RU2853037C1 - Method for predicting the effectiveness of therapy including selexipag in patients with pulmonary arterial hypertension - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention can be used to predict the effectiveness of selexipag therapy in patients with pulmonary arterial hypertension (PAH). To implement the method, the level of brain natriuretic peptide (NT-proBNP) in the blood is determined. In addition, the duration of the period from the diagnosis of PAH to the moment of prescribing selexipag is established in months, the functional class (FC) (WHO), the distance covered in the 6-minute walk test in metres (6MWT), the right atrial area in cm² (RAA), and the cardiovascular coupling between the right ventricle and the pulmonary artery (TAPSE/PLA) in mm/mm Hg. A period of 0 months from the diagnosis of PAH to the prescription of selexipag, an NT-proBNP level of less than 300 pg/ml, a PP area of less than 18 cm², a TAPSE/PAP pressure ratio of more than 0.32 mm/mm Hg, I-II FC (WHO), D6MX greater than 440 m predict the effectiveness of seleksipag therapy. If the period from the diagnosis of LAH to the prescription of seleksipag is more than 0 months, NT-proBNP level is greater than or equal to 300 pg/ml, LVEDD is ≥ 18 cm², TAPSE/LVEDD ratio is less than or equal to 0.32 mm/mm Hg, III-IV FC (WHO), D6MCH less than or equal to 440 m predict the ineffectiveness of selexipag therapy as part of combined LAG-specific therapy regimens and adjust the LAG-specific therapy regimen.

EFFECT: method is effective and facilitates accurate prediction of the effectiveness of LAG therapy.

1 cl, 1 tbl, 3 ex

Description

The invention relates to medicine, in particular to cardiology and pulmonology, and can be used to predict the effectiveness of specific therapy for patients with pulmonary arterial hypertension (PAH).

According to the World Health Organization, pulmonary arterial hypertension (PAH) is one of the most dangerous cardiovascular diseases, with a high incidence of serious complications. In the compensated stage, this disease may not manifest any symptoms and only become apparent as severe forms develop. Pulmonary arterial hypertension (PAH) is a pathological condition in which the pressure in the pulmonary artery trunk (PA) at rest exceeds 25 mmHg, with a normal range of 9-16 mmHg. This condition can be either independent (primary) or secondary. Primary PAH is a relatively rare condition, occurring in up to 1% of all patients with this condition. PAH is most often a complication resulting from diseases of the heart, blood vessels, and other organs and systems. Untreated PAH can lead to heart failure and death. Therefore, a successful outcome directly depends on appropriate medication.

A method is known for predicting the effectiveness of treatment of patients with pulmonary hypertension using captopril, in which the initial level of angiotensin II (AN) in ng/l is examined and the discriminant equation D=0.362-AII is solved, and with a value of D>12.30 a positive therapeutic effect from the use of captopril is predicted, and with D<12.30 the absence of a positive therapeutic effect is predicted.

(Patent of the Russian Federation No. 2111748, IPC A61K 31/40, published May 27, 1998)

Low prediction accuracy is a drawback of this method, as drugs that affect the renin-angiotensin-aldosterone system are not recommended for the treatment of patients with PAH. Therefore, assessing angiotensin II levels is no longer a relevant approach for predicting the effectiveness of PAH-specific therapy.

The 2015 guidelines of the European Cardiology and European Respiratory Society proposed a mortality risk stratification scale developed for patients with PAH and based on the clinical, functional, and hemodynamic status, the severity of right heart remodeling, and the level of N-terminal pro-brain natriuretic peptide (NT-proBNP). For a comprehensive assessment of the status of patients with PAH at baseline and over time, it is important to consider clinical data, cardiopulmonary exercise test results, biochemical markers, hemodynamic and echocardiographic (EchoCG) parameters, etc. Low, intermediate, or high-risk status in patients with PAH corresponds to a 1-year mortality rate of <5%; 5-10%, and >10%, respectively. In a specific patient, clinical, functional, and hemodynamic status parameters, laboratory tests, EchoCG/MRI data, etc. may belong to different risk categories. In the presence of even a single factor indicating a higher risk of mortality, the initial and achieved risk in patients with PAH is aggravated, which should be taken into account when choosing treatment tactics.

Among the laboratory markers of prognosis, brain natriuretic peptide (BNP) and NT-proBNP retain the greatest significance; their levels reliably correlate with indicators of functional and hemodynamic status, as well as the structural and functional state of the right ventricle (RV). Thus, a BNP level of <50 pg/ml and NT-proBNP level of <300 pg/ml indicate a low risk of death. Accordingly, when assessing this indicator dynamically during therapy, this value will reflect the achievement of treatment goals and its effectiveness. While a BNP level of >300 pg/ml and NT-proBNP level of >1400 pg/ml reflect a high risk of death within a year and, accordingly, when assessing it dynamically during therapy, reflect treatment ineffectiveness for patients with PAH.

[Galie N., Humbert M, Vachiery J.L., et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016. 37(1): 67-119].

However, the assessment of these markers is carried out in conjunction with both non-invasive and invasive parameters for a comprehensive assessment of the prognosis of a fatal outcome.

There is also known a method for predicting the effectiveness of long-term therapy in patients with pulmonary hypertension by examining the patient and determining the level of pro-brain natriuretic peptide (NT-proBNP) in the blood, wherein the examination is carried out at the time of initiation of therapy with determination of the right ventricular end-diastolic volume (RV EDV) and the level of NT-proBNP and 12 months after the start of therapy, repeated determination of the NT-proBNP level, after which the effectiveness of long-term therapy is determined by the indicator of the dynamics of the NT-proBNP level over 12 months in combination with the RV EDV at the time of initiation of therapy, and when the NT-proBNP level reaches <30.4 pg / ml after 12 months in combination with the RV EDV <150.5 ml at the time of initiation of therapy, its effectiveness is predicted, and with values 12 months from the start of therapy of the NT-proBNP level> 30.4 pg / ml at the time of initiation of therapy, or the NT-proBNP level <30.4 pg/ml in combination with the value of the prostate end-diastolic volume>150.5 ml predicts the ineffectiveness of the therapy.

(Patent of the Russian Federation No. 2729033, IPC G01N 33/48, published on August 3, 2020, Bulletin No. 22)

The disadvantage of this method is its lack of selectivity in relation to drugs used for PAH-specific therapy, as well as the need to repeat the measurement of indicators after 12 months to predict the effectiveness.

The objective of the invention is to create an accurate and effective method for predicting the effectiveness of therapy, including selexipag, in patients with pulmonary arterial hypertension, allowing for adjustment of the PAH-specific therapy regimen, thereby ensuring monitoring of the patient's condition, optimizing the prevention of the risk of unwanted complications and increasing the effectiveness of treatment.

The technical result is an increase in the efficiency and accuracy of forecasting.

This is achieved by the fact that in the claimed method for predicting the effectiveness of long-term specific therapy in patients with PAH by examining the patient at the time of initiation of therapy and determining the NT-proBNP level in the blood, according to the invention, the duration of the period from the diagnosis of PAH to the time of possible prescription of selexipag in months, the functional class (FC) (WHO), the distance in the 6-minute walk test in meters (D6MWT), the area of the right atrium in cm ² (S RA), the value of the cardiovascular coupling between the right ventricle and the pulmonary arteries (TAPSE/SPPA) in mm / mm Hg are additionally established and with a duration of the time period from the diagnosis of PAH to the possible prescription of selexipag of 0 months, an NT-proBNP level of less than 300 pg / ml, an RA area of less than 18 cm ² , a TAPSE / SPPA ratio of more than 0.32 mm / mm Hg. art., I-II FC (WHO), the D6MH value of more than 440 m is predicted to be effective with selexipag therapy, and if the period from the diagnosis of PAH to the possible prescription of selexipag is more than 0 months, the NT-proBNP level is more than or equal to 300 pg/ml, the PP area is ≥18 ^cm2 , the TAPSE/SPLA ratio is less than or equal to 0.32 mm/mmHg, III-IV FC (WHO), the D6MH value is less than or equal to 440 m, the ineffectiveness of selexipag therapy as part of combination PAH-specific therapy regimens is predicted, which requires correction of the PAH-specific therapy regimen.

Despite significant progress in the development of new drugs for PAH-specific therapy over the past several decades, PAH remains a severe disease with a poor prognosis in this patient population. Nonspecific symptoms and the subtle clinical presentation at onset increase the time to diagnosis and treatment. The importance of timely diagnosis and regular assessment of the risk of PAH progression is enshrined in current clinical guidelines for both Russian and European patients and is fundamental when prescribing PAH-specific therapy. The primary goal of PAH therapy is to achieve and maintain a low risk of poor prognosis.

The efficacy of selexipag was first evaluated in the largest randomized clinical trial, GRIPHON, its open-label continuation, GRIPHON OL, and in large international registries on the use of selexipag as part of PAH-specific therapy regimens in real-world clinical practice, SPHERE and EXPOSURE. Improvement in functional status, hemodynamic parameters, and right heart function, regardless of the etiology and initial PAH-specific therapy regimen, was achieved in each of the above-mentioned studies. An important result of the randomized clinical trial, GRIPHON, was an increase in the time to the first event (PAH deterioration/death) by 40% (OR=0.60; 99% CI 0.46-0.78; p<0.001), regardless of the PAH etiology, initial severity of the patient's condition, or the PAH-specific therapy regimen.

Implementation of the method.

In a patient with an established diagnosis of pulmonary arterial hypertension (PAH); In PAH associated with systemic connective tissue disease (PAH-CTD), residual PAH after correction of congenital heart disease (PAH-CHD), before deciding on the choice of a PAH-specific therapy regimen including selexipag, the following parameters are analyzed: the duration of the period from the diagnosis of PAH to the moment of possible prescription of selexipag in months, functional class (FC) (WHO), the distance in the 6-minute walk test in meters (D6MWT), the level of the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) in pg / ml, the area of the right atrium in cm ² (S RA), the value of cardiovascular coupling between the right ventricle and pulmonary arteries (the ratio of the systolic excursion of the tricuspid annulus to the systolic pressure in the pulmonary artery) (TAPSE / SPPA) in mm / mm Hg.

If the time period from PAH diagnosis to possible prescription of selexipag is 0 months, NT-proBNP level <300 pg/ml, RA area <18 ^cm2 , TAPSE/SPPA ratio >0.32 mm/mmHg, WHO FC I-II, 6MH value >440 m, the effectiveness of selexipag therapy is predicted as part of PAH-specific combination therapy regimens, and if the time period from PAH diagnosis to possible prescription of selexipag is >0 months, NT-proBNP level ≥300 pg/ml, RA area ≥18 ^cm2 , TAPSE/SPPA ratio ≤0.32 mm/mmHg, Art., III-IV FC (WHO), the value of D6MH≤440 m predicts the ineffectiveness of selexipag therapy as part of combination PAH-specific therapy regimens, which requires correction of the PAH-specific therapy regimen.

Clinical examples,

Example 1. In patient B., 38 years old, with pulmonary arterial hypertension, clinical improvement was predicted before the administration of selexipag according to the claimed method for predicting the effectiveness of PAH-specific therapy. The patient's baseline profile included the time period from the diagnosis of PAH to the administration of selexipag of 0 months, NT-proBNP level of 155.1 pg/ml, SPP of 12 ^cm2 , TAPSE/SPPA ratio of 0.38 mm/mmHg. art., II FC (WHO), D6MX 525 m. After 6 months of taking combined PAH-specific therapy, including selexipag, patient B. achieved three improvement parameters according to the French non-invasive scale: II FC (WHO) (1-II), D6MX 560 m (>440 m), NT-proBNP level 151.7 pg/ml (<300 pg/ml), which indicates the effectiveness of the therapy, including selexipag.

Example 2. In patient M., 59 years old, with PAH-CTD, according to the claimed method for predicting the effectiveness of PAH-specific therapy, at the time of therapy escalation, an unfavorable prognosis was noted in case of the prescription of selexipag. When assessing the patient's initial profile, the time period from the diagnosis of PAH to the prescription of selexipag was 4 months, the NT-proBNP level was 1896 pg/ml, S PP 32 cm ² , the TAPSE/SPPA ratio was 0.2 mm/mm Hg, III FC (WHO), 6MH 300 m. Due to the predicted ineffectiveness of selexipag therapy, patient M. was prescribed starting PAH-specific therapy with inhaled iloprost, sildenafil and macitentan.

Example 3. In patient P., 35 years old, with PAH-CHD, according to the claimed method for predicting the effectiveness of PAH-specific therapy, at the time of therapy escalation, an ineffective prognosis was noted in case of the prescription of selexipag. When assessing the patient's baseline profile, the time period from the diagnosis of PAH to the prescription of selexipag was 204 months, the NT-proBNP level was 2113 pg/ml, S PP 22 cm ² , the TAPSE/SPLA ratio was 0.09 mm/mm Hg, III FC (WHO), 6MH 250 m. Due to the predicted ineffectiveness of selexipag therapy, the patient was prescribed inhaled iloprost in addition to the ongoing therapy with sildenafil and macitentan.

The study included an analysis of various scales for stratifying the risk of poor prognosis. The efficacy of PAH-specific therapy, including selexipag, was assessed using a French non-invasive scale that utilizes the achievement of three improvement parameters (functional class (FC) (WHO) I-II, 6-minute walk test (6MWD)>440 m, N-terminal pro-brain natriuretic peptide (NT-proBNP) level <300 pg/ml) when assessing patients' condition after 6 months of selexipag therapy compared with baseline data. Patients were divided into two subgroups: those who achieved three clinical improvement factors (n=21) and those who did not (n=56). Comparative characteristics between patient groups depending on the achievement of improvement factors are shown in Table 1.

According to the logistic analysis, it was revealed that the predictors of failure to achieve a clinical response when prescribing selexipag were a long period of time from the diagnosis of PAH to the prescription of selexipag (>0 months), an elevated level of NT-proBNP (≥300 pg/ml), an increase in the area of the RA (≥18 ^cm2 ), a decrease in the TAPSE/SPLA ratio (≤0.32 mm/mmHg), worsening of FC (WHO) (to III-IV), a decrease in the value of 6MH (≤440 m).

Thus, the use of selexipag as part of combination PAH-specific therapy regimens in patients with preserved functional status, no manifestations of heart failure, normal RA area, and an initial TARSE/SPLA ratio of > 0.32 corresponds to the profile of a patient with a potential clinical response when prescribed selexipag.

Claims (1)

A method for predicting the effectiveness of therapy including selexipag in patients with pulmonary arterial hypertension by examining the patient at the time of initiation of therapy and determining the level of pro-brain natriuretic peptide (NT-proBNP) in the blood, characterized in that the duration of the period from the diagnosis of pulmonary arterial hypertension (PAH) to the time of possible prescription of selexipag in months, the functional class (FC) (WHO), the distance in the 6-minute walk test in meters (D6MWT), the area of the right atrium in ^cm2 (S RA), the value of cardiovascular coupling between the right ventricle and the pulmonary arteries (TAPSE/SPPA) in mm/mmHg are additionally established. and if the time period from the diagnosis of PAH to the possible prescription of selexipag is 0 months, the NT-proBNP level is less than 300 pg/ml, the RA area is less than 18 ^cm2 , the TAPSE/SPPA ratio is more than 0.32 mm/mmHg, I-II FC (WHO), the 6MH value is more than 440 m, the effectiveness of selexipag therapy is predicted, and if the time period from the diagnosis of PAH to the possible prescription of selexipag is more than 0 months, the NT-proBNP level is more than or equal to 300 pg/ml, the RA area is ≥18 ^cm2 , the TAPSE/SPPA ratio is less than or equal to 0.32 mm/mmHg. Art., III-IV FC (WHO), the value of D6MX less than or equal to 440 m predicts the ineffectiveness of selexipag therapy as part of combination PAH-specific therapy regimens, which requires correction of the PAH-specific therapy regimen.