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Analysis Supports Initial Combination Therapy For Patients With PAH, Comorbidities

Patients with pulmonary arterial hypertension and cardiopulmonary comorbidities are typically started on monotherapy, but new data suggest some patients would do well with initial combination therapy.

Patients with pulmonary arterial hypertension (PAH) and one or two cardiac comorbidities experience a similar benefit from initial combination therapy with macitentan (Opsumit) and tadalafil (Cialis) as patients without comorbidities, according to a new analysis.

The findings are important because they call into question existing guidelines for patients with cardiopulmonary comorbidities, which suggest beginning with initial monotherapy with either an endothelin receptor antagonist (ERA; e.G. Macitentan) or phosphodiesterase 5 inhibitor (PDE5i; e.G. Tadalafil) and then escalating as appropriate based on individual patient responses.

The new analysis comes as the demographics and characteristics of people diagnosed with PAH appear to have shifted in recent decades. For instance, a 2016 study from Sweden found the majority of patients diagnosed with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) were over the age of 65, and tended to have "several" comorbidities, including systemic hypertension, diabetes, ischemic heart disease, and atrial fibrillation.

Similarly, a 2012 report based on a registry of patients with pulmonary hypertension in the United Kingdom and Ireland suggested that patients were being diagnosed at older ages, and that those patients were more likely to have more comorbidities but also better survival. At the time, the investigators said the change might be due to changes in referral patterns, rather than changes in the actual disease.

For instance, they noted an increase in referrals to pulmonary hypertension specialty centers over the years of the study. An alternative cause, they said, could be that there were emerging subtypes of the disease: older patients with more comorbidities and younger patients with fewer comorbidities, higher functional capacity, and more severe hemodynamic impairment.

Vallerie V. McLaughlin, MD, of the University of Michigan, and colleagues, noted that to date there is limited data on the use of initial combination therapy in patients with few comorbidities. In a new study published in the European Journal of Heart Failure, they explain that more data are needed to better understand how to tailor treatment to individual patients and risk profiles.

"While this stepwise approach may particularly resonate for older patients with a high cardiopulmonary comorbidity burden, the question remains whether a more aggressive treatment strategy with initial combination therapy would be beneficial for younger patients with a lower comorbidity burden," they wrote.

Fortunately, they said data already exist regarding how patients with PAH and 1-2 cardiac comorbidities respond to initial combination macitentan and tadalafil—it just needed to be analyzed. The authors turned to the TRITON and REPAIR studies, both of which included patients who received initial combination therapy. The investigators noted that most trials now exclude patients with pulmonary comorbidities or with 3 or more cardiac comorbidities, but patients with 1-2 cardiac comorbidities are generally included.

McLaughlin and colleagues identified a set of 148 patients between the two studies who weretreated with initial macitentan and tadalafil combination therapy. From that pool, they constructed two subgroups of patients: those with no cardiac comorbidities (62 participants), and those with one or two cardiac comorbidities (78 participants). Overall, patients in the two trials had a median duration of exposure to the combination of 513.0 days, which the authors said was similar between the two subgroups.

From baseline to week 26, both groups benefited from the combination. The no-comorbidity subgroup had an average reduction of pulmonary vascular resistance (PVR) of 55%, an improvement of six-minute walking distance (6MWD) of 67 meters, and a reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) of 77%.

In the group with one or two comorbidities, participants had a 50% reduction of PVR, 54-meter increase in 6MWD, and 76% decrease in NT-proBNP. Patients in both groups also had improvement inWorld Health Organization functional class, McLaughlin and colleagues found. Both cohorts had similar safety profiles, and their experiences were consistent with previously reported safety data, the authors said.

The investigators said this information should be helpful to clinicians treating newly diagnosed patients, though they cautioned that comorbidity burden should be assessed on an individualized basis.

"It is important to acknowledge that comorbidity burden cannot be measured by simply counting the number of comorbidities; information on severity, duration and controlled/not controlled status must also be considered," they wrote.

However, they concluded that these data suggest some patients with comorbidities might be good candidates for initial combination therapy.

PAH Risk Scoring Systems Can Also Predict Survival In Pulmonary Hypertension

Risk stratification scoring systems designed for pulmonary arterial hypertension (PAH) that include 3 or 4 strata can also predict survival in patients with non-PAH pulmonary hypertension (PH), according to study findings published in Chest.

Researchers assessed whether risk scores originally developed for PAH had prognostic value in pulmonary hypertension groups 1 to 4. Toward that end, the researchers compared how well several major 3- and 4-strata PAH risk scoring systems predicted PH survival in patients who enrolled in the Pulmonary Vascular Research Institute (PVRI) GoDeep meta-registry.

Patients included for analysis had a right heart catheter-confirmed PH diagnosis from a participating PH expert center and were at least 18 years of age at diagnosis. The analysis included the REVEAL Lite 2 risk score, the REVEAL 2.0 risk score, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 risk score, and the COMPERA registry 3-/4-strata risk scores.

The PVRI GoDeep meta-registry had 27,070 patients on October 16, 2023, including 8565 incident and treatment-naïve patients in 15 PH centers. Among the cohort, 3537(41%) patients were diagnosed with group 1 PH, 1807 (21%) had group 2 PH, 1635 (19%) had group 3 PH, and 1586 (19%) patients had group 4 PH. Their median age was 65 (range, 52-74) years, and 39% were male. The median pulmonary arterial pressure was 42 (range, 33-52) mm Hg, and the median pulmonary vascular resistance was 7 (range, 4-11) WU.

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This comprehensive study with real-world data from 15 PH centers substantially extends our understanding of the predictive power of PAH-designed risk scores, including their potential application in PH patients beyond the PAH group.

All the risk scores predicted survival for patients with incident PH. The REVEAL scores were significantly better than the ESC/ERS risk 2022 score and compared favorably to the COMPERA registry 3-strata risk score. Among patients with REVEAL Lite 2.0 score of 6 or less, the overall 1-, 3-, and 5-year survival rates were 93%, 78%, and 66%, respectively, including patients in all PH groups. Those with higher scores had a significantly worse prognoses.

In univariate Cox regression analysis, significantly increased hazard ratios were confirmed for each point increase in REVEAL 2.0 and REVEAL Lite 2, compared with patients with a total score of 6 points or less. The COMPERA registry 4-strata risk score was able to discriminate between intermediate-low and intermediate-high risk patients and significantly outperformed the ESC/ERS risk 2022 score.

In PH group-based analyses, all included risk scores predicted survival in PH groups 1 to 4. The ESC/ERS 2022 risk score had an uneven distribution with strong predominance of the intermediate risk score group for the 4 PH groups. The COMPERA 4-strata risk score discriminated intermediate-low and intermediate-high patients in all groups. REVEAL scores C-indices in a continuous scoring system were the highest for each individual PH group.

PAH-designed 3- and 4-strata risk scores had predictive power in each subgroup, with strong discrimination of the continuous REVEAL scores and efficacy of the 4-strata risk score to discriminate between intermediate-low and intermediate-high cohorts.

Similar results were observed when dichotomizing the overall PH cohort and each PH group for severe vs nonsevere PH (PVR ≥5 WU and PVR <5 WU).

Limitations include the retrospective study design, the ability to perform only limited subgroup analyses, and possible selection bias.

"This comprehensive study with real-world data from 15 PH centers substantially extends our understanding of the predictive power of PAH-designed risk scores, including their potential application in PH patients beyond the PAH group," the investigators stated.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors' disclosures.

This article originally appeared on Pulmonology Advisor

Ventricular Septal Defect (VSD) Repair

Content

Heart defect repair is surgery to fix a heart problem that prevents blood from flowing as it should through the heart. The doctor will make a large cut in your chest. The cut is called an incision. It usually is made through the breastbone (sternum). But some types of heart defects are repaired through a cut in the side of the chest between the ribs. The doctor will connect you to a machine that does the jobs of the heart and lungs. It's called a heart-lung bypass machine. This machine lets the doctor stop your heart while working on the heart.

After the heart is repaired, the doctor will restart your heart. Then the doctor will disconnect the heart-lung machine. He or she will use stitches to close the incision in your chest.

Some heart defects can be fixed with one surgery. But you may need more than one surgery to fix the defect.

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