Drug Criteria & Outcomes: Under pressure: A review of pulmonary hypertension and its treatments
Drug Criteria & Outcomes
Under pressure: A review of pulmonary hypertension and its treatments
By Karla Hinds, Pharm. D. student at Auburn (Al) University,
[Editor's note: Hinds graduated from Auburn in May 2007.]
Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder, but it is associated with high morbidity and mortality. Pulmonary arterial hypertension (PAH) affects about one to two people per million, usually those in the 20 to 30 year age range. Though treatment options have increased, the search for the ideal drug and/or combination therapy is an ongoing one for many patients with arterial hypertension.
Women are three times more likely than men to be diagnosed with PAH. Additional risk factors for PAH include portal hypertension or hepatic cirrhosis, pregnancy, obesity, cocaine abuse, use of oral contraceptives, fenfluramine, or dexfenfluramine, HIV infection, and genetic predisposition.1 Due to the nonspecificity of initial symptoms, such as fatigue and shortness of breath, the average length of time from onset of symptoms to diagnosis is approximately two years. As the disease progresses, other symptoms can include dizziness on exertion, chest pain, and peripheral edema. At this time, there is an average survival time of 2.8 years after diagnosis.2-3
The diagnosis of IPAH is based on exclusion of other conditions, including COPD, left-sided heart disease, rheumatoid diseases, HIV, or liver disease. Other common etiologies of PAH are due to congenital heart defects or connective tissue disease. Right heart catheterization is required to confirm the diagnosis by measuring hemodynamic parameters.2 According the American College of Chest Physicians (ACCP), PAH is defined as a sustained mean pulmonary arterial pressure (MPAP) greater than 25mmHg, or greater than 30 mmHg during exercise, and mean pulmonary capillary wedge pressure less than 15mmHg.2-4
Major advances in the treatment of IPAH have occurred in the past 30 years, with four new drug approvals since the year 2001.2 Sitaxsentan, a selective endothelin receptor antagonist is the newest drug for the treatment of PAH in the pipeline.5 Available therapies for PAH are palliative, at best, and are not without consequence; therefore, it is important to carefully weigh the risks and benefits of each medication when choosing therapy. The treatment options for IPAH have increased tremendously in the past decade, and new treatments are still under development. For example, though no cure exists to date, epoprostenol has significantly increased the number of patients surviving to three years. Attempts to ease the delivery of this drug resulted in treprostinil and iloprost, which unfortunately did not show the same efficacy results as epoprostenol. Further studies should be conducted to determine if combination therapy with any of the available agents result in improved patient outcomes. The ideal drug would be one that targeted all pathological components of IPAH, could be orally-administered, and had few side effects. Until this product is developed, improved quality of life and increased survival time will remain the optimal level of treatment that can be provided for patients with IPAH.
Until recently, mainstays of treatment for IPAH included warfarin, calcium channel blockers (CCBs), digoxin, and diuretics. CCBs proved only to be efficacious in 10-25% of patients,2-3 so treatments were quite limited for a vast majority of patients. Epoprostenol came to market in 1995,2 and is now considered first-line therapy by the ACCP.4 The poor outcomes of the available treatments prompted research for drugs to correct the underlying pathophysiology of IPAH. Here is an update on some of the current options:
Calcium Channel Blockers: Once a diagnosis of PAH has been made, the patient's vasoreactivity should be measured.2-4 ACCP guidelines recommend the use of IV epoprostenol, adenosine, or inhaled nitric oxide4 for this trial due to risk of systemic hypotension and the long half-life associated with the use of CCBs for this testing.2 Patients with PAH are classified as responders or non-responders based on the fall in MPAP when these drugs are administered. Responders have a fall in MPAP of at least 10 mmHg to less than or equal to 40 mmHg while maintaining cardiac output. Patients who are classified as "responders" show improved survival when treated with high-dose longterm oral CCB. One study by Rich, Kauffman, and Levy showed a 94% five-year survival rate in responders treated with high-dose CCBs as opposed to a 55% five-year survival rate in non-responders treated with diuretics, digoxin, and/or warfarin.2,6
The risk of systemic hypotension and decreased cardiac output associated with the use of high-dose CCBs can limit their utility, even in responders. If CCB therapy is indicated and deemed safe, a low to moderate dose of amlodipine, diltiazem, or nifedipine should be initiated, and titrated upwards as tolerated to a maximum dose of 40mg/day6, 720 mg/day, or 120mg/day, respectively. Verapamil should be avoided due to its increased negative inotropic effects2 and greater number of drug interactions when compared to other agents in its class.2,4,6
Warfarin: Patients with idiopathic PAH often have in situ thrombosis, as well as a higher risk of pulmonary thromboembolism due to right ventricular failure and venous stasis. Patients already possess compromised pulmonary circulation, and any obstruction in blood flow due to thrombus formation can greatly increase the risk of mortality. Another risk of thrombus associated with IPAH is catheter-associated when patients are treated with epoprostenol. Oral anticoagulation has been shown to increase the number of patients with IPAH surviving to three years; therefore, adults and children older than five years of age with IPAH should be treated with warfarin to a goal international normalized ratio (INR) of 1.5 to 2.5. Children less than five years of age should be treated to a lower goal INR. As with any medication, the benefit in warfarin therapy should outweigh the risk.2,4 Routine monitoring should include signs and symptoms of bleeding, as well as routine INR measurement. Furthermore, patients should receive extensive counseling regarding adverse drug reactions, diet, and the importance of adherence to drug therapy and labwork.
Digoxin: Although digoxin has never been shown to have a long-term benefit in preventing mortality, it does have a niche in the treatment on IPAH. As previously mentioned, CCBs can have negative inotropic effects that can severely limit their utility in those with IPAH who are considered responders. The positive inotropic effects of digoxin can help to balance the effects of CCBs. Digoxin can also help to increase cardiac output in patients with right ventricular failure; however, the increased risk of sudden cardiac death should be carefully considered when determining if treatment with digoxin is warranted. Furthermore, hypoxemia, hypokalemia and renal insufficiency can also increase the risk of digoxin toxicity. Patients taking digoxin should be aware of the symptoms of toxicity, including nausea, vomiting, fatigue, and visual disturbances, and should be instructed to report to their health-care provider in the event of new onset of these symptoms.2,4
Diuretics: Fluid overload can be problematic in patients with IPAH and right ventricular failure. Diuretics can be used cautiously in this population to reduce peripheral edema and ascites and improve quality of life. However, excess diuresis can lead to decreased preload and decreased cardiac output resulting in systemic hypotension and compromised renal perfusion. Loop and thiazide diuretics are commonly used, but potassium-sparing diuretics are considered the agents of choice in IPAH. The choice of potassium-sparing diuretic is dependent upon whether or not the patient is concomitantly taking digoxin. Digoxin levels are altered when taken with spironolactone, but this drug interaction is not observed with triamterene; for this reason, triamterene is the preferred agent when a patient is taking digoxin. The renin-angiotensin-aldosterone system (RAAS) is commonly activated in IPAH due to increased filling pressure in the right heart. The ability of spironolactone to block the effects of the RAAS make it the preferred diuretic in patients not taking digoxin. If the use of monotherapy with these agents does not result in the desired diuresis, a loop diuretic may be added to the medication regimen. Renal function, fluid status, electrolytes (especially potassium), and blood pressure should be carefully assessed on a regular basis in patients with IPAH treated with diuretics.2
Prostacyclin Analogs: Continuous IV infusion of epoprostenol, a synthetic analog of prostacyclin has been demonstrated to have long-term efficacy in IPAH, and is considered an alternative to transplant. It is FDA approved for the treatment of IPAH associated with NYHA functional class III or IV symptoms. Epoprostenol decreases MPAP and PVR, while it increases cardiac output, exercise tolerance, quality of life, and survival. There is also some evidence to suggest that long-term treatment with epoprostenol can reverse some of the vascular remodeling seen with IPAH. Optimal dosing of epoprostenol is one that minimizes side effects and tachyphylaxis while maintaining efficacy. Studies have determined that this dose must be individualized to the patient periodically during right heart catheterization, and adjusted to a target cardiac index of 2.5-4 L/minute/m2.2 There is clearly a marked benefit associated with epoprostenol, which has led to the ACCP recommendation that epoprostenol be considered first-line therapy for IPAH in patients who do not respond to treatment with CCBs.4 There are, however, some significant downfalls to epoprostenol therapy. Firstly, because epoprostenol has a half-life of three to five minutes and no oral bioavailability, it must be administered via continuous IV infusion, requiring the placement of an indwelling subclavian or jugular catheter and the use of a portable infusion pump. Patients and their caregivers must also be instructed on mixing the drug using aseptic technique. Furthermore, epoprostenol must be protected from heat and light, so it must be stored in a container with an ice pack to maintain the integrity of the drug. This complicated drug delivery system puts the patient at risk of a pulmonary hypertensive emergency should therapy be interrupted, catheter-associated thrombus or infection, sepsis, and even death should these events occur. All of the aforementioned ADRs are in addition to those associated with the class, including nausea, headache, flushing, and jaw pain.2,4 The ACCP recommends that clinical centers of excellence manage these patients so as to prevent these complications.4 In attempts to overcome the burden of administering epoprostenol, two other prostacyclin analogs have been introduced to the market in the past five years. Treprostinil, given as a continuous subcutaneous infusion, is FDA approved for IPAH with NYHA functional class II to IV symptoms to improve exercise capacity; and iloprost, a nebulized inhalation, is FDA approved for IPAH with NYHA class III to IV symptoms. The advantages of treprostinil are its increased half-life (two to four hours) and its stability at room temperature. Furthermore, the subcutaneous infusion device is much like an insulin pump, and involves far fewer risks. Benefits of treatment with iloprost include the local administration of the drug, which limits ADRs related to systemic administration. It also has a longer duration of action than that of epoprostenol, with effects lasting from 60-120 minutes. This allows the patient to have a 10-minute nebulizer treatment six to nine times daily.2 An oral formulation of prostacyclin has been used in Japan, but has not been pursued for FDA approval in the United States.2 Although there are decreased risks associated with the use of these newer prostacyclin analogs, they have not been proven to be as effective in treating IPAH as epoprostenol; therefore, ACCP recommends that these agents be considered second-line therapies.4
Endothelin Receptor Antagonists: Bosentan (Tracleer™) is the only endothelin receptor antagonist available, and is FDA approved for the treatment of IPAH with NYHA class III or IV symptoms. It non-selectively inhibits the effects of endothelin on ET-A and ET-B, and causes a reduction in vasoconstriction and vascular remodeling. Improvements in exercise capacity, hemodynamics, and functional class have been demonstrated in clinical trials. Furthermore, bosentan is administered orally as a twice-daily dose,2 and is considered a first-line therapy for IPAH in those who are considered "non-responders" to CCBs.4 Bosentan contains a black box warning concerning the risk of teratogenecity and liver toxicity. The liver toxicity is associated with elevated liver transaminases and increased total bilirubin, is dose-dependent, and reversible upon discontinuation of the drug.7 Nonetheless, treatment with bosentan does require frequent monitoring of liver enzymes and enrollment in the TracleerTM Access Program, a distribution and reimbursement program.8
Phosphodiesterase Inhibitors: Sildenafil (Revatio™) is commonly known by the trade name Viagra ™ for the indication of erectile dysfunction. It works by inhibiting the type-5 phosphodiesterase receptor, thus increasing levels of cyclic guanosine monophosphate, a potent vasodilator in pulmonary and penile tissues.1 Sildenafil is FDA approved to increase exercise capacity in patients with NYHA class II-IV symptoms, and is the newest treatment for IPAH.2,10 Sildenafil has shown substantial improvement in hemodynamics and exercise tolerance during clinical studies with little systemic hypotension, and the SUPER-1 and 2 trials indicate that there might be a long-term mortality benefit with its treatment. Sildenafil has also been shown to be beneficial when used in combination with bosentan or prostacyclin analogs.2 Dosing of sildenafil for IPAH is 20 mg three times daily by mouth, and the most common adverse reactions are headache, visual disturbances, and nasal congestion.10 Currently, the ACCP recommends that sildenafil be used only when patients do not qualify for other treatments, or other therapy fails.4 It should be noted, however, that the most recent ACCP recommendations were published in 2004,4 and sildenafil was FDA approved for IPAH in 2005.2 With official FDA approval and more clinical trials available, ACCP will likely update their recommendations to include use of sildenafil as first-line monotherapy for mild cases of IPAH and its use in combination therapy for severe cases.10
[Editor's note: On June 15, 2007 the Food and Drug Administration advised Encysive Pharmaceuticals that its development program for sitaxsentan (Thelin) did not demonstrate the evidence of effectiveness needed for approval. The company recently met with the FDA and was expected to file a request for a formal dispute resolution as this issue went to press.]
References:
- Raissy HH, Harkins M, Marshik PL. Drug-Induced Pulmonary Diseases. In: Dipiro, JT, Talbert RL, Yee GC, et al, editors. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 587-8.
- Hackman AM and Lackner TE. Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years. Pharmacotherapy. 2006;26(1):68-94.
- Benza RL, Mehta S, Keogh A, et al. Treatment for Patients with Pulmonary Arterial Hypertension Discontinuing Bosentan. J Heart Lung Transplant.2007;26:63-9.
- Badesch DB, Abman SH, Ahearn GS, et al. Medical Therapy for Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Chest. 2004; 126(1):35s-63s.
- Drug Information Department. Encysive Pharmaceuticals Houston, TX. March 21, 2007.
- Robbins I. The Role of Calcioum Channel Blockers in Pulmonary Arterial Hypertension. Medscape Cardiology [serial online]. 2006;10(1). Available at: http://www.medscape.com/viewarticle/523338. Accessed March 29, 2007.
- Tracleer [package insert]. San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2001.
- Tracleer website. Available at: www.tracleer.com. Accessed March 18, 2007.
- Benedict NJ. Sitaxsentan in the Management of Pulmonary Arterial Hypertension.Am J Health-Syst Pharm.2007;64:363-8
- Sildenafil. DrugDex Evaluations [database online]. Greenwood Village, CO. Thomson Micromedex; Accessed March 29, 2007.
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