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 Table of Contents  
BOOKS AND TRIALS
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 27-30

Landmark trials in pulmonary hypertension and pulmonary embolism


Principal Consultant and Head, Non-invasive Cardiology, Max Super Speciality Hospital, Saket, New Delhi, India

Date of Web Publication26-Dec-2016

Correspondence Address:
Rahul Mehrotra
NIC lab, Max Super Speciality Hospital, Saket (East Block), 2, Press Enclave Road, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2250-3528.196658

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How to cite this article:
Mehrotra R. Landmark trials in pulmonary hypertension and pulmonary embolism. J Clin Prev Cardiol 2017;6:27-30

How to cite this URL:
Mehrotra R. Landmark trials in pulmonary hypertension and pulmonary embolism. J Clin Prev Cardiol [serial online] 2017 [cited 2019 Jul 16];6:27-30. Available from: http://www.jcpconline.org/text.asp?2017/6/1/27/196658

Pulmonary hypertension is a grave disease of the pulmonary vasculature. It was virtually considered a death sentence in the 1990s with almost no treatment being available but things have changed a lot in the past decade. We now have more than a dozen drugs approved for use in PAH. Also, the treatment approach is also likely to change with the excellent results of the AMBITION trial reviewed here. Other landmark trials like IMPRES -with the use of Imatinib and FREEDOM-M, using oral prostacyclin analog are also reviewed. The use of tenecteplase in non-massive pulmonary embolism has always been debatable. A trial (PEITHO), has added useful information in this and is also being reviewed in this section.


  Initial Use of Ambrisentan Plus Tadalafil in Pulmonary Arterial Hypertension Top


Galié N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834-44.

Background: There are scarce data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes, in patients with pulmonary arterial hypertension.

Methods: A total of 500 patients with pulmonary arterial hypertension, symptomatic with the World Health Organization functional Class II or III, who had not previously received any treatment were included in the study. The patients were randomly divided into three groups in a ratio of 2:1:1 to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg tadalafil (combination-therapy group, n = 253), 10 mg ambrisentan plus placebo (ambrisentan-monotherapy group, n = 126), or 40 mg tadalafil group (tadalafil-monotherapy group, n = 121) administered once daily. In this event-driven trial, the primary end point was defined as the first occurrence of a composite of death, hospitalization for worsening of pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.

Results: The primary end-point event occurred in 18% of the participants in the combination-therapy group, in 34% of the participants in the ambrisentan-monotherapy group, in 28% of the participants in the tadalafil-monotherapy group, and in 31% of the participants in pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35-0.72; P < 0.001). Greater reductions in N-terminal pro-brain natriuretic peptide levels at week 24 from baseline were also seen in the combination-therapy group as compared to the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P < 0.001). Higher percentage of patients had a satisfactory clinical response in the combination-therapy group as compared to pooled-monotherapy group at week 24 (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05-2.32]; P = 0.03), and a greater improvement in the 6 min walk distance was also seen in the combination-therapy group (median change from baseline, 48.98 m vs. 23.80 m; P < 0.001). Headache, nasal congestion, peripheral edema, and anemia occurred more frequently in the combination-therapy group than in either monotherapy group.

Conclusions: This trial demonstrated that among patients with pulmonary arterial hypertension who had not received previous treatment, initial therapy with a combination of ambrisentan and tadalafil resulted in a significantly lower risk of clinical failure events than the risk with monotherapy with ambrisentan or tadalafil.

Perspective

There is a paucity of good quality, prospective trials in pulmonary arterial hypertension with hard end points. Besides, most of the trials on combination therapy have used the approach of sequential addition of therapy with placebo in patients already receiving background therapy with approved drugs.

In this prospective trial, early combination therapy with drugs targeting different pathways was shown to be beneficial. The risk of first clinical failure was 50% lower in the participants receiving initial combination therapy with ambrisentan and tadalafil than among those receiving monotherapy with either of the drugs. Although the treatment effect with respect to the primary end point (first clinical event) was largely driven by reduction in hospitalization for pulmonary arterial hypertension with no significant difference in rates of hospitalization for any cause, the importance of this cannot be underscored since hospitalizations for worsening of pulmonary hypertension indicate poor prognosis, disease progression, and entails expense. Upfront combination therapy was also superior to pooled-monotherapy group but similar to ambrisentan-monotherapy group in terms of the secondary end points - absence of clinical events, improved exercise capacity, reduction of symptoms, or maintenance of the World Health Organization (WHO) functional class.

The trial has opened the way for initiating new patients directly on combination therapy to achieve clinical benefit. However, it is not known whether other drugs from the same class will have the same effect in combination and whether these results can be extrapolated on other drugs as monotherapy. Furthermore, the WHO functional class was similar in the three groups at the end of 24 weeks. What would have been the results if switch over of patients not responding to a particular class of monotherapy was done to any other class of drug is also not possible. More large scale trials are needed with hard end points to address these issues.


  Efficacy and Safety of Oral Treprostinil Monotherapy for the treatment of Pulmonary Arterial Hypertension: A Randomized, Controlled Trial Top


Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: A randomized, controlled trial. Circulation 2013;127:624-33.

Background: Prostacyclins and their analogs are powerful drugs for the treatment of pulmonary artery hypertension (PAH). Parenteral prostacyclin therapy has been shown to improve hemodynamics, exercise capacity, and survival in patients with PAH. Sodium salt of treprostinil, an analog of prostacyclin, has been approved for use in intravenous, subcutaneous, and inhaled form. Treprostinil diethanolamine is a stable oral form of treprostinil.

Methods: Patients of PAH who were not receiving any therapy (phosphodiesterase type-5 inhibitors, endothelin receptor antagonist, or prostacyclins) were included in this international, multicenter, double-blind placebo-controlled, randomized (2:1 oral treprostinil: placebo) trial of 12 weeks. The primary end point was change in 6 min walk distance (6MWD) from baseline and secondary end points were Borg dyspnea index, clinical worsening, and symptoms of PAH at 12 weeks. Oral treprostinil was administered initially as 1 mg twice daily but later, as 0.5 and 0.25 mg daily as the protocol was modified, up to a maximal dose of 12 mg daily. Dose escalations were done in up to 0.125 mg increments, every 3 days.

Results: Three hundred and fifty-nine (359) patients were included in the study and defined as intent-to-treat population (treprostinil, n = 233; placebo, n = 116). The primary analysis population, the patients with access to 0.25 mg tablet at the time of randomization (modified intent-to-treat) included 228 patients (treprostinil, n = 151; placebo, n = 77). At week 12, there was a significant improvement in the 6MWD in the treprostinil group in the modified intent-to-treat population (mITT) (23.0 m; 95% confidence interval [CI] 4-41, P = 0.0125). The 6MWD change from baseline at week 8 was also significantly improved (17.0 m; 95% CI, 1-33 m; P = 0.0307) in this population. For the mITT population, 52% of patients taking oral treprostinil (vs. 39% of patients on placebo) experienced an improvement in 6MWD of ≥20 m and 34% (vs. 23% of patients on placebo) improved by ≥50 m. In the intent-to-treat population also, 6MWD improvements were observed at peak (26.0 m; P = 0.0001) and trough (17.0 m; P = 0.0025) plasma study drug concentrations at week 12.

In the secondary outcomes, in mITT population, there was a significant improvement in the combined 6MWD/Borg dyspnea score at week 12 (P = 0.0497). For the ITT population also, significant improvements in the combined 6MWD/Borg score were observed at week 4 (P = 0.014), week 8 (P = 0.004), and week 12 (P = 0.0007).

There was no difference in a clinical worsening in the two treatment groups in both, mITT and ITT populations. There was also no significant treatment effect observed in terms of improvement in the World Health Organization class, symptoms of PH or Borg Dyspnea score. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%).

Perspective

Parenteral prostacyclins are the most efficacious drugs available for treatment of PAH. However, the problems associated with continuous intravenous or subcutaneous infusions have prevented them from being used routinely in patients with less advanced disease. The first-in-class oral prostacyclin analog, beraprost did not do well in follow-up studies and was not approved. Oral treprostinil, however, has shown promise, and the results of this study have put it at par with other drugs since the improvement in 6MWD is same as that achieved with phosphodiesterase type-5 inhibitors and endothelin receptor antagonist in placebo-controlled trials. Oral treprostinil has thus been approved for use by the Food and Drug Administration and is now undergoing trial as an add-on therapy (TDE-PH 310 and 311). The results of this study, of which India is also a part of, are likely to have important implications for the management of PAH patients with oral therapy alone.


  Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study Top


Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galiι N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: Results of the randomized IMPRES study. Circulation 2013;127:1128-38.

Background: Pulmonary hypertension is a progressive disease characterized by pulmonary vascular remodeling. The histopathology of pulmonary vascular bed reveals endothelial and smooth muscle cell hypertrophy and hyperplasia. It has been shown that platelet-derived growth factors play an important role in this remodeling.

Methods: Symptomatic patients of pulmonary artery hypertension (PAH) receiving at least two drugs for PAH and having pulmonary vascular resistance (PVR) ≥800 dyne/s/cm (−5) were included in this double-blind, placebo-controlled, multicenter, randomized trial of 24 weeks duration. The primary outcome was change in 6-min walk distance, and the secondary outcomes were changes in functional class, hemodynamics, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the study period, the patients could enter the long-term open-label extension study with imatinib. The starting dose of imatinib was 200 mg which was increased to 400 mg after 2 weeks, if tolerated by the patient.

Results: Two hundred and two patients were randomized (103 in the imatinib arm and 99 in the placebo arm). At the end of 24 weeks, imatinib significantly improved the 6 min walk distance (the mean between-group difference was 32 m, 95% confidence interval [CI] 12-52; P = 0.002). The patients on imatinib also had better hemodynamics at the end of 24 weeks. PVR reduced by 367 dyne/s/cm (−5) in the imatinib arm (n = 74), whereas it increased by 12 dyne/s/cm (−5) in the placebo arm (n = 80) with the between-group difference of 379 dyne/s/cm (−5) (95% CI, −502-−255; P < 0.001). This equates to a change of − 31% (95% CI, −42.2-−21.4; P < 0.001). Mean pulmonary artery pressure, right atrial pressure, and cardiac output also improved with imatinib as compared to placebo. There was no difference in the functional class, time to clinical worsening, and mortality between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% vs. 30% and 33% vs. 18%, respectively). Subdural hematoma occurred in eight patients (two in the core study and six in the extension) receiving imatinib and anticoagulation.

In the open-label extension arm also, the patients who had been on imatinib in the core study for 24 weeks and continued on imatinib for further 24 weeks (n = 54), the 6 min walk distance (6MWD) had increased by 44.7 ± 45.5m (mean ± SD), compared with core study baseline. In the patients who had been on placebo in the core study and on imatinib in the extension study had a 6MWD increase of 19.3 ± 71.6 m (mean+/-SD) as compared to core study baseline.

Perspective

PAH continues to be a devastating disease in spite of the advances made in drug therapy and without a lung transplant, the disease proves fatal in about three years. The available drugs, primarily belonging to three pathways (prostacyclin, endothelin, and nitric oxide), mostly accomplish disease stabilization. The current study enrolled sick patients (around 40% were on three drugs and 30% on parenteral prostacyclin analog) and demonstrated significant improvements in hemodynamic parameters and 6MWD. 6MWD has been a primary end point in all trials involving the drugs approved for PAH. Imatinib demonstrated a mean improvement of 32 m at the end of 24 weeks, in spite of the patients receiving at least two approved drugs. This is a remarkable achievement and coupled with hemodynamic improvement, it means an inroad into disease reversal has been achieved. Tyrosine kinases mediate reactions involved in cell proliferation. The results of this Phase III trial involving tyrosine kinase inhibitor, imatinib, indicate that the drugs targeting this pathway could be very useful in patients who are at advanced stages and are worsening in spite of the use of currently available drugs. The area of concern, however, was the high discontinuation rates with imatinib and the adverse events, particularly, subdural hematoma. Besides, the precise mechanism of action needs to be worked out.


  Fibrinolysis for Patients with Intermediate-risk Pulmonary Embolism Top


Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.

Background: The role of thrombolytic therapy in intermediate-risk pulmonary embolism has not been clearly defined.

Methods: This randomized, double-blind trial included 1005 patients with intermediate-risk pulmonary embolism (defined as normotensive patients with right ventricular (RV) dysfunction on echocardiography or computed tomography, and evidence of myocardial injury as indicated by a positive cardiac troponin I or troponin T). The patients were randomized to receive either tenecteplase plus heparin or placebo plus heparin. The primary outcome was death or hemodynamic decompensation (or collapse) occurring within 7 days of randomization. The main safety outcomes were stroke (ischemic or hemorrhagic) within 7 days after randomization and major extracranial bleeding.

Results: In the intention-to-treat analysis, primary end point occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared to 28 of 499 patients (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23-0.87; P = 0.02). A total of six patients (1.2%) in the tenecteplase group and nine (1.8%) in the placebo group died (P = 0.42). Extracranial bleeding occurred in 32 patients in the tenecteplase group (6.3%) and 6 patients (1.2%) in the placebo group (P < 0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients. Stroke occurred in just one patient (0.2%) in the placebo group, which was hemorrhagic (P = 0.003).

Perspective

High-risk acute pulmonary embolism is associated with high case fatality rate. Risk stratification in patients with acute pulmonary embolism is done primarily using the criterion of hemodynamic instability (hypotension) since clinical trials, and epidemiological evidence has clearly demonstrated that these patients benefit from thrombolytic therapy. However, a subset of patients without hemodynamic instability, but with myocardial necrosis and presence of RV dysfunction due to acute pressure overload may also be at high risk of adverse short-term clinical outcome. Unfortunately, there is no clear evidence of benefit of thrombolytic therapy in these intermediate-risk patients. The PEITHO trial with the use of single bolus thrombolytic agent tenecteplase clearly demonstrated the benefit in terms of reduced risk of death and hemodynamic decompensation (5.6% vs. 2.6%) in this population. Although the risk of intracranial bleeding with the use of tenecteplase was significantly high (2%), it was similar to that seen in studies with other fibrinolytic agents in acute pulmonary embolism (1.8%-2.2%). This study has, therefore, brought into focus once again, the need to devise strategies to reduce the bleeding risk maintaining the efficacy. Age-adjusted dose strengths or controlled, local delivery of thrombolytic agent in the affected pulmonary bed, can be tried in future clinical studies for getting the answer to this vexing problem.




 

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