Pulmonary hypertension (PH) is frequently referred to as "the other high blood pressure." PH is a challenging diagnosis for clinicians, as well as patients. We've come a long way to understanding PH in the last 20 years and have many exciting new treatment options for patients. Unfortunately, the non-specific symptoms of a PH patient such as shortness of breath, dizziness, fainting, fatigue and/or fluid retention can all lead to extended diagnosis times (Badesch DB1, 2010). With pulmonary arterial hypertension (PAH), the earlier diagnosis and treatment, the better the overall outcomes.
Screening for PH begins with a history and physical which should include complete patient and family histories regarding connective tissue disease, congenital heart disease, portal hypertension, HIV and environmental/drug factors. Typically drug factors were associated with anorexigen use in the 1990s. Their use was found to lead to a higher risk of PAH (very similar clinically and histopathologically to idiopathic PAH). Current data suggest that other agents such as methamphetamines could have a similar association and increase the risk of developing PAH. (McGoon M1 & Physicians, 2004) (Chin K.M., 2006)
Testing would include a chest x-ray, pulmonary function testing, arterial blood gases, 6 minute walk testing, echocardiogram, electrocardiogram, ventilation perfusion scan and labs with serologies for ruling out underlying (and potentially causative) conditions. In the end, the patient will also need a right heart catheterization (RHC) which is the "gold standard" to confirm the diagnosis and help determine the correct diagnostic World Health Organization (WHO) group.
PH is high blood pressure in the blood vessels of the lungs, which can lead to right-sided heart failure. In order for patients to get the appropriate treatment, it's important for it to be classified correctly. A PH diagnosis does not tell us the entire story. Unfortunately, PH is "bucket" terminology which includes all forms of PH for which treatments are very different. If patients are given the wrong therapy, it could harm them and potentially lead to serious complications. For this reason, it's imperative that once a PH patient is identified, they be directed to an appropriately trained medical team for a more thorough diagnosis and treatment plan.
The 5th World Symposium on Pulmonary Hypertension (WSPH) Consensus (Galiè N, 2013) defines WHO Group 1 Pulmonary Arterial Hypertension (PAH) as a mPAP must be ≥ 25 mmHg PLUS the mean pulmonary artery wedge pressure (PAWP) must be ≤ 15 mmHg PLUS they must have a pulmonary vascular resistance (PVR) > 3 Wood units as measured by RHC. (Hoeper MM, 2013). PH WHO Groups 2-4 are defined with a mean pulmonary artery pressure (mPAP) as ≥ 25 mmHg. A PH diagnosis must be categorized into an appropriate diagnostic group as illustrated in the 5th WSPH WHO Group Classification 1 table below so appropriate therapy can be prescribed.
5th WSPH WHO Group Classification 1:
Currently, the only FDA-approved PH specific medications for are for WHO Group 1 and WHO Group 4 patients. A patient diagnosed with WHO Group 2 PH, if given a pulmonary vasodilator, may develop pulmonary edema and respiratory failure. If a WHO Group 3 patient is given pulmonary vasodilators, it could lead to increased V/Q mismatch and worsening hypoxemia.
Thus, for any patient who has PH associated with left heart failure, lung diseases and/or hypoxia, or any of the miscellaneous ailments contained in WHO Group 5, the best therapy options we have at this time are to treat the underlying conditions to the best of our ability.
General treatment for all PH patients potentially includes cardiac or pulmonary rehabilitation, Oxygen supplementation for hypoxemia, diuretics for fluid retention, and possible anticoagulation. In addition, most patients should be counseled to restrict sodium and fluid with specific limits as prescribed by the PH physician.
In many cases, patients require high flow oxygen which is becoming much more difficult to obtain. With Center for Medicaid and Medicare Services mandated competitive bidding for oxygen that went into effect in 2013, many of the smaller companies who worked with high flow oxygen patients are no longer able to service them. In addition, the companies that "won" the competitive bids are now dictating that they are no longer going to provide the higher liter flows (or liquid oxygen) they had previously been providing.
Unfortunately, no PH therapy will achieve its maximal potential benefit in a hypoxic environment. The body's response to hypoxia is to constrict blood vessels to facilitate getting oxygenated blood to vital organs. This is in direct opposition to the specialty medications that we may be delivering to the patient whose purpose is to dilate blood vessels. Therefore, it's imperative that a patient's SpO2 be maintained ≥ 90% at all times. In many cases, we have seen mild decreases in patients' pulmonary pressures and right heart size just by maintaining them on appropriate oxygen therapy.
There are now a plethora of treatment options available for WHO Group 1 PAH. Therapies for PH target endothelial cell dysregulation as well as smooth muscle cell tone and proliferation. Thus far, the three major pathways that have been identified are the endothelin pathway, nitric oxide (NO) pathway and the prostacyclin pathway (Humbert M, 2004).
Approved Therapeutic Targets 1
All PAH medications should result in pulmonary vascular vasodilation. With the vasodilation effect, there are several common "side effects" that all of these medications may have. The most common are headache, nausea, flushing, diarrhea and vomiting. Depending on the administration method and drug, some effects may be worse. Those issues will be highlighted in the discussion of individual medications and pathways.
Endothelin is a very potent vasoconstrictor that binds to smooth muscle endothelin receptors, of which there are two subtypes: ETA and ETB. ERAs deter the effects of overexpression of endothelin (ET) by blocking either both (ETA and ETB) receptors or ETA receptors alone. Tracleer (bosentan) and Opsumit (macitentan) are both ERAs that work with a dual effect by blocking the constriction property of ETA and stimulating the nitric oxide effect of ETB. Bosentan may cause elevation of hepatic aminotransferases in approximately 10% of patients; therefore, the FDA has instituted mandatory monthly liver function testing (LFT). Letairis (ambrisentan) is an ERA that is a selective ETA receptor antagonist and neither macitentan nor ambrisentan require monthly LFTs.
All three medications have potential side effects that include nasal congestion, potential decrease of hemoglobin and/or hematocrit and edema (which may require diuretic adjustment or ERA discontinuation in severe cases). Since this class of medication also can cause embryo-fetal toxicity, the FDA also requires dual contraceptive methods and monthly pregnancy testing for all female patients with reproductive potential.
Nitric Oxide Pathway
Revatio (sildenafil) and Adcirca (tadalafil) are both phosphodiesterase-5 inhibitors (PDE5) inhibitors which also work in the NO pathway. PDE5 is a substance produced in the body that breaks down another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP causes the blood vessels (arteries) to relax and widen. By decreasing the activity of PDE5, more cyclic GMP is available for the blood vessels inside the lungs which results in vasodilation.
The newest addition to treat PAH through the NO pathway is Adempas (riociguat). Riociguat is a stimulator of soluble guanylate cyclase (sGC) which is an enzyme in the cardiopulmonary system and the receptor for (NO). Riociguat works in the same pathway as the PDE5 inhibitors; therefore, the combination may lower systemic blood pressure. It is contraindicated to give riociguat and PDE5 inhibitors concomitantly. Riociguat also carries a risk of teratogenicity. Females of childbearing potential must have monthly pregnancy testing and utilize dual contraceptive methods as per FDA guidelines. It is the only PH specific medication that is FDA approved for a diagnostic group other than WHO Group 1. Riociguat is FDA approved for Chronic Thromboembolic Pulmonary Hypertension (WHO Group 4) as well as WHO Group 1 PAH.
All treatments that work in the NO pathway are contraindicated with the use of nitrates due to potential systemic hypotension. Side effects can include nose bleed, headache, nausea, flushing, diarrhea and visual changes.
There are more options for delivering prostacyclin therapy than ever before. Epoprostenol (which is available as generic, brand name Flolan and brand name Veletri) and Remodulin (treprostinil) are intravenous (IV) options. They are usually delivered through an implanted central venous catheter (CVC) with a small portable home pump. The major drawback to this administration of medication is that the CVC exit site opens up the possibility of infection. Additionally, once the IV is started, if it is abruptly stopped, the patient could develop rebound PH which may result in worsening symptoms and/or death.
Treprostinil can also be given subcutaneously (SQ) with a small, continuous flow pump. With this administration, the patient places the SQ site and changes it themselves as necessary. While it is much less infection risk than the IV administration, it can be painful when a new site has to be placed. In some cases, patients have to replace the site (commonly referred to as re-siting) every week or two. For most patients, their sites last anywhere from 2 weeks to 6 months and the patient knows when it's "time" to re-site by the site becoming irritated. If left for too long, the SQ site can also develop infection.
When patients are weighing their options for prostacyclin therapy, the lack of pain involved with the IV administration can make it a slightly more attractive option.
Tyvaso (treprostinil) and Ventavis (iloprost) are inhaled prostacyclins. Since they are not continuous administrations, they can have peaks and valleys of benefit. The major side effects to inhaling a prostacyclin are coughing and throat irritation. That, coupled with the multiple administrations that must be done every day on a set schedule, can make the inhaled option a tough sell for some. The benefit to inhaled prostacyclin therapy is that the majority of the blood vessels being vasodilated are the ones that are getting ventilation (as opposed to IV, SQ or oral formulations). If we vasodilate non-ventilated blood vessels, we run the risk of increasing the VQ mismatch and worsening oxygenation status.
Lastly, treprostinil is now available in pill form (Orenitram). Oral treprostinil is very new to the market and its major side effects are headache, nausea and diarrhea. As with the inhaled prostacyclins, it is not a continuously delivered medication and can have peaks and valleys of effectiveness. That being said, it may be a wonderful option for patients to start prostacyclin therapy earlier in their disease process.
With any therapy for any disease, it's about finding the right fit for the patient and their lifestyle. We must have an open dialog about expectations of their everyday lifestyle and what benefits versus risks they are weighing when trying to select the appropriate therapy. It's critical to know our patients' goals are. With this information, we can work together to create a treatment plan that is successful.
Tonya Zeiger is Mayo Clinic Pulmonary Hypertension coordinator, and an Associate in Pulmonary Medicine. To learn more, visit the Pulmonary Hypertension Association's website.
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