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Hans Lennernas - One of the best experts on this subject based on the ideXlab platform.
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Correlation of Intestinal Drug Permeability in Humans (In Vivo) with Experimentally and Theoretically Derived Parameters
Molecular Modeling and Prediction of Bioactivity, 2020Co-Authors: Anders Karlén, Hans Lennernas, Susanne Winiwarter, Nicholas M. Bonham, Anders HallbergAbstract:The extent of intestinal drug absorption, often described by the fraction of drug absorbed (Fa), is governed by several different processes: (a) dose/dissolution ratio, (b) chemical degradation and/or metabolism in the lumen, (c) complex binding in the lumen, intestinal transit, and (d) effective permeability (Peff) across the intestinal mucosa. In many cases Peff is considered to be the rate-limiting step in the overall absorption process and is therefore an interesting parameter in bioavailability studies.
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Regional Intestinal Permeability in Rats: A Comparison of Methods
Molecular Pharmaceutics, 2017Co-Authors: Carl Roos, David Dahlgren, Christer Tannergren, Bertil Abrahamsson, Erik Sjögren, Hans LennernasAbstract:Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (Peff) and apparent (Papp) permeability in all three regions and at both pH levels. Metoprolol had high Peff in all regions and at both pHs and high Papp at both pHs and in all regions except the jejunum, where Papp was low. Atenolol had low Peff in a...
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Regional Intestinal Permeability of Three Model Drugs in Human.
Molecular Pharmaceutics, 2016Co-Authors: David Dahlgren, Carl Roos, Anders Lundqvist, Christer Tannergren, Bertil Abrahamsson, Erik Sjögren, Per M. Hellström, Hans LennernasAbstract:Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II–IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10–4 cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10–4 cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10–4 cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestin...
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Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms
Molecular Pharmaceutics, 2016Co-Authors: David Dahlgren, Carl Roos, Pernilla Johansson, Anders Lundqvist, Christer Tannergren, Bertil Abrahamsson, Erik Sjögren, Hans LennernasAbstract:The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10–4 cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10–4 cm/s in the LI, for atenolol, enalaprilat...
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Human in Vivo Regional Intestinal Permeability: Quantitation Using Site-Specific Drug Absorption Data
Molecular Pharmaceutics, 2015Co-Authors: Erik Sjögren, Carl Roos, David Dahlgren, Hans LennernasAbstract:Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration–time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r2 = 0.96, slope = 1.24, intercept = 0.030) was establis...
Gordon L. Amidon - One of the best experts on this subject based on the ideXlab platform.
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Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse and Caco-2 Cells: Use as a Reference Standard for BCS Classification
Molecular Pharmaceutics, 2013Co-Authors: Tuba Incecayir, Yasuhiro Tsume, Gordon L. AmidonAbstract:The purpose of this study was to investigate labetalol as a potential high permeability reference standard for the application of Biopharmaceutics Classification Systems (BCS). Permeabilities of labetalol and metoprolol were investigated in animal intestinal perfusion models and Caco-2 cell monolayers. After isolating specific intestinal segments, in situ single-pass intestinal perfusions (SPIP) were performed in rats and mice. The effective permeabilities (Peff) of labetalol and metoprolol, an FDA standard for the low/high Peff class boundary, were investigated in two different segments of rat intestine (proximal jejunum and distal ileum) and in the proximal jejunum of mouse. No significant difference was found between Peff of metoprolol and labetalol in the jejunum and ileum of rat (0.33 ± 0.11 × 10–4 vs 0.38 ± 0.06 × 10–4 and 0.57 ± 0.17 × 10–4 vs 0.64 ± 0.30 × 10–4 cm/s, respectively) and in the jejunum of mouse (0.55 ± 0.05 × 10–4 vs 0.59 ± 0.13 × 10–4 cm/s). However, Peff of metoprolol and labetalol...
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The fraction dose absorbed, in humans, and high jejunal human permeability relationship.
Molecular Pharmaceutics, 2012Co-Authors: Arik Dahan, Hans Lennernas, Gordon L. AmidonAbstract:The drug intestinal permeability (Peff) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (Fabs) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo Peff measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding Fabs and Peff in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal Peff as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejuna...
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High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations
Molecular Pharmaceutics, 2010Co-Authors: Arik Dahan, Lawrence X. Yu, Hans Lennernas, Jonathan M. Miller, John M. Hilfinger, Shinji Yamashita, Gordon L. AmidonAbstract:The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (Fabs) in humans is 90% or higher. This direct correlation between human permeability and Fabs has been recently controversial, since the β-blocker sotalol showed high Fabs (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and Fabs. The effective permeabilities (Peff) of sotalol and metoprolol, a FDA standard for the low/high Peff class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher Peff at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol’...
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segmental dependent membrane permeability along the intestine following oral drug administration evaluation of a triple single pass intestinal perfusion tspip approach in the rat
European Journal of Pharmaceutical Sciences, 2009Co-Authors: Arik Dahan, Brady T West, Gordon L. AmidonAbstract:Abstract In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine. Data was evaluated in comparison to the traditional method. Metoprolol and propranolol showed similar Peff values in the modified model in all segments. Segmental-dependent permeability was obtained for cimetidine, with lower Peff in the distal parts. Similar Peff values for all drugs were obtained in the traditional method, illustrating that the modified model is as accurate as the traditional, throughout a wide range of permeability characteristics, whether the permeability is constant or segment-dependent along the intestine. Three-fold higher statistical power to detect segmental-dependency was obtained in the modified approach, as each subject serves as his own control. In conclusion, the Triple SPIP model can reduce the number of animals utilized in segmental-dependent permeability research without compromising the quality of the data obtained.
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The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique.
European Journal of Pharmaceutical Sciences, 2002Co-Authors: Hans Lennernas, L Knutson, T. Knutson, Ajaz S. Hussain, Lawrence J. Lesko, T. Salmonson, Gordon L. AmidonAbstract:Abstract The purpose of this human intestinal perfusion study (in vivo) was twofold. Firstly, we aimed to determine the effective in vivo jejunal permeability (Peff) of amoxicillin and to classify it according to the Biopharmaceutics Classification System (BCS). Secondly, we investigated the acute effect of amiloride on the jejunal Peff of amoxicillin. Amoxicillin, a β-lactam antibiotic, has been reported to be absorbed across the intestinal mucosa by both passive diffusion and active transport. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut® perfusion tube in 14 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The concentration of amoxicillin entering the jejunal segment was 300 mg/l in both periods, and amiloride, an inhibitor of the Na+/H+ exchanger, was added at 25 mg/l in period 2. The concentrations of amoxicillin and amiloride in the outlet jejunal perfusate were measured with two different HPLC-methods. Antipyrine and [14C]PEG 4000 were added as internal standards to the perfusion solution. Amiloride had no significant effect on the jejunal Peff of amoxicillin. The human in vivo jejunal Peff for amoxicillin was 0.34±0.11×10−4 and 0.46±0.12×10−4 cm/s in periods 1 and 2, respectively. The high jejunal Peff for amiloride was 1.63±0.51×10−4 cm/s which predicts an intestinal absorption of more than 90%. Following the BCS amoxicillin was classified as a low Peff drug, and amiloride had no acute effect on the in vivo jejunal Peff of amoxicillin.
Arik Dahan - One of the best experts on this subject based on the ideXlab platform.
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Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine
Aaps Journal, 2013Co-Authors: Moran Fairstein, Rotem Swissa, Arik DahanAbstract:Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (Peff) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (Fabs) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized Peff–Fabs correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine’s BCS classification. Pseudoephedrine’s BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine’s permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine’s complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between Peff and Fabs is involved in its absorption. Rather, it reflects the complexity behind Peff when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with Peff that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.
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The fraction dose absorbed, in humans, and high jejunal human permeability relationship.
Molecular Pharmaceutics, 2012Co-Authors: Arik Dahan, Hans Lennernas, Gordon L. AmidonAbstract:The drug intestinal permeability (Peff) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (Fabs) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo Peff measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding Fabs and Peff in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal Peff as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejuna...
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High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations
Molecular Pharmaceutics, 2010Co-Authors: Arik Dahan, Lawrence X. Yu, Hans Lennernas, Jonathan M. Miller, John M. Hilfinger, Shinji Yamashita, Gordon L. AmidonAbstract:The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (Fabs) in humans is 90% or higher. This direct correlation between human permeability and Fabs has been recently controversial, since the β-blocker sotalol showed high Fabs (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and Fabs. The effective permeabilities (Peff) of sotalol and metoprolol, a FDA standard for the low/high Peff class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher Peff at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol’...
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segmental dependent membrane permeability along the intestine following oral drug administration evaluation of a triple single pass intestinal perfusion tspip approach in the rat
European Journal of Pharmaceutical Sciences, 2009Co-Authors: Arik Dahan, Brady T West, Gordon L. AmidonAbstract:Abstract In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine. Data was evaluated in comparison to the traditional method. Metoprolol and propranolol showed similar Peff values in the modified model in all segments. Segmental-dependent permeability was obtained for cimetidine, with lower Peff in the distal parts. Similar Peff values for all drugs were obtained in the traditional method, illustrating that the modified model is as accurate as the traditional, throughout a wide range of permeability characteristics, whether the permeability is constant or segment-dependent along the intestine. Three-fold higher statistical power to detect segmental-dependency was obtained in the modified approach, as each subject serves as his own control. In conclusion, the Triple SPIP model can reduce the number of animals utilized in segmental-dependent permeability research without compromising the quality of the data obtained.
Frédéric Sériès - One of the best experts on this subject based on the ideXlab platform.
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Accuracy of an unattended home CPAP titration in the treatment of obstructive sleep apnea.
American Journal of Respiratory and Critical Care Medicine, 2000Co-Authors: Frédéric SérièsAbstract:Treatment of sleep apnea–hypopnea syndrome (SAHS) by fixed continuous positive airway pressure (CPAP) requires an in-laboratory titration procedure to determine the effective pressure level (Peff ). We recently reported that one auto-CPAP machine can be used without titration study allowing Peff determination. The aim of this study was to evaluate the accuracy of an auto CPAP trial at home. A 1- or 2-wk automatic CPAP trial was done at home in 40 patients by estimating the reference pressure (Pref ) to be set and a Pref + 3 cm H2O/ − 4 cm H2O pressure interval. Peff was then determined according to the percentage of CPAP time that was spent ⩽ Pref. This Peff value was set on a fixed CPAP machine for two additional weeks and a control sleep study was done. The pressure setting on fixed CPAP had to be increased by 1 ± 1 cm H2O (mean ± SD) above estimated Pref. Sleep improved with fixed CPAP, with a normalization of the apnea + hypopnea index (AHI) in 38 of 40 and resumption of diurnal hypersomnolence. CPAP ...
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efficacy of auto cpap in the treatment of obstructive sleep apnea hypopnea syndrome
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Jeanclaude Meurice, Isabelle Marc, Frédéric SérièsAbstract:The auto-CPAP (Morphee Plus) is characterized by its ability to modify the positive-pressure level applied during the night for the presence or absence of sleep-induced respiratory disorders. The aim of the study was to compare the efficacy of this new mode of CPAP therapy with that of conventional constant-CPAP in the treatment of sleep apnea/hypopnea syndrome (SAHS). Sixteen patients with SAHS were randomly allocated to two groups that were paired for age, apnea/hypopnea index, and mean sleep latency. In the auto-CPAP group, the pressure level could change within fixed limits in both directions (+2 to -4 cm H2O) of the previously determined effective pressure level (Peff). In the constant-CPAP group, patients used the same apparatus (Morphee Plus) in a constant mode at Peff level. At the beginning of the study, the Peff level was determined during a polysomnographic recording. Day-time vigilance was measured subjectively by a standardized questionnaire and objectively by the maintenance of wakefulness t...
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Efficacy of auto-CPAP in the treatment of obstructive sleep apnea/hypopnea syndrome.
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Jeanclaude Meurice, Isabelle Marc, Frédéric SérièsAbstract:The auto-CPAP (Morphee Plus) is characterized by its ability to modify the positive-pressure level applied during the night for the presence or absence of sleep-induced respiratory disorders. The aim of the study was to compare the efficacy of this new mode of CPAP therapy with that of conventional constant-CPAP in the treatment of sleep apnea/hypopnea syndrome (SAHS). Sixteen patients with SAHS were randomly allocated to two groups that were paired for age, apnea/hypopnea index, and mean sleep latency. In the auto-CPAP group, the pressure level could change within fixed limits in both directions (+2 to -4 cm H2O) of the previously determined effective pressure level (Peff). In the constant-CPAP group, patients used the same apparatus (Morphee Plus) in a constant mode at Peff level. At the beginning of the study, the Peff level was determined during a polysomnographic recording. Day-time vigilance was measured subjectively by a standardized questionnaire and objectively by the maintenance of wakefulness t...
Vanessa Van Empel - One of the best experts on this subject based on the ideXlab platform.
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validation of the hfa Peff score for the diagnosis of heart failure with preserved ejection fraction
European Journal of Heart Failure, 2020Co-Authors: Arantxa Barandiaran Aizpurua, Sandra Sandersvan Wijk, Hanspeter Brunnerla Rocca, Michiel Henkens, Stephane Heymans, Lauren Beussinknelson, Sanjiv J Shah, Vanessa Van EmpelAbstract:AIMS: Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. The newly proposed HFA-Peff algorithm entails a stepwise approach. Step 1, typically performed in the ambulatory setting, establishes a pre-test likelihood. The second step calculates a score based on echocardiography and natriuretic peptides. The aim of this study is to validate the diagnostic value and establish the clinical impact of the second step of the HFA-Peff score. METHODS AND RESULTS: The second step of the HFA-Peff score was evaluated in two independent, prospective cohorts, i.e. the Maastricht cohort (228 HFpEF patients and 42 controls) and the Northwestern Chicago cohort (459 HFpEF patients). In Maastricht, the HFA-Peff score categorizes 11 (4%) of the total cohort with suspected HFpEF in the low-likelihood (0-1 points) and 161 (60%) in the high-likelihood category (5-6 points). A high HFA-Peff score can rule in HFpEF with high specificity (93%) and positive predictive value (98%). A low score can rule out HFpEF with a sensitivity of 99% and a negative predictive value of 73%. The diagnostic accuracy of the score is 0.90 (0.84-0.96), by the area under the curve of the receiver operating characteristic curve. However, 98 (36%) are classified in the intermediate-likelihood category, where additional testing is advised. The distribution of the score shows a similar pattern in the Northwestern (Chicago) and Maastricht HFpEF patients (53% vs. 65% high, 43% vs. 34% intermediate, 4.8% vs. 1.3% low). CONCLUSION: This study validates and characterizes the HFA-Peff score in two independent, well phenotyped cohorts. We demonstrate that the HFA-Peff score is helpful in clinical practice for the diagnosis of HFpEF.
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Validation of the HFA‐Peff score for the diagnosis of heart failure with preserved ejection fraction
European Journal of Heart Failure, 2019Co-Authors: Arantxa Barandiaran Aizpurua, Sandra Sandersvan Wijk, Hanspeter Brunnerla Rocca, Michiel Henkens, Stephane Heymans, Sanjiv J Shah, Lauren Beussink-nelson, Vanessa Van EmpelAbstract:AIMS: Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. The newly proposed HFA-Peff algorithm entails a stepwise approach. Step 1, typically performed in the ambulatory setting, establishes a pre-test likelihood. The second step calculates a score based on echocardiography and natriuretic peptides. The aim of this study is to validate the diagnostic value and establish the clinical impact of the second step of the HFA-Peff score. METHODS AND RESULTS: The second step of the HFA-Peff score was evaluated in two independent, prospective cohorts, i.e. the Maastricht cohort (228 HFpEF patients and 42 controls) and the Northwestern Chicago cohort (459 HFpEF patients). In Maastricht, the HFA-Peff score categorizes 11 (4%) of the total cohort with suspected HFpEF in the low-likelihood (0-1 points) and 161 (60%) in the high-likelihood category (5-6 points). A high HFA-Peff score can rule in HFpEF with high specificity (93%) and positive predictive value (98%). A low score can rule out HFpEF with a sensitivity of 99% and a negative predictive value of 73%. The diagnostic accuracy of the score is 0.90 (0.84-0.96), by the area under the curve of the receiver operating characteristic curve. However, 98 (36%) are classified in the intermediate-likelihood category, where additional testing is advised. The distribution of the score shows a similar pattern in the Northwestern (Chicago) and Maastricht HFpEF patients (53% vs. 65% high, 43% vs. 34% intermediate, 4.8% vs. 1.3% low). CONCLUSION: This study validates and characterizes the HFA-Peff score in two independent, well phenotyped cohorts. We demonstrate that the HFA-Peff score is helpful in clinical practice for the diagnosis of HFpEF.