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 Table of Contents  
RECENT LANDMARK TRIALS
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 120-126

Why majority of heart failure with preserved ejection fraction randomized controlled trials fail? Part: I


Division of Clinical and Preventive Cardiology, Medanta Heart Institute, Medanta The Medicity, Gurgaon, Haryana, India

Date of Web Publication10-Jul-2018

Correspondence Address:
Dr. Satyanarayana Upadhyayula
Medanta-Mediclinic, Room No 5, E-18 Defence Colony, New Delhi - 110 024
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCPC.JCPC_28_18

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  Abstract 

Today, heart failure with preserved ejection fraction (HFpEF) remains one of the toughest Gordian knots in cardiovascular medicine with no visible effective and acceptable therapies. Owing to the complexity, urgency, and gravity of the problem of HFpEF, the present article has been divided into two parts – Part I deals with the description of the problem, and in Part II, the authors suggest innovative methodologies to deal with the problem globally. All the while we have been searching for a size which fits HFpEF, a less understood complex syndrome due to maladaptive changes in structural, functional, and biochemical aspects of the myocyte. Inflammation appears to be the underlying string which weaves together nitrosative/oxidative stress, endothelial dysfunction, downregulation of nitric oxide (NO) bioavailability/NO-mediated signaling, impaired myocardial bioenergetics, disturbed calcium handling, and concentric hypertrophy. Most of the HF with reduced EF (HFrEF) randomized controlled trials (RCTs) are positive, while the majority of HFpEF RCTs are either neutral, borderline, or negative leading to a huge vacuum in the therapeutic space of HFpEF. While few understand the statistical complexity of RCTs, many pretend to do so. Endeavor has been made in the present article to make the underlying concepts loud and lucid without going into statistical complexities. Attempts are being made to negotiate this problem by adopting/experimenting with innovative designs, enrichment trials, adaptive trials, umbrella trials, basket trials, and machine learning-based trials leading to what may be termed as “precision medicine, precision diagnosis, and precision therapy.” We have compared two recent negative HFpEF RCT's (TOPCAT trial - Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist, INDIE trial - Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF) with one positive HFrEF RCT (CASTLE AF trial - Catheter Ablation Versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation), one negative HFrEF RCT (IRONOUT HF trial - Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), one positive HFmEF / HFpEF randomized, parallel-group, blinded, multicenter trial (REDUCE LAP-HF TRIAL Phase 2: A Study to Evaluate the DC Devices, Inc. IASD™ System II to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure), one positive HFmEF / HFpEF non-randomized, multicenter, open label, single arm study (REDUCE LAP-HF TRIAL Phase 1: A Study to Evaluate the DC Devices, Inc. IASD™ System II to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure) in order to understand why majority of HFpEF Clinical Trials fail.

Keywords: Catheter ablation, atrial fibrillation, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, iron repletion, aldosterone antagonist


How to cite this article:
Upadhyayula S, Kasliwal RR. Why majority of heart failure with preserved ejection fraction randomized controlled trials fail? Part: I. J Clin Prev Cardiol 2018;7:120-6

How to cite this URL:
Upadhyayula S, Kasliwal RR. Why majority of heart failure with preserved ejection fraction randomized controlled trials fail? Part: I. J Clin Prev Cardiol [serial online] 2018 [cited 2020 Nov 24];7:120-6. Available from: https://www.jcpconline.org/text.asp?2018/7/3/120/236327

In a large population, same size doesn't fit all, A size that fits everyone has to be the tailored size.


  Catheter Ablation Versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation. (CASTLE-AF) (NCT00643188) Top


Publication: Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417-27.


  Trial Summary Top


Hypothesis: Catheter ablation is superior to medical therapy (rate or rhythm control) with regard to death or hospitalization for HF in HF with reduced ejection fraction (HFrEF) with atrial fibrillation (AF).

Background: HFrEF is often associated with AF (vicious twins) as a comorbid condition. Such patients have increased risk of stroke, hospitalization for HF, and death. The 2002 AF Follow-up Investigation of Rhythm Management (AFFIRM) trial was the first and largest study (n = 4060) to compare rate-control and rhythm-control strategies for the treatment of nonvalvular AF. In high-risk patients, AFFIRM demonstrated no survival advantage between rate-control and rhythm-control strategies.

Methods: Based on the above hypothesis, the 2018 Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and AF (CASTLE-AF) investigators randomized 363 patients to catheter ablation versus medical therapy and assessed for a primary outcome of death or hospitalization for HF. Inclusion criteria were Age ≥18 years, symptomatic paroxysmal or persistent AF, AF episodes had to be documented in the past 3 months before enrollment by electrocardiography, Holter, loop recorder, or implanted device, failure of antiarrhythmic drug therapy or patients unwillingness to take antiarrhythmic drugs, left ventricular dysfunction with left ventricular EF (LVEF) ≤35% (measured within last 6 weeks), New York Heart Association (NYHA) class II-IV and implanted defibrillator for primary or secondary prevention. Out of 363 patients, 179 patients underwent catheter ablation and 184 patients treated with medical therapy (rate or rhythm control) for AF as well as guidelines-based therapy for HF. All the patients had NYHA Class II, III, or IV HF, an LVEF of 35% or less, and an implanted defibrillator. The primary endpoint was a composite of death from any cause or hospitalization for worsening HF.

Results: The median follow-up was 37.8 months. In the ablation group, the primary composite endpoint occurrence was significantly less than in the medical therapy group. In the ablation group, fewer deaths were reported from any cause. There were also less number of hospitalizations for worsening HF.

Conclusion: Compared to medical therapy, catheter ablation for AF in patients with HF was associated with a significantly lower rate of primary composite endpoint occurrence of death from any cause or hospitalization for worsening HF [Table 1].
Table 1: Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation trial primary outcome

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  Clinical Perspective Top


CASTLE-AF provides data that prove that catheter ablation is associated with improved rhythm control in patients with AF and symptomatic HFrEF. It also improves cardiovascular outcomes in this population, with lower rates of death and hospitalization for HF. The inclusion of a rate control arm in CASTLE-AF is a critical first step toward considering catheter ablation as a first-line treatment option for AF in patients with HFrEF. More good quality randomized controlled trials (RCTs) are needed before catheter ablation can be fully established as a first-line treatment option for AF with HFrEF.


  Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure. (IRONOUT-HF Trial) (NCT02188784) Top


Publication: Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: The IRONOUT HF randomized clinical trial. JAMA 2017;317:1958-66.


  Trial Summary Top


Hypothesis: In patients with iron deficiency and symptomatic HFrEF, oral iron replacement improves exercise capacity.

Background: Iron plays an important role in oxygen delivery. It is crucial for the production of red blood cells. It is also a cofactor for enzymes needed for cellular respiration and vascular homeostasis. About 50% of patients with symptomatic HFrEF have an iron deficiency which has been linked with reduced exercise capacity, quality of life, and increased mortality. In the 2009 Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) trial, patients with symptomatic HFrEF and iron deficiency (with or without anemia) given IV iron replacement had improvements in functional capacity, HF symptoms, and quality of life. Iron Repletion Effects on Oxygen Uptake in HF (IRONOUT-HF) trial was conducted to see if inexpensive and readily available oral iron replacement would confer similar benefits.

Methods: The 2017 IRONOUT-HF trial investigators randomized 225 patients with symptomatic HFrEF (LVEF <40% with NYHA II–IV symptoms) and iron deficiency (either ferritin 15–100 ng/mL or 100–299 ng/ML with TS at <20%) to either oral iron polysaccharide (150 mg twice daily) or placebo. The primary endpoint was increase in peak oxygen uptake (VO2 max) on cardiopulmonary exercise testing (CPET).

Results: There was no significant improvement in the primary endpoints (VO2 max on CPET) or the secondary outcomes (6-min walk distance, NT pro-B-type natriuretic peptide [BNP] levels, quality of life). Iron markers were only modestly improved with oral iron therapy. This points out to the fact that route of administration is very important in increasing iron stores.

Conclusion: In patients with iron deficiency (ferritin 15–100 or 100–299 with transferrin saturation <20%) and symptomatic HFrEF (LVEF ≤40% with NYHA II–IV), oral iron replacement had no significant positive effect on primary endpoints (VO2 max on CPET) [Table 2].
Table 2: Iron Repletion Effects on Oxygen Uptake in Heart Failure trial primary outcome

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  Clinical Perspective Top


IRONOUT-HF trial results suggest that there is currently no role for routine oral iron supplementation iron deficient HFrEF patients. However, FAIR-HF trial randomized 459 patients with symptomatic HFrEF (defined as LVEF ≤40% with NYHA II–III symptoms or LVEF ≤45% with NYHA III symptoms) and concomitant iron deficiency (ferritin <100 μg/L or ferritin 100–299 μg/L with iron saturation <20%) with mild or no anemia (hemoglobin 9.5–13.5 g/dL) and assessed the effects of administration of IV ferric carboxymaltose versus placebo on functional status. FAIR-HF showed that the use of IV iron repletion resulted in a 20% absolute increase moderate improvement in HF symptoms, 17% absolute increase in the number of patients with improvement to NHYA Class I or II, a mean 35 m increase in 6-min walk distance at 24 weeks and lower rate of first cardiac hospitalization. However, there was no significant difference in adverse event rate between the IV iron and placebo groups. One may conclude that IV iron therapy better replenishes the iron stores of the body than the oral route iron therapy. This probably explains why FAIR-HF trial is a positive and IRONOUT-HF trial is negative.


  Reduce LAP-HF Trial: A Study to Evaluate the DC Devices, Inc. IASD™ System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure. (NCT01913613) Top


Publication: Hasenfuss G, Hayward C, Burkhoff D, Silvestry FE, McKenzie S, Gustafsson F, et al. Atranscatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): A multicenter, open-label, single-arm, phase 1 trial. Lancet 2016;387:1298-304.


  Trial Summary Top


Hypothesis: An inter atrial shunt device (IASD, Corvia Medical, Qp:Qs 1.2 to 1.3), can unload the LA in the setting of increased LA pressure (LAP), transferring the excess LA blood volume to the larger reservoir of the right atrium (RA) and systemic veins, leading to decrease in LAP, pulmonary venous pressures (PVP), pulmonary capillary wedge pressure (PCWP). This mechanistic effect should improve quality of life and exercise capacity in HFmEF / HFpEF patients.

Background: HFmEF / HFpEF patients have increased LAP, PCWP & LVEDP during rest as well as exercise. This trial evaluated the safety and functionality of the IASD System II in the treatment of HFmEF / HFpEF patients with elevated LAP, who remain symptomatic despite optimal guideline directed medical therapy (GDMT). Theoretically an artificial shunt created across the IAS with an IASD should attenuate the LAP and its surrogates PVP, PCWP & LVEDP during rest/exertion.

Methods: Out of 68 patients 64 met the inclusion / exclusion criteria and underwent the IASD implantation. The primary safety endpoint was major adverse cardiac, cerebrovascular events (MACCE) at 1 month. PCWP during rest / exercise was compared between treatment groups. Safety and robust performance of the IASD at 6 months, functional capacity as well as clinical status constituted the co-primary endpoints.

Results: The REDUCE LAP-HF phase I study was a multicenter, open-label, single-arm study designed to assess the performance and safety of a transcatheter IASD in patients > 40 years of age with symptoms of HFpEF despite GDMT, LVEF≥40%, and an increased PCWP at rest (>15 mmHg) or during exercise (>25 mmHg). IASD implant proved to be safe and well tolerated and was accompanied by a reduction in PCWP. The primary outcomes were encouraging as shown in [Table 3]. During subsequent 6 months of follow-up there was no peri-procedural or major adverse cardiac, cerebro vascular event (MACCE) or need for IASD related cardiac surgical intervention. IASD patency was confirmed by left-to-right shunting at 6 months.
Table 3: Reduce Elevated Left Atrial Pressure in Patients with Heart Failure I Phase 1 trial primary outcome

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Conclusions: Implantation of an IASD is feasible, seems to be safe, reduces LAP during exercise, and could be a new strategy for the management of HFPEF. The efficacy of IASD compared with existing treatments for patients with HFPEF requires validation in a RCT.

Clinical Perspective: In severe mitral stenosis LA is dilated due to pressure and volume overload. However in Lutembachers syndrome where severe mitral stenosis is associated with congenital atrial septal defect (ASD), the pulmonary arteries, veins and the LA appear to acquire partial protection from the deleterious effects of pressure / volume overload. This observation has lead to the logical conclusion that IASD can transfer excess LA pressure / volume load to the RA and systemic veins during rest as well as exertion without significant increase in RV pressure / volume load.

In this non-randomized, open-label, single-arm study it is evident that IASD implant significantly lowers PCWP a surrogate of LAP, pulmonary venous pressure, PCWP and LVEDP during rest / exercise in HFmEF / HFpEF patients. The trial also proved that IASD was safe and associated with fewer symptoms. It also improved quality of life, and exercise capacity, without the occurrence of right-sided HF or pulmonary hypertension.

Gerd et al have made a commendable and fairly successful attempt to cut the Gordian knot of HFpEF by circumventing the pathophysiology and trying to partially equate the atrial pressures (LA unloading) leading to attenuation of the LAP and its surrogates PVP, PCWP and LVEDP. The IASD is designed to dynamically (at rest and during exercise) decompress LA in HFmEF / HFpEF patients.

However since this a non-randomized, open-label, single arm study with its associated bias and confounding factors, a larger RCT is warranted to prove the effectiveness of the IASD.


  Reduce LAP-HF Trial: A Study to Evaluate the DC Devices, Inc. IASD™ System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure. (NCT02600234) Top


Publication: Feldman T, Mauri L, Kahwash R, Litwin S, Ricciardi MJ, van der Harst P, et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce elevated left atrial pressure in patients with heart failure]): A Phase 2, randomized, sham-controlled trial. Circulation 2018;137:364-75.


  Trial Summary Top


Hypothesis: IASD can unload the LA in the setting of increased LA pressure, transferring the excess LA blood volume to the RA and systemic veins, leading to decrease in LAP and its surrogates PVP, PCWP and LVEDP. The change in hemodynamics should improve quality of life and exercise capacity in HFmEF / HFpEF patients.

Background: HFmEF / HFpEF patients have increased LAP and its surrogates PVP, PCWP, LVEDP during rest as well as exercise. Theoretically an artificial shunt created across the IAS with an IASD should attenuate the LAP, PVP, PCWP & LVEDP. Feldman et al conducted the first randomized, sham-controlled trial to evaluate the utility of IASD in HFmEF / HFpEF patients.

Methods: REDUCE LAP-HF phase 2, is a randomized, parallel-group, blinded, multicenter trial in patients with NYHA class III or ambulatory class IV HF. Patients were randomized (1:1) to the IASD vs. a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebro vascular, renal event (MACCRE) at 1 month. PCWP during exercise was compared between treatment groups using a mixed effects repeated measures model analysis of covariance. This included data from all available stages of exercise.

Results: A total of 94 patients were enrolled, of which n=44 met inclusion / exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared to sham-control. There were no peri-procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal function) in the control group (P = 1.0) [Table 4].
Table 4: Reduce Elevated Left Atrial Pressure in Patients with Heart Failure I Phase 2 trial primary outcome

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Conclusions: In patients with HFmEF and HFpEF, IASD implant (Corvia Medical) reduces PCWP during exercise. Further high quality trials will be required to prove that these beneficial mechanistic effects of IASD will improve symptoms and outcomes in HFmEF / HFpEF patients.

Clinical Perspective: Just as inflammation appears to be the underlying common factor regarding etiology and pathophysiology of HFpEF / HFmEF leading to stiff LV (impaired compliance / relaxation), elevated LAP at rest and/or during exertion appears to be the common platform on which the heterogenous signs, symptoms and syndromes of HFmEF / HFpEF orchestrate.

Feldman et al report a novel therapy for HFmEF / HFpEF patients by utilizing an implanted device to create an atrial shunt (Inter Atrial Shunt Device [IASD]). The objective of the IASD is to dynamically (at rest and during exercise) decompress LA pressure overload associated with HFmEF/HFpEF. Feldman et al conducted a randomized, sham-controlled trial to evaluate the mechanistic effect of the IASD on invasively measured PCWP. At 1 month after randomization, the IASD treatment group had a significantly greater reduction in PCWP during exercise compared to the control group. In addition, PCWP during passive leg rise as well as during 20W of exercise decreased to a greater degree in the patients randomized to IASD compared to sham-control. In patients with HFmEF / HFpEF creation of an interatrial shunt with the IASD unloads the LA and reduces PCWP during exercise. This hemodynamic study demonstrates the beneficial mechanistic effect of the IASD. The IASD could have beneficial clinical effects in patients with HFmEF / HFpEF. A larger trial to examine the effects of the IASD on symptoms, quality of life, exercise capacity, and clinical outcomes such as HF hospitalization is warranted.

The REDUCE LAP-HF I Phase 2, randomized, sham-ontrolled trial that included 44 symptomatic HF patients with EF ≥ 40% (IASD group; n = 22 and control group; n = 22) showed that treatment with IASD System II reduced significantly PCWP during exercise, relative to the sham group. [Table 4] LA unloading and partial equalization of atrial pressures using an inter atrial shunt device (IASD, Corvia Medical, Qp:Qs 1.2 to 1.3) lowers PCWP, improves quality of life and exercise capacity in patients with HFmEF and HFpEF.


  Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) (NCT00094302) Top


Publication: Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-92.


  Trial Summary Top


Hypothesis: Spironolactone an aldosterone antagonist reduces cardiovascular mortality, aborts cardiac arrest, or HF hospitalizations in HFpEF patients when compared to placebo. The hypothesis was based on evidence from randomized aldactone evaluation study and Eplerenone in Mild Patients Hospitalization and Survival Study in HF trials.

Methods: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) investigators randomized 3445 HFpEF patients in a multicenter study involving 233 sites in 6 countries and 3 distinct geographic regions: North America (United States and Canada); Eastern Europe (Russia and the Republic of Georgia); and South America (Argentina and Brazil) for evaluating the effectiveness and safety of spironolactone (15 mg titrated to 45 mg) compared to placebo in patients with HFpEF: spironolactone (n = 1722), placebo (n = 1723), enrollment: 2006–2012, mean follow-up: 3.3 years, analysis: Intention-to-treat.

Results: It was a negative trial with no significant spironolactone treatment effect (primary endpoint hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.77–1.04). However, the HR varied across geographies. Interestingly, in the Americas (HR: 0.82; 95% CI: 0.69–0.98; P = 0.026) treatment effect was significant, but not in Eastern Europe (HR: 1.10; 95% CI: 0.79–1.51; interaction P = 0.12). Possible factors responsible for the paradox are genetic, nongenetic, racial characteristics, medical infrastructure, and medical practice patterns. Most of the hospitalizations in Russia/Georgia were based on ischemia rather than HF consistent with ischemic heart disease prevalence data from the I-PRESERVE (Irbesartan in HF with Preserved Systolic Function) and Efficacy of Vasopressin Antagonism in HF: Outcome Study with Tolvaptan trials.

Conclusion: In patients with HFpEF, spironolactone did not significantly reduce the incidence of the primary composite outcomes. In addition, Spironolactone had no treatment effect in Russia and Georgia where event rates were extremely low. The hospitalizations were skewed with Georgia getting 200% of its enrollment target followed by another 666 more enrollments for Eastern Europe (Russia and the Republic of Georgia). However, for this skewed enrollment, the outcomes could have been positive. In conclusion, Spironolactone does not reduce the primary endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations when compared to placebo [Table 5].
Table 5: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial primary outcome

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  Clinical Perspective Top


The lack of favorable evidence from clinical-outcome trials involving patients with HFpEF is reflected in current guidelines. There are no specific evidence-based recommendations for the management of HFpEF. In the absence of proven therapies, HFpEF treatment remains empirical with extra attention being conferred to comorbidities.

All good quality RCTs should expect the unexpected and should have inbuilt mechanisms to identify, explain, and manage such situations. Most HFrEF RCTs are positive leading to multiple effective regimens (e.g., beta blockers, Angiotensin-converting enzyme-inhibitors/angiotensin II receptor blockers, Aldosterone antagonists). In dire contrast majority of the HFpEF RCTs are either neutral, borderline, or negative creating substantial vacuum in the HFpEF therapeutic space.

Post hoc analysis indicated marked regional differences in event rates in the Americas (the United States, Canada, Brazil, and Argentina) and Eastern Europe (Russia and Georgia) as shown in [Table 5]. Spironolactone significantly reduced the rate of the primary outcome among patients enrolled on the basis of an elevated BNP level but not among those enrolled on the basis of a previous hospitalization for HF. Marked regional variation in event rates was observed, with patients in the placebo group who were enrolled in Eastern Europe (Russia or Georgia) having a much lower likelihood of a primary-outcome event than those enrolled in the Americas. This discrepancy in event rates was unexpected. Regional heterogeneity of coexisting conditions and medical practice patterns as well as differential use of hospitalization with added difficulty of diagnosing HFpEF may explain the paradoxical outcomes. While positive primary outcomes were observed in the Americas (where event rates are high and most of the patients are in the BNP stratum). Negative Primary outcomes were observed in the Eastern Europe (where event rates are very low and most of the patients are in the hospitalization stratum).


  Inorganic Nitrite Delivery to Improve Exercise Capacity in Hfpef. (INDIE HFpEF) (NCT02742129) Top


Publication: Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;373:2314-24.


  Trial Summary Top


Hypothesis: In patients with HFpEF (LVEF ≥50%) and mild-moderate (NYHA II–III) symptoms, the long-acting nitrate isosorbide mononitrate improves activity tolerance.

Background: It is well known that long-acting nitrates provide symptomatic benefit in patients with angina. However, they do not improve mortality in any cardiac condition. In smaller trials long-acting nitrates improved exercise tolerance in HFrEF patients probably by improving cardiac filling pressures.

Methods: Inorganic Nitrite Delivery to Improve Exercise Capacity/Nitrate's Effect on Activity Tolerance (INDIE/NEAT-HFpEF) trial investigators randomized 110 patients with chronic HFpEF. It was a Multicenter, double-blind, placebo-controlled, double crossover study: isosorbide mononitrate (n = 51), placebo (n = 59), setting: 20 sites in the United States, duration of follow-up: 6 weeks, analysis: Intention-to-treat. The study assessed the effect of extended-release isosorbide mononitrate on daily activity tolerance in HFpEF patients who predominantly had mild to moderate symptoms (NYHA II–III).

Results: In HFpEF patients with mild-moderate (NYHA II–III) symptoms, activity levels appear to be reduced by the addition of long-acting nitrate isosorbide mononitrate. Long-acting nitrate therapy on HFpEF patients lead to a borderline significant reduction in total activity units. In addition, there was a 20-min absolute reduction in activity time per day. However, there was no effect on 6-min walk distance, quality of life, or clinical biomarkers. After a 6 weeks treatment period, Isosorbide Mononitrate use was associated with a borderline significant decrease in total activity. The activity was measured using continuous accelerometry. Increased doses of Isosorbide Mononitrate resulted in a progressive decrease in daily activity. Although accelerometer units are difficult to quantify, an analysis of total hours of activity per day suggested about a 20-min absolute reduction in activity time with nitrate therapy.

Conclusion: Accelerometer units are not a common measure of activity in patients with HFpEF. However, the accelerometer findings were supported by the failure of isosorbide mononitrate to improve 6-min walk distance, subjective dyspnea on several validated patient questionnaires, and cardiac biomarkers. HFpEF patients on Isosorbide mononitrate were less active. They did not have better quality of life or submaximal exercise capacity as compared to placebo group [Table 6].
Table 6: Inorganic Nitrite Delivery to Improve Exercise/Nitrate's Effect on Activity Tolerance heart failure with preserved ejection fraction trial primary outcome

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  Clinical Perspective Top


Exercise intolerance is a salient feature of HFpEF. It leads to sedentary behavior, deconditioning, and frailty. In early studies in patients with HFrEF, long-acting nitrates improved activity tolerance. Nitrates are commonly prescribed for symptom relief in HF. The effects of nitrates in HFpEF patients have not been studied in sufficient detail. Nitrates might decrease pulmonary congestion and improve exercise capacity. The hemodynamic effects of nitrates might attenuate with exertion in HFpEF. However, the unique pathophysiology, multiple comorbidities, and polypharmacy that are characteristic of HFpEF tend to limit hemodynamic improvements and predispose to hypotension. Nitrates are commonly used for symptom control in HFrEF. However, there is no authentic data to support and justify the administration of nitrates to HFpEF patients. The beneficial effect of nitrates in HFrEF need not be expected in HFpEF due to well-known differences in epidemiology, pathophysiology, and response to treatment between HFpEF and HFrEF. INDIE/NEAT-HFpEF trial was designed and launched to explore the probable role of nitrates in HFpEF. This trial suggests that there is currently no role for long-acting nitrates in patients with HFpEF. In fact nitrates may actually lead to worsening of symptoms and functional capacity. However, nitrates may be administered for indications such as angina in HFpEF patients.


  Why Majority of Heart Failure with Preserved Ejection Fraction Randomized Controlled Trials's Fail? Top


With the major chunk of the HF patients being in the HFpEF category which has no evidence-based effective therapy at the moment, we submit probable reasons as to why HFpEF RCTs give neutral, borderline positive or negative results. Those therapies which appear to be theoretically acceptable but could not pass RCTs cannot be recommended by Regulatory Bodies and Guideline Committee Faculty. This portends gloom for the HFpEF patients as well as the medical fraternity. The RCTs which have been enumerated and the stratification of HF based on LVEF are given in the [Table 7] and [Table 8].
Table 7: Heart failure randomized controlled trials

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Table 8: Heart failure stratification by left ventricular ejection fraction

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After analyzing the above five randomized and one non-randomized recent landmark clinical trials in HF, we found that there are multiple factors responsible for the failure of HFpEF RCTs as shown in the [Table 9] and [Table 10]. These factors and possible solutions will be discussed in Part-II of this article.
Table 9: Heart failure with preserved ejection fraction versus heart failure with reduced ejection fraction differential randomized controlled trial outcomes

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Table 10: Diagnostic dilemmas of HFpEF: An example - LVEF cut off value

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.





 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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