Showing posts with label PULMONARY HYPERTENSION. Show all posts
Showing posts with label PULMONARY HYPERTENSION. Show all posts

Bayer withdraws Phase 2 Trial of PH drug in IPF due to death risk

By Dr Deepu


Potentially higher risk of death seen in people with rare disease that has no approved treatments

Bayer has stopped a Phase 2 clinical trial (NCT02138825) evaluating riociguat (Adempas) in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) on the recommendation of the study’s Data Monitoring Committee (DMC).
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The committee — sometimes called a data and safety monitoring board — is an independent group of experts who monitor patient safety and treatment efficacy data during a clinical trial. While reviewing the riociguat data, the DMC determined that patients receiving this treatment were at a potentially higher risk of death and other serious adverse events compared to those receiving a placebo. The DMC did not find any particular cause or common characteristic in the patients who died, but many were found to have more advanced lung disease than the clinical trial cohort as a whole.

People taking part in the trial will be monitored for safety for a minimum of four months after discontinuing treatment, Bayer said.

PH-IIP is a severe and rare disease. Pulmonary hypertension (PH) is an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, leg swelling, and other symptoms. PH is increasingly recognized as a complication of interstitial lung disease (ILD). It can exist when ILD is mild, but is more common when hypoxemia and severe pulmonary dysfunction exist.

IIPs are ILDs of unknown etiology that share similar clinical and radiologic features, and are distinguished primarily by the histopathologic patterns found in a lung biopsy, being characterized by varying degrees of inflammation and fibrosis. All IIPs cause dyspnea. Treatment varies by subtype, as does disease prognosis.

Patients with PH-IIP are a high-risk patient population with an estimated mortality rate of over 20% within one year. Currently, there are no approved treatments for PH-IIP.

Riociguat’s positive benefit-risk profile for its approved indications has not been altered, including its use to treat pulmonary hypertension patients in WHO Groups 1 and 4. Bayer announced that it is carefully examining riociguat’s efficacy and safety on an ongoing basis.

“We understand that the need to terminate the study in PH-IIP is very disappointing for patients suffering from this disease, as well as for their doctors and healthcare providers. There is a significant unmet medical need for PH-IIP patients as there are no approved treatments, and finding an effective treatment remains a challenge,” said Dr. Joerg Moeller, a member of the Bayer Pharmaceuticals Executive Committee and head of Global Development, in a press release. “Bayer remains committed to identifying new therapeutic options and to improving the lives of patients in disease areas where there is a high unmet medical need such as pulmonary hypertension.”

Adempas is Bayer’s novel formulation to treat PH patients. Chemically known as riociguat, the drug is the first of a new class of stimulators of soluble guanylate cyclase (sGC), an enzyme responsible for vasodilation and lowering of blood pressure, and the only receptor of nitric oxide in the body.

Combination therapy may be more effective than monotherapy for slowing disease progression in patients with PAH, suggests Meta-analysis

By Dr Deepu

Combination therapy was significantly more effective than monotherapy for slowing disease progression in patients with pulmonary arterial hypertension.
          Investigators found that “compared with treatment with a single drug, combination therapy was associated with a significantly lower risk for clinical disease worsening and disease-related hospital admissions, and it was associated with a trend toward reduced all-cause mortality and pulmonary arterial hypertension (PAH)-related mortality.” The findings were published in Lancet Respiratory Medicine.

Source: read Full article on LANCET

Ambrisentan and Tadalafil combination highly effective in scleroderma associated PAH

By Dr Deepu

Scleroderma associated PAH is a rare entity and has a very dismal response to currently available Pulmonary arterial hypertension therapy. Hasson et al recently published a study in AJRCCM November issue (vol 192 no.9). They assessed the effect of up-front combination PAH therapy in ssc-PAH.
 Patients, newly diagnosed with SSc- PAH  were given ambrisentan 10mg and Tadalafil daily for 36 weeks.
Primary endpoints - Right ventricular mass and Pulmonary Vascular resistance (Functional, hemodynamic and Imaging )
Secondary end points- stroke volume, 6MWD, pro-bnp .
Results showed a reduction in median RV mass and mean pulmonary vascular resistance and a improved median Stoke volume, 6MWD, pro-bnp.
So the study demonstrated, up-front combination therapy with ambrisentan and Tadalafil could be very effective in treatment naive SSc- PAH.
Read the research paper

Benefit Confirmed for Combo Therapy in PAH-'Concrete, A-plus evidence' for better outcomes with tadalafil-ambrisentan

By Dr Deepu
Combination therapy with ambrisentan (Letairis) and tadalafil (Adcirca, Cialis) can significantly reduce the risk of clinical-failure events for pulmonary arterial hypertension (PAH) patients compared with either drug alone, according to complete results from a clinical trial now published in a major peer-reviewed journal.
Risk of first clinical failure -- defined as either death, hospitalization for worsening PAH, disease progression or unsatisfactory long-term clinical response to medication -- was reduced by half in the combination therapy group versus the two single therapy groups combined (hazard ratio 0.50; 95% CI 0.35-0.72; P<0.0001), Nazzareno Galiè, MD, of the University of Bologna, Italy, and colleagues reported in the New England Journal of Medicine.
Major findings from the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study were also presented earlier this year at the American Thoracic Society's annual meeting. The NEJM publication confirms and extends that report.
AMBITION was a randomized, double-blind, 14-center study that included 500 treatment-naïve patients with World Health Organization class II or III symptoms of PAH.
During the trial, patients were randomly assigned in a 2:1:1 ratio to receive either 10 mg of ambrisentan plus 40 mg of tadalafil, 10 mg of ambrisentan plus placebo, or 40 mg of tadalafil plus placebo once a day. A clinical failure event occurred in 46 of 253 patients (18%) in the combination therapy group, 43 of 126 patients (34%) in the ambrisentan monotherapy group and 34 of 121 patients (28%) in the tadalafil monotherapy group, for a total of 77 of 247 patients (31%) in the two monotherapy groups combined.
At 24 weeks, the combination therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than the pooled monotherapy group (-67.2% vs. -50.4%; P<0.001). Those receiving combination therapy also had a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio 1.56, 95% CI 1.05-2.32; P=0.03), and a greater improvement in 6-minute walk distance (median change from baseline 48.98 m vs. 23.80 m; P<0.001).
"Most previous clinical studies that have investigated combination therapy for PAH have evaluated sequential add-on therapies," the authors wrote. "The AMBITION trial supports the rationale for targeting multiple pathways in pulmonary arterial hypertension and showed that early combination therapy can be beneficial."
Mean duration of use of a study medication was 517 days (550 in the combination therapy group and 484 in the pooled monotherapy group, P=0.03). Mean duration of study participation was 609 days (629 for combination therapy and 593 for pooled monotherapy, P=0.27). Sixty-four participants (13%) withdrew from the study before having a clinical failure event.
Peripheral edema, headache, nasal congestion and anemia were among the adverse events (AEs) that occurred more frequently in the combination therapy group than in either monotherapy group. Dizziness was more common with combination therapy than with tadalafil alone, and syncope was more common with tadalafil monotherapy than with the other groups. The most common AEs resulting in discontinuation of a study drug were peripheral edema and dyspnea; the most common serious AEs were worsening of PAH and pneumonia.
There were several limitations to the study, the authors noted, including finding no significant difference in WHO functional class among the study groups at week 24. In addition, they said, it isn't known whether the study findings can be extrapolated to other drugs in the same classes or whether initial combination therapy with drugs for other classes of approved therapies for PAH would produce similar results.

PULMONARY HYPERTENSION

Pulmonary hypertension is considered present when the mean PA pressure is greater than 25 mm Hg at rest or 30 mm Hg during exercise.
Etiology and Classification
  • Secondary pulmonary hypertension is present when there is a identifiable cause with hemodynamic sequelae leading to pulmonary hypertension. Disease of the left heart, pulmonary embolism, chronic hypoxemia and left to right shunts are common etiologies.
  • Primary pulmonary hypertension is obviously idiopathic. However, it is often associated with cirrhosis , AIDS and can be familial.

Pathogenesis
Elevated pressure, through endothelial cell dysfunction, produces structural changes in the pulmonary vasculature. These changes ultimately decrease pulmonary blood flow and stress the heart to the point of failure. Based on etiology, pulmonary hypertension is divided into two categories.
  • Primary (idiopathic): The cause is unknown.
  • Secondary: The hypertension is secondary to a variety of conditions which increase pulmonary blood flow or increase resistance to blood flow. Example: Interstitial fibrosis.
Pathology
The changes involve large and small pulmonary blood vessels and range from mild to severe. The major changes includeatherosclerosis, striking medial hypertrophy and intimal fibrosis of small arteries and arterioles, and plexogenic arteriopathy. Refer to Figure 15-7 in your textbook.

Pathophysiology 

Dyspnea and fatigue eventually give way to irreversible respiratory insufficiency,

 cyanosis and cor pulmonale
Clinical Features
  • Primary pulmonary hypertension often occurs in young females. Dyspnea on exertion, fatigue, syncope, dizziness, edema and angina occur during the course of illness.
  • Loud pulmonary component of the second heart sound, pulmonary ejection click, RV lift, S4 gallop, syst murmur of tricuspid regurgitation and a diastolic murmur of pulmonary regurgitation can be recognized. Findings are subtle and the diagnosis is often missed.
  • Complex testing is often required to establish the presence of pulmonary hypertension and to rule out secondary causes.
Therapy

  • Prognosis is poor and five year survival is between 22-33%.
  • See cor pulmonale for therapeutic measures for secondary pulmonary hypertension.
  • Anticoagulation, Calcium channel blocks, Nitric oxide and Prostacyclin are current therapeutic options.
  • Anticoagulation has to given indefinitely.
  • 20-35 % of patients respond to vasodilators acutely and benefit from their use.
  • Infusion of prostacycline, continuously and chronically, improves hemodynamics, symptoms and survival. This requires implantation of a permanent central venous catheter, use of an external portable infusion pump and comprehensively trained support staff.
  • Lung transplant is an option for patients refractory to medical management.

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