AMBITION: Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

Data on the effect of initial combination therapy with ambrisentan and tadalafil on
long-term outcomes in patients with pulmonary arterial hypertension are scarce.

In this event-driven, double-blind study, patients were randomly assigned, in a 2:1:1 ratio,
participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive
initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentanmonotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily.

The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.

The primary analysis included 500 participants; 253 were assigned to the combination-
therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the 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 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.

Among participants with pulmonary arterial hypertension who had not received
previous treatment, initial combination therapy with ambrisentan and tadalafil
resulted in a significantly lower risk of clinical-failure events than the risk with
ambrisentan or tadalafil monotherapy.

Source :

Approach to Arrhythmia part 1: Bradycardia

Approach to Arrhythmia part 1: Bradycardia

Bradycardia is defined as heart rate <60/min. To understand the cause of bradycardia we have to understand the structures involved in the production and conduction of cardiac impulse.

The normal cardiac structures involved in electrical activity of the heart are
1. SA node- It is the pacemaker of the heart, because it fires at the highest rate hence predominates over other pacemakers of the heart.
2.AV node – In normal hearts its function is to conduct impulses generated in the SA node to the ventricles through the Bundle of His and bundle branches.It can act as a slow pacemeker when the SA node is diseased
3. Bundle of His and bundle branches- Normally their function is conduction of cardiac impulses. They can act as a slow pacemeker when the proximal structures (SA node & AV node) are diseased.
4. Purkinje fibres
5. Ventricular myocardium- In complete heart block the ventricular myocardium produces escape rhythm at a slow rate of 20-40/min

Disease in any of the structures can lead to bradycardia.

The diagnosis is made from ECG in most of the cases.
Now we will discuss how to systematically analyze an ECG for diagnosing a bradycardia.

Step 1: Calculate the rate first. Bradycardia by definition heart rate <60/min
Step 2: Analysis of rhythm begins with search for P-wave. Normally P-waves are produced by SA node, so absence of P-waves indicate disease of SA node. Which is called as sick sinus syndrome
Step 3: Absent P-waves can be due to
1. Sick sinus syndrome with escape rhythm. (R-R intervals fixed)
2. Atrial fibrillation with slow ventricular rate. (R-R intervals variable)

Sick sinus syndrome: no visible P waves, fixed R-R intervals.
Sick sinus syndrome: no visible P waves, fixed R-R intervals.


Step 4: P-waves present
If P-waves are present look for P-P interval, PR-interval and relation between P and R waves.

Step 5: P-P interval variable
Nonconducted APCs
Step 6: P-P interval fixed
The next stepis evaluation of PR-interval and relation between P and R waves

Step 7: PR interval normal and fixed: Sinus bradycardia

Sinus bradycardia
Sinus bradycardia

PR interval prolonged but fixed and each QRS complex is preceeded by P wave: First degree AV block

1st degree AV block: Prolonged fixed PR interval
1st degree AV block: Prolonged fixed PR interval

(ECG courtesy of
PR interval lengthens then dropped beat and return with short PR interrval: Mobitz type 1 second degree AV block

Wenckebach block
Wenckebach block

(ECG courtesy of
PR interval fixed then dropped beat : Mobitz type 2 second degree AV block
No PR relationship : Third degee AV block

Complete heart block
Complete heart block

(ECG courtesy of


The flow chart below summarizes the whole approach

ECG  approach to bradycardia
ECG approach to bradycardia