For patients with pulmonary arterial hypertension (PAH) an early diagnosis and referral to a PAH centre of excellence are the factors most likely to make a difference in patient outcomes, says eminent researcher and clinical director of the Heart Research Institute, Professor David Celermajer. But for many patients it can take up to three years1 from the time they first experience symptoms to the time they are correctly diagnosed and treated by a PAH expert.
It’s a delay that will have a significant adverse impact on a patient’s prognosis and some patients won’t survive long enough to be accurately treated with effective medications1.
“Those are three years where treatment has not been given and the evidence is that you never catch up from that gap so early treatment is the most likely thing to make a difference to a patient’s outcome,” Professor Celermajer, told the limbic.
An Australian study1 looking into the factors that contribute to this delay found that the average person with the disease has five GP visits before being referred to a specialist.
They then have a further three specialist visits before having the confirmatory right-heart catheterisation and a definitive diagnosis, the study showed.
The timely diagnosis of PAH is challenging for a number of reasons, explains Professor Celermajer who says symptoms are usually very subtle and non-specific making it difficult for clinicians to identify patients at an early stage.
“It’s not until the disease progresses that non specific symptoms like breathlessness and fatigue develop and it’s often the case that more common conditions such as asthma, chronic heart failure or even lack of fitness are considered before PAH,” he said.
It’s during this period that most patients’ disease severity will deteriorate from WHO functional class II to WHO functional class III2 – a deterioration that has been associated with considerably poor outcomes even on treatment, with a number of international studies3,4 demonstrating that PAH patients classified as WHO-FC I/II had significantly better long-term survival and five-year cumulative mortality rate than those patients in WHO-FC III/IV.
PAH: an important cause of breathlessness
According to Professor Celermajer, in a lot of cases the abnormalities that are present on physical examination or on a chest x-ray or ECG that are suggestive of a PAH diagnosis when patients first present to doctors are often not recognised because people are not looking specifically for them.
“That’s fair enough,” he says acknowledging that the condition is relatively rare.
“For every 100 people with asthma and 100 people with heart failure there’ll be one with PAH, so this is a rare condition and we usually look for common conditions first.”
He says unless the diagnosis is considered and actively investigated, it is likely to be missed simply because people don’t think of PAH as an important cause of breathlessness.
“Breathlessness always has to be explained and in cases where there is not another obvious cause, we need to consider the possibility of PAH – and if there’s a suspicion that PAH might be present you need to get a right heart catheterisation done to investigate that possibility.”
Professor Celermajer, who is heading up a trial looking into new non-invasive methods for the early detection of pulmonary vascular disease, says that a high index of suspicion combined with a careful patient and family history and physical examination is critical in the evaluation of patients with suspected pulmonary hypertension.
Initial symptoms typically include shortness of breath, fatigue, weakness, angina and syncope. Less commonly, patients may also describe dry cough and exercise-induced nausea and vomiting.
Meanwhile, abdominal distension and ankle oedema will develop with progressing right ventricular failure.
While there has been some uncertainty about the definition and prognostic value of pulmonary hypertension during exercise, Professor Celermajer argues that symptoms at rest occur only in advanced cases and that there is accumulating evidence that suggests that stress testing of the pulmonary circulation can unmask clinically important early disease.
“The pulmonary pressure doesn’t rise at rest until half the lung volume has been lost so you can take out one lung and the pulmonary pressure is still normal at rest but when you stress someone with PAH then the pulmonary pressure rises abnormally so by stressing the system with exercise you bring out the abnormality in the early stages much more easily.”
Gold standard test for PAH
Findings on physical examination that are suggestive of PAH include a loud pulmonary second sound, a prominent right ventricular lift, a high JVP, pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency, a RV third sound and/or an enlarged liver.
An enlarged right ventricle or an enlarged pulmonary artery seen on a chest x-ray or the signs of heart strain on an ECG is also suggestive of PH.
According to Professor Celermajer prominent right ventricular electrical forces is a common measure of right ventricular function suggestive of PAH.
“There’s a big R wave in AVR or V1, there’s a big S wave in V5 or V6 and sometimes there’s evidence of right atrial hypertrophy,” he noted.
However, an abnormal ECG is more likely in severe rather than mild PAH and a normal ECG should not rule out diagnosis, he cautioned.
If PAH has not been ruled out at this stage then echocardiography is recommended and lung function tests should be used to rule out other causes, Professor Celermajer said.
According to Professor Celermajer, the echocardiogram may show a hypertrophied, dilated or hypokinetic right ventricle, tricuspid regurgitation and elevated pulmonary arterial pressure, and lung function tests show a disproportionate reduction in carbon monoxide diffusion in the lung with a mild-to-moderate restrictive lung defect.
But ultimately the gold standard test for PAH is right heart catheterisation, providing a direct measure of pulmonary pressures which will be >25 mmHg at rest and >30 mmHg with exercise.
“We’re very conscious about over testing but you have to counterbalance that with missing an important diagnosis in a young person that’s got devastating consequences. If someone’s breathless you’ve got to keep going until you know what the cause is … that’s not over testing, that’s testing until you reach the point where you understand what the cause might be.”
Expert centres improving patient outcomes
Professor Celermajer says with modern therapies that can ‘dramatically’ improve patient outcomes and delay disease progression, there is more reason than ever for clinicians to refer patients they suspect may have PAH to expert centres so that a multidisciplinary team can go about the complex task of determining the specific cause of the PAH which will guide treatment options.
“What the screening does – the chest x-ray, ECG, echocardiogram, the right heart catheterisation – that tells us whether PAH is present as a cause of breathlessness but that’s not an end in itself.
“Once PH is detected the diagnosis of the specific cause of the disease is a complex and specialised process – there are over 20 different causes. There’s a comprehensive workup that must be carried out to determine the specific cause of the diseases in each patient because the appropriate treatment will depend on the underlying cause.”
There are currently over 60 PAH designated – centres5 that are approved by Medicare to prescribe certain PAH medications. Their role says Professor Celermajer is to prescribe the appropriate treatment for the specific cause of the hypertension and monitor the response to that treatment.
“In expert centres with modern therapies we seem to have made a dramatic effect on outcomes – at the moment we seem to have changed the average survival rate from about three years to around eight or nine years. We can’t cure the disease but we have certainly made major strides in improving outcomes – and especially when the condition is diagnosed early. ”
For a full list of PAH designated centres in Australia click here.
- Strange G, Gabbay E, Kermeen F, Williams T, Carrington M, Stewart S, et al. Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study. Pulm Circ 2013;3:89-94
- Hoeper MM et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013 Dec 24;62(25 Suppl):D42-50
- Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010; 122: 156–163
- Dimopoulos K, Inuzuka R, Goletto S, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010; 121: 20–25