Lincy Varughese

Preceptor: Dr. Crystal

Rendon-Brown
June 25,2014
Rotation: Ambulatory
Care 4275
Original Article found in the New England Journal of Medicine: July 25,
2013
Riociguat for the Treatment of Pulmonary Arterial
Hypertension
INTRODUCTION
- This study was completed due to the lack of effective medication
within the disease state of Pulmonary Arterial Hypertension, the
authors state that current standards of medicine are not
impacting the rate of mortality and medical management in PAH
patients.
- The purpose is to determine efficacy and side-effect profile of
riociguat.
OVERALL STUDY DESIGN
- The study design was a 12 week, double-blinded [patients and
investigators], randomized, placebo-controlled, multi-centered
trial [124 centers across 30 countries]
- There were three arms to the study in which 443 patients were
assigned
o Placebo arm [126]
o Individual adjusted doses of up to 2.5 mg TID [254]
o Individually adjusted doses capped at 1.5 mg TID [63]
METHODOLOGY
- Inclusion
o Patients with symptomatic PAH [predominantly idiopathic
pulmonary hypertension] were included if they had a
pulmonary vascular resistance greater than 300
dyn*sec*cm-5, a mean pulmonary artery pressure of at
least 25 mmHg and a 6 minute walk distance of 150 to 450
meters. The majority of patients were in WHO functional
Class 2 or 3.
o Patients who were:
Receiving no treatment for PAH [50%]
Receiving ERA treatment [44%] or non-IV prostanoids
[6%] at doses that had been stable for at least 90
days
Receiving oral anticoagulant agents, diuretics, and
supplemental oxygen [at stable doses]
- Exclusion
o Patients who were receiving PDE-5 inhibitors
- Assignment

o 443 patients with symptomatic pulmonary arterial

hypertension were randomly assigned in a 2:4:1 ratio to
one of the three regimens
Those on the riociguat therapy were all initially
placed on 1 mg TID and then adjusted according to
the systolic systemic arterial blood pressure and
signs or symptoms of hypotension
The final range of therapy was 0.5 mg to 2.5 mg TID
Dose adjustments were stopped at 8 weeks
Statistical Analysis
o Researchers of the study decided that by placing 250
patients in the 2.5 mg maximum group and 125 in the
placebo group they would achieve a 90% power [90%
power in a clinical trial means that the study has a 90%
chance of ending up with a p value of less than 5% in a
statistical test which would allow for rejection of the null
hypothesis] in the 6 minute walk distance of 25 minutes.
o Efficacy analysis was performed on data from the modified
intention to treat population which is all those who
underwent randomization and received at least one dose of
the study drug

RESULTS
- Study took place from December of 2008 to February of 2012
with 443 patients randomly assigned to three arms. 38 patients
withdrew from the study before week 12. All efficacy data is
considered for the 2.5 mg max group and the placebo control
group.
- Dosing
o In the 2.5 mg max group
75% of the patients were receiving the maximal dose
at week 12
15% were receiving 2.0 mg TID
6% were at 1.5 mg TID
3% continued the initial 1.0% TID
2% were decreased to 0.5 mg TID
31 patients in this group required a decrease in
dosing compared to 11 patients in the placebo
group
o In the 1.5 mg max group 96% of the patients were
receiving 1.5 mg TID at week 12
- Primary End Point
o In the 2.5 mg max group:
At week 12 the 6-minute walk distance had increased
from baseline by an average of 30 meters

o In the placebo group:

At week 12 the 6-minute walk distance had
decreased from baseline by an average of 6 meters
o Data was found at a 95% confidence interval and p value
<0.001
o Sub-groups based on WHO functional class those in class
3 or 4 showed a significantly greater benefit with riociguat
therapy than those in class 1 or 2.
- Secondary End Points
o Pulmonary Vascular Resistance
In the 2.5 mg max group decreased by 223
dyn*sec*cm-5
In the placebo it decreased by 9 dyn*sec*cm-5
o Significant improvements in other hemodynamic variables
[mean PAP and CO] were also evident in those treated with
therapy
o Other secondary end points including NT-proBNP levels,
WHO functional class, and Borg dyspnea scores were also
improved in those treated with riociguat. They also
experienced significantly lower indicidence of events
including clinical worsening.
o The EQ-5D score did not differ significantly between the
groups and the LPH questionnaire was considered to be
exploratory.
- Safety and Adverse Events
o These were measured from the time of administration of
the first dose until 2 days after the administration of the
last dose.
o The most frequently occurring serious adverse events:
Syncope
1% of Riociguat group
4% of placebo group
Worsening pulmonary hypertension
<1% of Riociguat group
2% in placebo group
Chest Pain
1% of patients in both groups
Right Ventricular Failure
1% of patients in both groups
DISCUSSION AND CONCLUSIONS
- In an overall consideration, Riociguat did show improvement in
both primary and secondary endpoints. The benefit was
consistent even if an individual was on ERA or prostanoids.
- Limitations

o The lack of follow-up efficacy measurements in patients

who withdrew from the study
o The exclusion of patients with PAH associated with HIV,
schistsomiasis, and chronic hemolytic anemia.
o The exclusion of patients receiving treatment with PDE-5
inhibitors or IV prostanoids
So we dont know the effect of the drug within these
populations
References
Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk
distance as a surrogate end point in pulmonary arterial hypertension
trials. Circulation 2012;126:349-356
Ghofrani, H.-A., et al. (2013). "Riociguat for the Treatment of Pulmonary
Arterial Hypertension." New England Journal of Medicine 369(4): 330340.
Riociguat. In: Lexi-Drugs [database online]. Hudson, Ohio: Lexi-Comp,
Inc. Updated periodically. Accessed June 24, 2014.
Tadalafil. In: Lexi-Drugs [database online]. Hudson, Ohio: Lexi-Comp,
Inc. Updated periodically. Accessed June 24, 2014.