, European ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 2172 P. Codina et al. Quality of Life-Visual Analog Scale (EQ-VAS), echocardiogra- Secondary endpoints included changes in systolic and dia- phy, and a lung ultrasound (LUS) exam. stolic PAP, mPAP change at Day 7 after Sac/Val initiation, change in daily diuretic dose, and changes in 6MWT, B-line sum in LUS, QoL (measured using the KCCQ-12 and EQ-VAS questionnaires), biomarkers [NT-proBNP, cancer antigen 125 Patient selection (CA-125), ST2, and high-sensitivity troponin T (hs-TnT)], and echocardiographic parameters (E/e0 and left atrium diameter From October 2020 to May 2021, we enrolled patients with index). HFpEF–PH. The inclusion criteria were as follows: (i) male or The investigators reported all adverse events (AEs). female patients ≥18 years of age, and exhibiting NYHA Class Pre-specified AEs of interest included decline in renal func- II–III HFpEF with LVEF > 45% (measured within the past year, tion (≥50% decrease in the eGFR, development of end-stage excluding patients with improved EF); (ii) NT-proBNP of renal disease, or death due to renal failure), hypotension >200 pg/mL in cases with HF-related hospitalization in the (SBP < 100 mmHg), hyperkalaemia (>5.5 mmol/L), and previous 9 months, or >300 pg/mL in cases without previous angioedema. HF hospitalization, or three times these values in patients The study was approved by the Spanish Agency of Medi- with atrial fibrillation; (iii) implantation of the CardioMEMS cines and Medical Devices (AEMPS) and the local institutional HF System, with the patient regularly transmitting informa- review board (AC-20-066-HGT-CEIM). All patients provided tion and system functioning appropriately; (iv) average signed informed consent. The study was monitored by an in- mPAP > 20 mmHg during the 7 days prior to enrolment, in- dependent committee and performed in accordance with the cluding at least five daily measurements13; (v) systolic BP Declaration of Helsinki and local and national regulations. (SBP) > 100 mmHg at most recent clinical assessment; and (vi) stable ambulatory patients not requiring a change in di- uretics or other HF drugs during the last week. The exclusion criteria were as follows: (i) estimated glo- Lung ultrasound exams merular filtration rate (eGFR) < 30 mL/min/1.73 m2, as mea- sured by Chronic Kidney Disease Epidemiology Collaboration Lung ultrasound examination was performed by an experi- (CKD-EPI); (ii) Sac/Val treatment within the past 30 days; enced investigator, blinded to clinical status and visit data. (iii) history of hypersensitivity, intolerance, or angioedema Patients were in a semi-supine position during the exam, upon previous treatment with renin-angiotensin system and 28 areas were examined, as established by a previous ex- (RAS) blocker, ACEI, ARB, or Sac/Val; (iv) serum pert panel.14 LUS was performed using a phased-array trans- potassium > 5.4 mmol/L; (v) acute coronary syndrome, ducer, perpendicular to the ribs, with an imaging depth of stroke, transient ischaemic attack, cardiovascular surgery, 14 cm. Clip videos of 6 s were recorded. The same investiga- PCI, or carotid angioplasty within the preceding 3 months; tor analysed the LUS images offline and recorded the number (vi) coronary or carotid artery disease likely to require surgi- of B-lines in the sagittal scan of every thoracic area. A B-line cal or percutaneous intervention within 3 months after trial was defined as a discrete laser-like vertical hyperechoic rever- entry; (vii) dyspnoea primarily caused by a non-cardiac beration artefact that arises from the pleural line, extends to condition(s); (viii) documented untreated ventricular arrhyth- the bottom of the screen without fading, and moves synchro- mia with syncopal episodes within the prior 3 months; (ix) nously with lung sliding. The presence of 10 B-lines was con- symptomatic bradycardia or second-degree or third-degree sidered to indicate pleural effusion. The main analyses were heart block without a pacemaker; (x) hepatic dysfunction, ev- performed using the sum of B-lines across the 28 lung zones. idenced by total bilirubin > 3 mg/dL; or (xi) pregnancy or One patient was excluded due to a previous diagnosis of pul- breastfeeding. monary fibrosis. Study endpoints Blood tests The primary endpoint was the change of mPAP with Sac/Val N-terminal pro-brain natriuretic peptide and hs-TnT levels (ARNI ON) compared with the pre-ARNI and ARNI OFF pe- were determined by electrochemiluminescence immunoas- riods. For analysis of this primary endpoint, we calculated says using a Cobas E601 platform (Roche Diagnostics, that a sample size of 14 participants was required, accepting Switzerland). Interleukin 1 receptor-like 1 (ST2) was mea- an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided con- sured based on immunoturbidimetry using the SEQUENT-IA trast, to detect an mPAP difference of ≥4 mmHg, assuming a reagent kit (Critical Diagnostics, Ireland), on an AU-5800 plat- standard deviation (SD) of 5 mmHg and 10% loss to follow- form (Bekman Coulter, Ireland). CA-125 was measured using up. the ARCHITECT CA-125 II chemiluminescent microparticle ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension 2173 immunoassay (CMIA), on the ARCHITECT i System (Abbott Comparison was performed using linear mixed-effects Laboratories). models, with the lmer function of the lme4 package.16 Multi- ple comparisons were corrected using the glht function of the multcomp package.17 Comparisons for secondary endpoints were performed using Student’s t-test for paired data or Statistical analysis the Wilcoxon test depending on whether the data distribu- tion was assumed normal or non-normal. Categorical vari- Categorical variables were expressed as absolute numbers ables were compared using χ 2, Fisher’s exact tests, or the and percentages. Continuous variables were expressed as McNemar test, as appropriate. the mean ± SD or median (quartile Q1 to Q3), depending Quality of life assessments were compared using the ob- on the assumption of the normality distribution criteria, tained data as continuous variables and also based on the assessed by means of normality Q–Q plots. For the primary proportion of patients showing an improvement of ≥5 points endpoint, data were plotted using the ggplot2 package,15 on the KCCQ-12 score (clinically meaningful change) with and a local polynomial regression (loess) was fitted. Sac/Val treatment. We recorded the average loop diuretic dose (in daily furosemide equivalents) at each follow-up visit Table 1 Baseline characteristics at which concomitant medications were collected (Weeks 6, 0, 2, 4, 6, and 12) and recorded the average Sac/Val dose Age in years, median [IQR] 79 [72–84] at Weeks 0, 2, 4, and 6. Because there were a very small num- Female sex, n (%) 11 (78.6) Medical history, n (%) ber of HF hospitalizations or urgent HF visits, we described Hypertension 12 (85.7) these using only descriptive statistics. Safety outcomes were Hyperlipidaemia 11 (78.6) assessed with descriptive statistics only. Diabetes 4 (28.6) Smoking 2 (14.3) Statistical analyses were performed using SPSS 24 (SPSS Atrial fibrillation or flutter 10 (71.4) Inc., Chicago, Illinois) and R (A language and environment Stroke 2 (14.3) for statistical computing. Version 4.1.0.; R Foundation for Sta- CKD 5 (35.7) COPD 1 (7.1) tistical Computing, Vienna, Austria). When available, a two- Hospitalization for heart failure 9 (64.3) sided P-value of <0.05 was considered significant. When a Myocardial infarction 1 (7.1) P-value was not available, 95% upper and lower confidence 2 Body mass index, kg/m 30.7 ± 4.2 Clinical features of heart failure interval (CI) limits were considered to indicate statistical sig- Aetiology, n (%) nificance if they did not cross zero. Hypertensive cardiomyopathy 8 (57.1) Valvular heart disease 4 (28.6) Ischaemic 1 (7.1) Amyloidosis 1 (7.1) Left ventricular ejection fraction, % 60.4 ± 7.2 Results Systolic blood pressure, mmHg 143 ± 14 Diastolic blood pressure, mmHg 77 ± 9 From October 25, 2020, through May 5, 2021, 15 patients re- Heart rate, beats/min 73 ± 16 NT-proBNP, ng/L 1506 ± 680 ceived an implanted PAP haemodynamic monitor (CardioMEMS NYHA functional class, n (%) device) and were considered for inclusion in this study. One II 1 (7.1) patient died due to COVID-19 before starting Sac/Val treat- III 13 (92.9) Baseline treatment, n (%) ment, and thus, 14 patients were finally included in the study. Loop diuretic 14 (100) Table 1 presents the demographic and clinical characteristics Other diuretic 1 (7.1) and treatment before Sac/Val initiation. During the study pe- ACE inhibitor or ARB 11 (78.6) Mineralocorticoid-receptor antagonist 9 (64.3) riod, 1717 PAP measurements were recorded (per patient: Beta-blocker 7 (50) mean 122.6 ± 7.8, minimum 96, maximum 128). Hydralazine 4 (28.6) Cardiac catheterization data Right atrial pressure, mmHg 6.9 ± 3.8 Primary endpoint Mean pulmonary artery pressure, mmHg 33.9 ± 7.6 Mean wedge pulmonary pressure, mmHg 16.1 ± 7.0 2 Cardiac index, L/min/m 2.6 ± 0.3 We observed statistically significant differences between Mean transpulmonary pressure gradient, mmHg 17.8 ± 7.1 study periods in mPAP longitudinal dynamics. Between the Diastolic transpulmonary pressure gradient, mmHg 5.8 ± 7.4 Pulmonary vascular resistance, Wood units 4.0 ± 1.6 pre-ARNI vs. ARNI ON periods, mPAP significantly declined Note: Values are shown as mean ± standard deviation, n (%), or by 4.99 mmHg [95% CI 5.55 to 4.43]. Between the ARNI median [interquartile range]. ON vs. ARNI OFF periods, mPAP significantly increased by Abbreviations: ACE, angiotensin-converting enzyme; ARB, angio- +2.84 mmHg [95% CI +2.26 to +3.42]. Figure 1 depicts the tensin receptor blocker; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; Loess curve of longitudinal mPAP measurements, showing a NYHA, New York Heart Association. smooth U-shaped morphology of the mPAP changes through- ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 2174 P. Codina et al. Figure 1 Loess curve of mean PAP measurements through the study. Smooth blue line displays mean PAP. Shaded regions around the blue line rep- resent the 95% confidence interval. Weeks 6 to 0: pre-ARNI treatment after CardioMEMS implantation. Weeks 0 to 6: ARNI ON period. Weeks 6 to 12: ARNI OFF period. ARNI, angiotensin receptor-neprilysin inhibitor; PAP, pulmonary artery pressure. out the study. Supporting Information, Figure S1 shows a sim- we observed a non-significant mPAP reduction following ilar morphology when assessing pulmonary artery pulse pres- CardioMEMS implantation. During ARNI ON, we detected a sure. As a single measurement, the change in mPAP from the significant mPAP decline during all weeks of the treatment day before starting Sac/Val to Day 7 of treatment showed a period. After Sac/Val withdrawal (ARNI OFF), we observed decline of 4.14 ± 5.7 mmHg (P = 0.019) (Figure 2). In a bino- an increase of mPAP, which was statistically significant during mial logistic regression, we did not find any relationship be- the first weeks after withdrawal. tween ARNI responders and age, sex, NT-proBNP, pulmonary Daily mPAP analyses revealed a slight downward trend artery pulse pressure, and LVEF, although LVEF was signifi- during the pre-ARNI period, observed from CardioMEMS im- cantly lower in responders (56 ± 5.5% vs. 65 ± 5.9%, plantation to Sac/Val initiation, with an estimated daily mPAP P = 0.013). change of 0.018 mmHg [95% CI 0.052 to +0.015]. During Table 2 shows the weekly mPAP dynamics relative to the ARNI ON, we observed a sharp and significant mPAP decline, pre-ARNI, ARNI ON, and ARNI OFF periods. During pre-ARNI, with an estimated daily mPAP change of 0.153 mmHg [95% Figure 2 Changes in mPAP at the seventh day of treatment. Black lines represent changes in individual patient measurements (solid for patients with a drop ≥4 mmHg in mPAP). Red squared boxes represent mean values, and red upright lines standard deviation. Solid red line represents mean changes. ARNI, angiotensin receptor-neprilysin inhibitor; mPAP, mean pulmonary artery pressure. ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension 2175 Table 2 Mean pulmonary artery pressure weekly changes before, vs. 298.3 ± 88.4 m (P < 0.001) (Figure 3). At the final ARNI during, and after treatment with sacubitril/valsartan OFF visit (6 weeks after Sac/Val withdrawal), we observed Phase Weeks Estimate 95% CI a significant reduction to 268.5 ± 109 m (P < 0.001) (Figure 3). Pre-ARNI 6 vs. 1 0.941 2.66 to 0.78 The highest improvement was observed in the patients with ARNI ON 1 vs. 0 3.93 5.60 to 2.26 * the lowest initial functional capacity. 1 vs. 1 5.15 6.79 to 3.51 * 1 vs. 2 5.56 7.21 to 3.90 * 1 vs. 3 5.62 7.26 to 3.97 * 1 vs. 4 6.55 8.21 to 4.90 * Lung ultrasound exams 1 vs. 5 5.72 7.37 to 4.07 * 1 vs. 6 3.86 5.51 to 2.21 * Figure 4 depicts changes of the B-lines sum from LUS exams. ARNI OFF 6 vs. 7 +2.16 +0.53 to +3.79 * We observed a significant B-line reduction between the first 6 vs. 8 +2.62 +0.99 to +4.25 * pre-ARNI visit and the visit at the end of ARNI ON (9.3 ± 6.2 6 vs. 9 +1.56 0.06 to +3.20 6 vs. 10 +1.00 0.64 to +2.63 vs. 4.9 ± 4.0, P = 0.04). At the final ARNI OFF visit, we ob- 6 vs. 11 +0.06 1.59 to +1.71 served a non-significant increase to 6.9 ± 8.4 B-lines Abbreviations: ARNI, angiotensin receptor-neprilysin inhibitor; CI, (P = 0.32). confidence interval. * Statistically significant. Quality-of-life questionnaires CI 0.181 to 0.125] during the first 4 weeks of treatment. Figure 5 and Supporting Information, Figure S2 show the re- During ARNI OFF, mPAP tended to progressively increase, sults obtained from KCCQ-12 and EQ-VAS between the first with an estimated mPAP change of +0.022 mmHg [95% CI pre-ARNI visit, the visit at the end of ARNI ON, and the final 0.013 to +0.058] during the first 4 weeks after Sac/Val ARNI OFF visit. We found that QoL was significantly improved withdrawal. with Sac/Val treatment during ARNI ON, according to both the HF-specific QoL questionnaire KCCQ-12 (P = 0.02) and the non-specific questionnaire EQ-VAS (P = 0.04). On KCCQ- Secondary endpoints 12, we observed a >5 point increase in 7 of the 14 patients, and an additional 3 patients had improved scores but did not Six-minute walking test reach the 5-point threshold for a clinically significant change. We observed a significant increase in the walked distance In the ARNI OFF period, we observed a reduced perception of between the first pre-ARNI visit (6 weeks before starting QoL, which reached statistical significance on the KCCQ-12 Sac/Val) and the visit at the end of ARNI ON: 270.6 ± 101.3 m questionnaire (P = 0.04). Figure 3 Changes in 6 min walk test distance. Black lines represent changes in the distance walked by individual patients. Solid lines indicate improve- ment ≥20 m (considered clinically meaningful). Red squared boxes represent mean values, red upright lines represent standard deviation, and solid red line represents mean changes. ARNI, angiotensin receptor-neprilysin inhibitor. ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 2176 P. Codina et al. Figure 4 B-lines sum on the lung ultrasound exam in the three study periods. Black lines represent changes in individual patient measurements (solid for patients with a drop ≥3 B-lines). Red squared boxes represent mean values, and red upright lines standard deviation. Solid red line represents mean changes. ARNI, angiotensin receptor-neprilysin inhibitor. Biomarkers ON, we observed no significant change in any studied bio- Supporting Information, Table S1 presents the serum concen- marker. During ARNI OFF, we observed a significant rise in trations of biomarkers for each study period. During ARNI hs-TnT (P = 0.03) and a trend of increase in CA-125 (P = 0.08). Figure 5 Changes in the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) items score. Black lines represent changes in measurements for in- dividual patients. Solid line indicates improvement ≥5 points (considered clinically meaningful). Red squared boxes represent mean values, red upright lines represent standard deviation, and solid red line represents mean changes. ARNI, angiotensin receptor-neprilysin inhibitor. ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension 2177 Table 3 Echocardiography data during the study periods # Pre-treatmenta With treatmentb After treatment withdrawalc P-value* P-value a a SPAP, mmHg 46.7 ± 14 35.4 ± 8.4 41.1 ± 10.8 0.012 0.042 LVEF, % 58.3 ± 5.6 60.9 ± 5.7 55.9 ± 5.6 0.15 0.043 2 iESLVD, mm/m 18.9 ± 3.6 18.9 ± 2.9 19.6 ± 3.2 1.00 0.33 2 iEDLVD, mm/m 25.2 ± 4.2 25.6 ± 3.4 26.7 ± 2.2 0.75 0.21 2 iLAD, mm/m 27.7 ± 3.4 26.1 ± 3.8 27.4 ± 4.4 0.029 0.044 a b c b E/e0 ratio 12.5 ± 5.6 9.9 ± 3.0 11.6 ± 5.2 0.13 0.27 b b b a a TAPSE, mm 17.5 ± 2.2 18.1 ± 2.3 17.8 ± 4.1 0.20 0.96 Abbreviations: iEDLVD, indexed end-diastolic left ventricular diameter; iESLVD, indexed end-systolic left ventricular diameter; iLAD, indexed left atrium diameter; LVEF, left ventricular ejection fraction; SPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion. a Available in 12 patients. b Available in 13 patients. c Available in 11 patients. * P-value between subscripts a and b. P-value between subscripts b and c. # Echocardiography studies hyperkalaemia (>5.5 mmol/L) or angioedema related to the Table 3 shows the echocardiography data obtained in every use of ARNI. study period. The left atrial diameter index decreased during ARNI ON (P = 0.029) and increased during ARNI OFF (P = 0.044). We observed no changes in left ventricular (LV) diameters, E/e0, or tricuspid annular plane systolic excursion Discussion (TAPSE). The main finding of this mechanistic study was that treat- ment with Sac/Val for 6 weeks led to a significant reduction CardioMEMS measurements of mPAP by ~5 mmHg in patients with HFpEF–PH who were Pulmonary artery pressure and cardiac output were obtained longitudinally monitored with CardioMEMS. These results from CardioMEMS recordings. Sac/Val treatment led to alter- were consistent for systolic and diastolic PAP and were ac- ations in systolic and diastolic PAP, similar to mPAP, with no companied by significant improvement in the distance changes in cardiac output. walked in the 6MWT, a significant reduction of B-lines deter- mined by LUS, and a significant and meaningful improvement Medication in QoL. The effect appeared early and was already significant The mean daily diuretic dose was 78 ± 47 mg during the at 1 week after treatment initiation, with an average mPAP pre-ARNI period, 67 ± 42 mg during ARNI ON, and decrease of 4.99 mmHg. Remarkably, after ARNI with- 70 ± 40 mg during ARNI-OFF (P > 0.05 for all comparisons). drawal, we observed a significant +2.84 mmHg mPAP re- ARNI was initiated at a low dose in all patients and bound, along with the deterioration of the 6MWT, LUS con- up-titrated every 2 weeks. The mean daily ARNI dose gestion signs, and QoL parameters. The vasodilatory effects achieved was 282 ± 127 mg. No changes in other baseline of Sac/Val in the pulmonary vascular system through in- medications were performed during the study. creases in the levels of biologically active peptides may have contributed to the improvement in QoL and decongestion. Adverse events The available clinical evidence regarding Sac/Val in HFpEF During the study, we recorded no deaths or hospitalizations, is mainly derived from the PARAGON-HF trial,10 in which nor any AEs leading to treatment discontinuation. The eGFR Sac/Val was examined in HFpEF patients without phenotype remained relatively stable during the three study periods: granularity. Notably, the PARAGON-HF trial did not examine 54 ± 16 mL/min in the pre-ARNI period, 49 ± 15 mL/min dur- the presence of concomitant PH in the enrolled patients (it ing ARNI-ON, and 44 ± 16 mL/min during ARNI-OFF (all was not an entry criteria) and did not provide longitudinal P > 0.05). No patient presented a significant decline in renal functional or haemodynamic data. A recent retrospective function—defined as a ≥50% decrease in the eGFR, develop- study suggested that Sac/Val was associated with and im- ment of end-stage renal disease, or death due to renal fail- provement of PH in HFpEF.12 ure. Baseline SBP was 143 ± 14 mmHg, decreased to To our knowledge, ARNIMEMS-HFpEF (Treatment of PH 133 ± 15 mmHg during ARNI ON period (P = 0.031), and re- With Angiotensin II Receptor Blocker and Neprilysin Inhibitor mained without significant changes during ARNI OFF period in HFpEF Patients With CardioMEMS Device) is the first trial (135 ± 22 mmHg, P > 0.05). No cases of symptomatic to evaluate the effect of Sac/Val in the subset of patients hypotension were reported. There were no cases of with HFpEF–PH monitored with CardioMEMS. Overall, our ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 2178 P. Codina et al. results highlight the role of Sac/Val in HFpEF–PH and thereby Limitations open a new therapeutic avenue in this patient phenotype. Pulmonary hypertension is a common comorbidity in pa- The results of our trial should be interpreted in the context of tients with cardiopulmonary diseases, and there is not yet several potential limitations. First, this was a mechanistic trial any targeted therapy approved for PH associated with HFpEF. with limited sample size. We have tried to mitigate these lim- In the experimental model of PH, Sac/Val treatment leads to itations by including over 1700 daily PAP values and designing reductions of pulmonary vascular remodelling and PAPs, a treatment protocol with three periods: pre-ARNI (6 weeks which are associated with increased natriuretic peptide/ of standard therapy after monitor implantation), ARNI ON cGMP signalling in the pulmonary vasculature. Both ANP (6 weeks of ARNI treatment), and ARNI OFF (6 weeks follow- and BNP result in pulmonary vasodilation, and Sac/Val treat- ing Sac/Val withdrawal and resumption of standard therapy). ment yielded increased lung levels of ANP and BNP, which Importantly, our frequent assessments of PAPs provided ade- are likely to mitigate vasoconstriction and medial thickening. quate power for the evaluation of the primary endpoint. Sec- In contrast, experimental data indicate that treatment with ond, the study was not designed to evaluate the mid-term valsartan alone has no effect in mitigating PH.9 to long-term functional and clinical effects of ARNI on Longitudinal assessment of PAP is likely the best direct HFpEF–PH. Third, although the correct definition of PH in this surrogate of LV filling haemodynamics and is highly predic- context would be mPAP > 20 mmHg + mean pulmonary tive of clinical events. Frequent measurement of PAP had artery wedge pressure (mPAWP) > 15 mmHg, some of the been difficult until recently, due to the requirement for inva- included patients presented an mPAWP < 15 mmHg at sive right-sided heart catheterization procedures. The advent implantation time, as they were clinically stable and well of remote PAP sensors has made this process substantially compensated and had a mixed precapillary and postcapillary easier. The CHAMPION trial utilized home transmission of PH due to pulmonary vascular remodelling. Lastly, despite PAP with an implanted PAP sensor, and the post hoc evi- the limited sample size, the exquisite phenotyping of the dence revealed that diuretic adjustment led to reduced HF included population revealed that the main endpoint was as- hospitalizations in patients with HFpEF, with and without sociated with positive changes in the LUS, echocardiography, PH.18,19 and functional capacity parameters, together with meaning- A clinical strategy of combining a pulmonary artery sensor ful improvement on the QoL scales. All these secondary end- with a powerful vasodilatory agent like Sac/Val may improve points were evaluated by study personnel blinded to patient the therapeutic accuracy of not only using this particulate treatment. guanylate cyclase donor in patients with HFpEF but also im- prove the target dose that will effectively achieve a treat- ment effect without causing the potential harm of dropping both pulmonary venous and systemic BPs. Therefore, the im- Conclusions plantation of a CardioMEMS device, as performed upon en- In patients with HFpEF–PH and an implanted CardioMEMS rolment in our study, may be considered a reasonable first PAP sensor, Sac/Val treatment yielded rapid reductions in management approach. Notwithstanding, in our study, the ef- PAPs, which were accompanied by significant improvement fect of Sac/Val treatment appeared to be independent of in the distance walked in the 6MWT, a significant reduction loop diuretic management. of B-lines according to LUS, and a significant and meaningful The CardioMEMS sensor has been successfully used to as- improvement in QoL. These effects appeared to be indepen- sess the pulmonary haemodynamic impact of other novel HF dent of loop diuretic management. Sac/Val may be a treat- therapies, such as sodium glucose co-transporter 2 ment of choice in the HFpEF phenotype associated with PH. inhibitors.20 The results of the EMBRACE-HF trial indicated that empagliflozin also reduces PAP in patients with HF. That study was conducted mainly in patients with reduced or mildly reduced EF, and the authors observed a modest Conflict of interest 1.7 mmHg decrease in PAPs following empagliflozin treat- ment, without significant benefits in terms of KCCQ scores A.B.-G. received speaker fees from Novartis. J.N. received or 6 min walking distance. In contrast, our present results speaker fees from Novartis, Vifor Pharma, Boehringer showed a 4.99 mmHg reduction following Sac/Val treat- Ingelheim, Astra Zeneca, Rovi, and Novonordisk. E.S.-V. re- ment in patients with HFpEF–PH. Moreover, this remarkable ceived speaker fees from Novartis. A.B.-G. and J.L. report a re- improvement in haemodynamic parameters was associated lationship with Critical Diagnostics. D.P.-F. received personal with significantly improved functional capacity and QoL. fees, non-financial support, and/or research grants from Notably, in the setting of PH, with regard to PAPs, every sin- Novartis, Astra Zeneca, Boehringer Ingelheim, Roche, Rovi, gle mmHg counts and is associated with an increased risk of Vifor, Abbot, Pfizer, Servier, and Medtronic. The rest of the adverse outcomes.21 authors have no conflicts of interest. ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension 2179 Supporting information three study periods. Figure S1. Loess Curve of Pulmonary Artery Pulse Pressure Additional supporting information may be found online in the Measurements Through the Study. Supporting Information section at the end of the article. Figure S2. Quality of life assessments (EQ-VAS) in the three study periods. Table S1. Biomarkers’ levels during the study periods. Table S2. Mean values obtained by CardioMEMS during the References 1. Maeder MT, Weber L, Buser M, Brenner dose study. Chest. 2014; 146: G, Chazova I, De Marco T. Pulmonary R, Joerg L, Rickli H. Pulmonary hyper- 1274–1285. hypertension due to left heart disease. tension in patients with heart failure 8. Borlaug BA, Anstrom KJ, Lewis GD, Eur Respir J. 2019; 53: 1801897. with mid-range ejection fraction. Front Shah SJ, Levine JA, Koepp GA, Givertz 14. Volpicelli G, Elbarbary M, Blaivas M, Cardiovasc Med. 2021; 9: 694240. MM, Felker GM, LeWinter MM, Mann Lichtenstein DA, Mathis G, Kirkpatrick 2. Lam CS, Roger VL, Rodeheffer RJ, DL, Margulies KB, Smith AL, Tang AW, Melniker L, Gargani L, Noble VE, Borlaug BA, Enders FT, Redfield MM. WHW, Whellan DJ, Chen HH, Davila- Via G, Dean A, Tsung JW, Soldati G, Pulmonary hypertension in heart failure Roman VG, McNulty S, Desvigne- Copetti R, Bouhemad B, Reissig A, Agric- with preserved ejection fraction: a Nickens P, Hernandez AF, Braunwald E, ola E, Rouby JJ, Arbelot C, Liteplo A, community-based study. J Am Coll Redfield MM, National Heart, Lung, Sargsyan A, Silva F, Hoppmann R, Cardiol. 2009; 53: 1119–1126. and Blood Institute Heart Failure Clini- Breitkreutz R, Seibel A, Neri L, Storti E, 3. Koller B, Steringer-Mascherbauer R, cal Research Network. Effect of inor- Petrovic T, International Liaison Com- Ebner CH, Weber T, Ammer M, ganic nitrite vs placebo on exercise ca- mittee on Lung Ultrasound (ILC-LUS) Eichinger J, Pretsch I, Herold M, pacity among patients with heart for International Consensus Conference Schwaiger J, Ulmer H, Grander W. Pilot failure with preserved ejection fraction: on Lung Ultrasound (ICC-LUS). Interna- study of endothelin receptor blockade the INDIE-HFpEF randomized clinical tional evidence-based recommendations in heart failure with diastolic dysfunc- trial. JAMA. 2018; 320: 1764–1773. for point-of-care lung ultrasound. Inten- tion and pulmonary hypertension 9. Clements RT, Vang A, Fernandez-Nicolas sive Care Med. 2012; 38: 577–591. (BADDHY-Trial). Heart Lung Circ. 2017; A, Kue NR, Mancini TJ, Morrison 15. Wickham H. ggplot2: Elegant Graphics 26: 433–441. AR, Mallem K, McCullough DJ, for Data Analysis. New York, NY: 4. Guazzi M, Vicenzi M, Arena R, Guazzi Choudhary G. Treatment of pulmonary Springer; 2009. MD. Pulmonary hypertension in heart hypertension with angiotensin II recep- 16. Bates D, Mächler M, Bolker B, Walker S. failure with preserved ejection fraction: tor blocker and neprilysin inhibitor sacu- Fitting linear mixed-effects models using a target of phosphodiesterase-5 inhibi- bitril/valsartan. Circ Heart Fail. 2019; lme4. J Stat Softw. 2015; 67: 1–48. tion in a 1-year study. Circulation. 12: e005819. 17. Hothorn T, Bretz F, Westfall P. Simulta- 2011; 124: 164–174. 10. Solomon SD, McMurray JJV, Anand IS, neous inference in general parametric 5. Hoendermis ES, Liu LC, Hummel YM, Ge J, Lam CSP, Maggioni AP, Martinez models. Biom J. 2008; 50: 346–363. van der Meer P, de Boer RA, Berger F, Packer M, Pfeffer MA, Pieske B, 18. Abraham WT, Stevenson LW, Bourge RM, van Veldhuisen DJ, Voors AA. Ef- Redfield MM, Rouleau JL, van RC, Lindenfeld JA, Bauman JG, fects of sildenafil on invasive haemody- Veldhuisen DJ, Zannad F, Zile MR, Desai Adamson PB. Sustained efficacy of pul- namics and exercise capacity in heart AS, Claggett B, Jhund PS, Boytsov SA, monary artery pressure to guide adjust- failure patients with preserved ejection Comin-Colet J, Cleland J, Düngen HD, ment of chronic heart failure therapy: fraction and pulmonary hypertension: a Goncalvesova E, Katova T, Kerr Saraiva complete follow-up results from the randomized controlled trial. Eur Heart JF, Lelonek M, Merkely B, Senni M, Shah CHAMPION randomised trial. Lancet. J. 2015; 36: 2565–2573. SJ, Zhou J, Rizkala AR, Gong J, Shi VC, 2016; 387: 453–461. 6. Liu LC, Hummel YM, van der Meer P, Lefkowitz MP, PARAGON-HF Investiga- 19. Benza RL, Raina A, Abraham WT, Berger RM, Damman K, van Veldhuisen tors and Committees. Angiotensin–- Adamson PB, Lindenfeld J, Miller AB, DJ, Voors AA, Hoendermis ES. Effects neprilysin inhibition in heart failure Bourge RC, Bauman J, Yadav J. Pulmo- of sildenafil on cardiac structure and with preserved ejection fraction. N Engl nary hypertension related to left heart function, cardiopulmonary exercise test- J Med. 2019; 381: 1609–1620. disease: insight from a wireless implant- ing and health-related quality of life 11. US Center for Drug Evaluation and Re- able hemodynamic monitor. J Heart measures in heart failure patients with search. Approval package for Entresto. Lung Transplant. 2015; 34: 329–337. preserved ejection fraction and pulmo- Accessed August 16, 2021. https:// 20. Nassif ME, Qintar M, Windsor SL, nary hypertension. Eur J Heart Fail. www.accessdata.fda.gov/drugsatfda_ Jermyn R, Shavelle DM, Tang F, Lamba 2017; 19: 116–125. docs/nda/2021/207620Orig1s018.pdf S, Bhatt K, Brush J, Civitello A, Gordon 7. Bonderman D, Pretsch I, Steringer- 12. Burgdorf C, Brockmöller J, Strampe H, R, Jonsson O, Lampert B, Pelzel J, Mascherbauer R, Jansa P, Rosenkranz Januszewski M, Remppis BA. Reduction Kosiborod MN. Empagliflozin effects on S, Tufaro C, Bojic A, Lam CSP, Frey R, of pulmonary hypertension after transi- pulmonary artery pressure in patients Ochan Kilama M, Unger S, Roessig L, tion to sacubitril/valsartan in patients with heart failure: results from the Lang IM. Acute hemodynamic effects of with heart failure with preserved ejec- EMBRACE-HF trial. Circulation. 2021; riociguat in patients with pulmonary hy- tion fraction. Front Cardiovasc Med. 143: 1673–1686. pertension associated with diastolic 2021; 7: 734697. 21. Maron BA, Hess E, Maddox TM, heart failure (DILATE-1): a randomized, 13. Vachiéry JL, Tedford RJ, Rosenkranz S, Opotowsky AR, Tedford RJ, Lahm T, double-blind, placebo-controlled, single- Palazzini M, Lang I, Guazzi M, Coghlan Joynt KE, Kass DJ, Stephens T, ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952 2180 P. Codina et al. Stanislawski MA, Swenson ER, Choudhary G. Association of borderline Clinical Assessment, Reporting, and Goldstein RH, Leopold JA, Zamanian pulmonary hypertension with mortality Tracking Program. Circulation. 2016; RT, Elwing JM, Plomondon ME, and hospitalization in a large patient co- 133: 1240–1248. Grunwald GK, Barón AE, Rumsfeld JS, hort: insights from the Veterans Affairs ESC Heart Failure 2022; 9: 2170–2180 DOI: 10.1002/ehf2.13952