With managed care decision-makers just starting to work the bugs out of the Medicare Modernization Act, pulmonary arterial hypertension (PAH) is hardly at the top of the "to-do" pile. PAH is an uncommon disorder with about 25,000 diagnosed patients in the whole United States.
The exact cause of the disease is not known. What is known is that there appear to be three pathways within the pulmonary vasculature that when activated in a pathologic manner lead to an increase in the absolute pressure within the pulmonary artery system (greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise). PAH seems to strike Caucasian females more than other groups. Mean age at the time of diagnosis is around the early 50s.
Severity of pulmonary hypertension is graded using the World Health Organization (WHO) functional classes, a range of I–IV. Class I is defined as no symptoms of dyspnea, fatigue, palpitation, or anginal pain after ordinary physical activity. Classes II–IV are marked by increasing limitation of physical activity. Patients with class IV have symptoms even while at rest.
As with other rare diseases, the molecular basis of PAH is becoming more defined. This knowledge has enabled scientists to develop targeted interventions for PAH. According to the WHO, the mainstay of therapy for PAH has been anticoagulation, diuretics, and, in those few patients (< 5 percent of patients with idiopathic PAH) who exhibit a strong vasodilatory response in the catheterization laboratory, high-dose calcium channel blockers. Only a small percentage of patients respond to this non-PAH-specific regimen and that response is quickly overwhelmed by the rapidly progressive nature of this disease. Before the specific targeted therapies became available, managed care had little interaction with this disease except for the occasional admission to the hospital as the lungs became dysfunctional.
But that all changed with the advent of the first targeted therapy. Few managed care medical directors will forget the first request they received for the prostacyclin analogue epoprostenol (Flolan) — with a price tag of over $100,000 per year, the need for redundant pumps to ensure continuous central line delivery, its half life of just six minutes, and the required daily mixing and refrigeration.
Next came treprostinil (Remodulin) — also given by infusion, administered either subcutaneously or intravenously. There is no mixing or refrigeration required, the agent has a longer half life compared to Flolan, and it is competitively priced. Subcutaneous administration results in a high rate of intolerable infusion pain and rash, however. The benefit came at the price of being forever tied to an infusion pump.
During that same period, the first oral therapy, bosentan (Tracleer), was making waves. Tracleer is an oral, BID, nonselective endothelin receptor antagonist currently priced at nearly $43,000 per year. Bosentan has one nagging safety concern — abnormal liver function — with an incidence rate over 11 percent in clinical trials.
In 2005, two additional agents were approved: sildenafil (Revatio), a phosphodiesterase-5 (PDE-5) inhibitor/vasodilator, administered three times per day and costing about $11,000 per year at the lowest dose, and inhaled iloprost (Ventavis), a six-times-per-day prostacyclin analogue/vasodilator costing roughly $65,000–75,000 per year depending upon dose.
We now have three different families of targeted therapies working on three different pathways: blocking the elevated endothelin-1 levels that are a hallmark of this disease, extending the benefits of nitric oxide through the inhibition of PDE-5, and replacing prostacyclin.
The latest entrant is sitaxsentan (Thelin). Sitaxsentan is an oral, second generation endothelin receptor antagonist (ET-A ) that acts selectively by blocking the binding of the ET-1 peptide to the ET-A receptor, causing a decrease in pulmonary pressure. Sitaxsentan is the only once-per-day medication for use in pulmonary arterial hypertension. It also has no drug-to-drug interactions with the PDE-5 family, a trait that differentiates it from bosentan and that will most likely become much more important as combination therapy becomes established.
In a bold move, the manufacturer performed a head-to-head, long-term, open label monotherapy trial against bosentan. This decision paid off — sitaxsentan demonstrated significant improvements in time-to-clinical worsening measured by reduced hospitalizations, need for new therapy, and other events including death, a lower rate of treatment discontinuations from treatment, and a lower rate of abnormal liver function tests. There was also an increasing trend toward improved survival versus bosentan in a long-term, open-label comparative analysis, a trend that did not reach significance at the end of the trial. This agent, as well as most of the other products for PAH, is to be distributed through specialty pharmacies and coupled with an outcome measurement and improvement program for patients with PAH.
Given the rapidly progressive, destructive nature of PAH, it is likely that combined therapy will become the focus of physicians seeking to slow this disease. Already, pulmonologists and cardiologists are using a variety of combinations of existing drugs, with the combination of ET-A and PDE-5 drugs becoming common. They are likely to be rewarded with new FDA-approved entrants into both of these classes. But this trend will massively increase the cost of care: high dose PDE-5 can cost $30,000 per year (although the FDA was clear in the package labeling that the maximum dose of Revatio should not exceed 20 mg TID).
Managed care will also be greeted with more patients, not because the incidence is increasing, but because diagnosis is becoming more accessible as more physicians identify the disease and learn about improved therapy. The prices of the primary and add-on therapy will significantly affect the cost of treating this disease, a reporting challenge as several of the current therapies are traditionally covered under the medical benefit. It will force pharmacy and medical directors to consider the implications of having separate reporting mechanisms for these drugs. Another issue managed care will have to tackle is diluted benefit design — more of the cost shifted to the patient. All of the current manufacturers offer compassionate access programs typically administered through specialty pharmacies that dispense the drug(s).
Although the cost of treating pulmonary arterial hypertension is high and will most assuredly rise, managed care directors are now in a position to study the clinical outcomes, especially the head-to-head data. Managed care will be wise to consider a stepped-care approach for formulary control for this dreaded disease. Insurers will also be wise to consider carefully following the utilization of the PDE-5 family of drugs. The current non-flat pricing of various Revatio doses versus Viagra flat pricing also offers an opportunity to substantially reduce yearly cost.
Again, new entrants into the targeted therapy realm should cause managed care decision-makers to continue to sharpen their management strategy and tactics in what will undoubtedly become a habit in this era of rapid targeted and biologic development, the hallmark of Tomorrow's Medicine!