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Correspondence |

Effect of Weight on Parenteral Prostacyclin Analogues Dosing in Pulmonary Hypertension FREE TO VIEW

Pejman Raeisi-Giglou, DO; Xiao-Feng Wang, PhD; Wael Dakkak, MD; Nancy Bair, CNS; Raed A. Dweik, MD; Adriano R. Tonelli, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

FUNDING/SUPPORT: A. R. T. is supported by the National Institutes of Health [Grant R01HL130307].

aDepartment of Hospital Medicine, Cleveland Clinic, Cleveland, OH

bRespiratory Institute Biostatistics Core, Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH

cDepartment of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH

dDepartment of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL

CORRESPONDENCE TO: Adriano R. Tonelli, MD, Respiratory Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(5):1189-1192. doi:10.1016/j.chest.2017.01.043
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Published online

Parenteral prostacyclin analogues (PPAs) are potent medications for the treatment of advanced forms of pulmonary arterial hypertension.,, The Food and Drug Administration approved PPAs, including IV epoprostenol and IV or subcutaneous treprostinil, which are both dosed based on weight (ng/kg/min). Given the narrow therapeutic range of PPAs, variations in weight may have important consequences on the adjusted dose of these medications. Current guidelines do not elaborate on how to manage the dosing of PPAs in the setting of pronounced weight variations. We hypothesize that weight changes after the initiation of PPAs may be pronounced in certain patients with pulmonary hypertension (PH), resulting in prominent differences in PPA dosing.

This retrospective study was approved by the Cleveland Clinic institutional review board (study No. 15-1649). Written informed consent was waived. Patients had to receive a minimum of 3 months of PPAs and be evaluated in person at our PH clinic both at baseline and at 3 months to allow for at least two weight determinations. We defined baseline weight as the one obtained immediately before the initiation of PPAs, and actual weight as the one measured at each follow-up interval. We recorded weight and doses of PPAs at baseline, 3, 6, 9, 12, 24, 36, 48, and 60 months. We obtained data on the 6-min walk test, echocardiogram, and right heart catheterization both at baseline and 1 year. Side effects associated with PPAs were recorded at each study time interval.

We included a total of 114 patients with PH (mean age ± SD, 46 ± 14 years), and 87 (76.3%) were women. Etiology of PH was predominantly pulmonary arterial hypertension (n = 107; 94%) and less commonly chronic thromboembolic PH (n = 5; 4%) or sarcoidosis (n = 2, 2%). Patients were treated with either parenteral epoprostenol (n = 64; 56%) or treprostinil (n = 50; 44%). At baseline, weight was 85.2 ± 24.2 kg (range, 39.9-190 kg). Variations in weight relative to the baseline determination became more pronounced over time. In fact, at 1 and 3 years, 20% and 24% of the patients lost > 10 kg, respectively (Table 1). The median dose difference in PPAs when using baseline instead of actual weight was < 5 ng/kg/min at any interval; however, the range was wide with variations > 40 ng/kg/min (Fig 1). When adjusting for actual weight, as opposed to baseline weight, 13% and 26% of the subjects received a dose ≥ 10 ng/kg/min at 1 and 3 years, respectively. The number of side effects was not associated with the difference between the PPA doses adjusted by baseline or actual body weight. At 12 months, the difference between the PPA dose adjusted by baseline or actual weight did not track with the change in 6-min walk distance, right ventricular systolic pressure and right ventricular function by echocardiography and right atrial pressure, pulmonary artery pressure, cardiac index, and pulmonary vascular resistance during right heart catheterization.

Table Graphic Jump Location
Table 1 Weight Change After Initiation of Parenteral Prostacyclin Analogues

Variations in weight compared with baseline became more pronounced with time, with a maximum median weight loss at 3 y. Less than 3% of the patients gained > 10 kg at any time interval. IQR = interquartile range.

Figure Jump LinkFigure 1 Box plots of doses of PPAs adjusted by baseline or actual weight. At each time point, the difference in PPA dose when adjusted for baseline or actual weight was statistically significant (all P values < .01). Mixed linear model revealed that the average dose of PPAs when using actual weight is 2.71 ng/kg/min higher than when using baseline weight and that this difference increased by 1.14 ng/kg/min every month. PPA = parenteral prostacyclin analogue.Grahic Jump Location

Potential alternatives to manage weight changes during treatment with PPAs include to always use the baseline or dosing weight, which will provide a constant variable and adjust the PPA dose based on measurements of efficacy or side effects, independently of weight variations. Another alternative is to adjust the PPA dose based on the weight measured at each follow-up visit. Even though this method would provide a precise dosing at a given point in time, it is unclear which magnitude of weight variation should trigger the adjustment and whether this more demanding approach leads to a more conservative up-titration of PPAs. We use baseline weight for PPA dosing, and only adjust by the actual body weight when variations are ≥ 10 kg. If patients develop side effects related to PPA administration, or if there is concern for a hyperdynamic state, we would measure the patient’s weight and calculate the PPA dose to determine whether the dose discrepancy could explain these findings. If a patient loses weight and has no PPA side effects, we do not down-titrate the PPAs.

In conclusion, after the initiation of PPAs, there is a significant weight loss that may impact the dose of this medication when baseline instead of actual weight is used for adjustment. The dose difference between the two methods did not track with the incidence of side effects, frequency of high cardiac output state, or measurements of efficacy.

References

Galie N. .Corris P.A. .Frost A. .et al Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60-D72 [PubMed]journal. [CrossRef] [PubMed]
 
Galie N. .Humbert M. .Vachiery J.L. .et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67-119 [PubMed]journal. [CrossRef] [PubMed]
 
McLaughlin V.V. .Shillington A. .Rich S. . Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Box plots of doses of PPAs adjusted by baseline or actual weight. At each time point, the difference in PPA dose when adjusted for baseline or actual weight was statistically significant (all P values < .01). Mixed linear model revealed that the average dose of PPAs when using actual weight is 2.71 ng/kg/min higher than when using baseline weight and that this difference increased by 1.14 ng/kg/min every month. PPA = parenteral prostacyclin analogue.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Weight Change After Initiation of Parenteral Prostacyclin Analogues

Variations in weight compared with baseline became more pronounced with time, with a maximum median weight loss at 3 y. Less than 3% of the patients gained > 10 kg at any time interval. IQR = interquartile range.

References

Galie N. .Corris P.A. .Frost A. .et al Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60-D72 [PubMed]journal. [CrossRef] [PubMed]
 
Galie N. .Humbert M. .Vachiery J.L. .et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67-119 [PubMed]journal. [CrossRef] [PubMed]
 
McLaughlin V.V. .Shillington A. .Rich S. . Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482 [PubMed]journal. [CrossRef] [PubMed]
 
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