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Adempas for PAH-CHD:
A subgroup of the PATENT-1 Study

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THE PAH-CHD PUBLICATION PDF Download

PAH-CHD = pulmonary arterial hypertension associated with congenital heart disease; PATENT-1 = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial.

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Dr. Mandras discuss the PATENT-1 study and PAH-CHD subgroup data

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    PATENT-1 Full Data Set

    PATENT-1 Study Design

    PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)1

    Randomized, double-blind, multinational, placebo-controlled, 12-week, phase 3 study

    Chart of PATENT-1 study design

    Primary endpoint1

    • Change in 6MWD from baseline to Week 12

    Baseline characteristics1

    • Mean age: 51 years (approximately 80% female)
    • PAH etiologies: idiopathic (61%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), familial (2%), or anorexigen or amphetamine use (1%)
    • Mean 6MWD was 363 m
    • Concomitant medications: oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed
    • Patient population: 50% treatment naïve, 44% pretreated with an endothelin receptor antagonist (ERA), and 6% pretreated with a prostacyclin analog (PCA)
    • The majority of patients had WHO FC II (42%) or III (54%) at baseline
    • Patients with systolic blood pressure <95 mm Hg were excluded

    6MWD = 6-minute walk distance; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PATENT-1 = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial; PVR = pulmonary vascular resistance; WHO FC = World Health Organization Functional Class.

    PATENT-1 Results

    IMPROVEMENT IN 6MWD WAS OBSERVED AT 2 WEEKS AND CONTINUED THROUGH 12 WEEKS

    SIGNIFICANT IMPROVEMENT IN 6MWD AT WEEK 12

    Chart of PATENT-1 6MWD results 36m improvement over placebo*

    6MWD = 6-minute walk distance; CI = confidence interval.

    Adempas can be used as monotherapy or in combination

    • In WHO FC II and III
    • As monotherapy
    • In combination with endothelin receptor antagonists (ERAs)
    • In combination with prostacyclin analogs (PCAs)

    50% MORE PATIENTS IMPROVED WHO FC ON ADEMPAS VS PLACEBO

    CHANGE IN WHO FC IN THE 12-WEEK PATENT-1 STUDY

    Chart of PATENT-1 WHO FC results

    ITT = intention-to-treat.

    ADEMPAS SIGNIFICANTLY DELAYED TIME TO CLINICAL WORSENING†

    Chart of PATENT-1 time to clinical worsening results

    †Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD, and persistent worsening of WHO FC.

    ‡The Kaplan-Meier plot of time to clinical worsening is presented in the figure above. Patients treated with Adempas experienced a significant delay in time to clinical worsening vs placebo-treated patients (p=0.0046; stratified log-rank test). Significantly fewer events of clinical worsening up to Week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate).

    ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 12

    Display of PATENT-1 hemodynamic results

    Right heart catheterization was performed at the beginning and end of the study period in 339 patients.
    NT-proBNP = n-terminal prohormone of brain natriuretic peptide; PVR = pulmonary vascular resistance.
    §Placebo-adjusted mean change from baseline.

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    PAH-CHD Subgroup

    PATENT-1 Study Design

    PATENT-1: A RANDOMIZED, DOUBLE-BLIND, MULTINATIONAL, MULTICENTER, PLACEBO-CONTROLLED PHASE 3 STUDY

    Chart of PATENT-1 study design: full data set

    BASELINE CHARACTERISTICS1,2

    Table of PATENT-1 full data set and PAH-CHD subgroup baseline characteristics
    Table of PATENT-1 full data set and PAH-CHD subgroup baseline characteristics
    Table of PATENT-1 full data set and PAH-CHD subgroup baseline characteristics
    • Efficacy data were only measured for the Adempas 2.5 and placebo arms
    • Concomitant medications: oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed
    • Patients with systolic blood pressure <95 mm HG were excluded
    • PATENT-1 PAH etiologies: idiopathic (61%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), familial (2%), or anorexigen or amphetamine use (1%)
    • CHD subtypes include corrected atrial septal defect, corrected ventricular septal defect, corrected persistent ductus arteriosus, and not specified1

    6MWD = 6-minute walk distance; SD = standard deviation; WHO FC = World Health Organization Functional Class.
    *exploratory subgroup analysis.

    PATENT-1 MEAN TREATMENT DIFFERENCE IN CHANGE FROM BASELINE TO LAST VISIT IN 6-MINUTE WALK DISTANCE (METER) BY PRESPECIFIED SUBGROUPS

    Table of PATENT-1 change in 6MWD results by patient subgroup

    PATENT-1 Results in the CHD Subgroup

    Data from the PAH-CHD subgroup analysis are exploratory, as PATENT-1 was not designed to show statistically significant differences in subgroup populations. The primary efficacy analysis was performed on data from the modified intent-to-treat population (all patients who were randomized and received one or more doses of the study drug). The data presented here are observed values and are analyzed descriptively; observed values were used due to the small sample size and the retrospective, exploratory nature of the analyses. The low patient numbers in the PAH-CHD subgroup should be taken into consideration when interpreting the data. Time to clinical worsening was not evaluated in the PAH-CHD subgroup within the PATENT-1 study.

    CHANGE IN 6MWD FROM BASELINE AT WEEK 121

    EXPLORATORY POST HOC SUBGROUP ANALYSIS

    Chart of PAH-CHD subgroup 6MWD results

    CHANGE IN WHO FC FROM BASELINE AT WEEK 121

    EXPLORATORY POST HOC SUBGROUP ANALYSIS

    Chart of PAH-CHD subgroup WHO FC results

    PVR AND NT-proBNP VALUES AT WEEK 121

    EXPLORATORY POST HOC SUBGROUP ANALYSIS

    Display of PAH-CHD subgroup hemodynamics results

    PAH-CHD IS A FORM OF ASSOCIATED PAH (WHO GROUP 1)1

    • CHD (congenital heart disease) refers to a range of cardiac defects resulting from structural abnormalities of the heart or blood vessels that develop before birth and can result in impaired cardiac blood flow3,4
      — PAH-CHD is the second most common form of associated PAH in adults1,5,6
    • 5-10% of adult patients with CHD will develop PAH6
    • PAH-CHD in adults is challenging to manage, due to the heterogeneous nature of the disease and an increase in comorbidities
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    MORE IMPORTANT SAFETY INFORMATION LESS IMPORTANT SAFETY INFORMATION
    Important Safety Information and Indications

    WARNING: EMBRYO-FETAL TOXICITY

    Do not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm.

    Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and one month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for one month after stopping treatment.

    For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

    Contraindications

    Adempas is contraindicated in:

    • Pregnancy. Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
    • Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form.
    • Concomitant administration with specific phosphodiesterase (PDE)-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.
    • Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators.
    • Patients with Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (PH-IIP).
    Warnings and Precautions

    Embryo-Fetal Toxicity. Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with Adempas and for at least one month after the last dose. 

    For females, Adempas is only available through a restricted program under the Adempas REMS Program. 

    Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program. 

    Important requirements of the Adempas REMS Program include the following: 

    • Prescribers must be certified with the program by enrolling and completing training.
    • All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
    • Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
    • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.

    Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.

    Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension. 

    Bleeding. In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter-site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. 

    Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas. 

    Most Common Adverse Reactions

    The most common adverse reactions occurring more frequently (≥3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%).

    Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension, and peripheral edema. 

    Indications
    • Adempas (riociguat) is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class.
    • Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.*

    Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominantly patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). 

    *Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD, and persistent worsening of WHO functional class.

    For important risk and use information, please see the full Prescribing Information, including Boxed Warning.

    References:

    1. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
    2. Galiè N, Humbert M, Vachiery JL, et al. ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.
    3. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D73-D81.

    References:

    1. Rosenkranz S, Ghofrani H-A, Beghetti M, et al. Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart. 2015;101(22):1792-1799.
    2. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
    3. Zaidi S, Brueckner M. Genetics and genomics of congenital heart disease. Circ Res. 2017;120(6):923-940.
    4. US Department of Health and Human Services, CDC website. What are congenital heart defects? Published January 24, 2022. Accessed June 10, 2022. 
      https://www.cdc.gov/ncbddd/heartdefects/facts.html
    5. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263.
    6. Opotowsky AR. Clinical evaluation and management of pulmonary hypertension in the adult with congenital heart disease. Circ. 2015;131(2):200-210. 

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