Debra Freiheit, RPh

Patients with a new diagnosis of acute coronary syndrome (ACS) often do not know a great deal about their disease, its treatment, or the lifestyle changes needed to prevent recurrence.

 Restenosis is common (39% of patients) after percutaneous coronary intervention.

 In addition, ACS recurrence lowers quality of life and is expensive.

Pharmacists have the ability to improve outcomes and increase the quality of life of their patients. Early, individualized education leads to better self-care and greater satisfaction with that care.

 Also, family and health care social support increases the perceived benefit,

 which improves adherence with self-care and thereby improves outcomes.

Self-care (eg, smoking cessation, regular health checks, medication adherence, diet, exercise) can prevent recurrence of ACS, but long-term adherence to self-care is key. Adherence to self-care depends on a patient’s beliefs, disease knowledge, overall ability to function, emotions (eg, anxiety, depression), and outside influences (eg, social and health care networks). Disease knowledge includes knowing about ACS characteristics, risk factors, medications, and dietary and exercise needs. Knowing more does not affect a patient’s anxiety, depression, or valuation of the benefits of self-care.

Self-efficacy, which includes the ability to manage one’s own medications, smoking, diet, and exercise, notably influences self-care. Encourage your patients to see past the likely occurrence of reduced body function. Help them understand there will be setbacks that increase the perception of barriers, which can be overcome with a positive attitude.

Patients may not like hearing it, but improvements in diet, as well as exercise and smoking cessation, can help.

Most individuals will adhere to self-care for a month after they are given an ACS diagnosis, but adherence drops at about 6 months after discharge from the hospital.

 Smoking, combined with a lack of exercise or dietary restraint, for even 6 months after an ACS incident, increases nearly 4-fold the incidence of acute myocardial infarction, stroke, and death.

 Regular monitoring and education on the benefits of diet and exercise, can improve patient adherence to healthy behaviors.

Lack of exercise, including excessive sitting, increases cardiac morbidity and mortality.3 At least a half hour of moderate exercise 5 times per week is recommended for patients who have been cleared for exercise by their doctor.

 Even moving, rather than sitting for extended periods, has health benefits for everyone.

 Having a workout program increases the likelihood of continuing to exercise.

It has repeatedly been shown that heart health can be improved and heart attacks prevented by having a healthy diet; engaging in physical activity; maintaining a healthy body weight, blood pressure and cholesterol levels; and reducing or eliminating alcohol and smoking. Healthy diets known to help patients with ACS, include the Mediterranean diet and a diet high in fruits, vegetables, whole grains, and seafood, with limited salt and sugar. Simply having a healthy diet and limiting alcohol reduces heart attack risk by onethird. The combination of a healthy diet, moderate alcohol use, moderate exercise (4-5 hours a week), smoking cessation, normal blood pressure and cholesterol levels, and a healthy body mass index decreases a woman’s chance of a first heart attack by 92%.

ACS management has improved with the use of interventional treatment strategies, antiplatelet drugs, and riskmodifying drugs.

 Outcomes after ACS are optimized by revascularization and aggressive medication therapy, including the use of anticoagulants and lipidlowering medications.

Once blood vessels are damaged, arterial plaque is more prone to forming.

 The risk of recurrence is high soon after the incident (within 1 month) and for the long term.

 A high cholesterol level, high blood pressure, diabetes, and smoking encourage clot formation.

 Statins are typically started, even if the cholesterol level is not particularly high, with a low-density lipoprotein goal of 100 mg/dL or lower.

 For patients with unstable angina, pravastatin can reduce the death rate by one-fourth, as well as reduce the risk of subsequent myocardial infarctions, coronary revascularization, and stroke.

After an ACS episode, use of nonsteroidal anti-inflammatory drugs, other than aspirin, should be stopped, as they increase cardiovascular risks and increase the bleeding risk associated with many anticoagulants. Anticoagulants, however, are often prescribed after an ACS episode.

Anticoagulants are used as secondary prevention after a diagnosis of ACS. Dabigatran, apixaban, rivaroxaban, edoxaban, and warfarin all reduce the risk for stroke, intracranial hemorrhage, and systemic embolism. Because warfarin requires regular monitoring, it is being used less often for treating ACS. The newer oral agents may be preferred to warfarin because they are easier to take, regular monitoring is not required, and they do not have dietary interactions. Bleeding is always a risk with the use of any anticoagulant. Dual antiplatelet treatments (eg, aspirin and clopidogrel) are commonly used, but increase the risk for major bleeding. The efficacy of ticagrelor and prasugrel compares favorably to clopidogrel for reducing ischemic events in patients with ACS. Pharmacists should help patients understand that anticoagulants are often lifelong treatments.

Support from family and health care providers can promote self-efficacy.

 If you notice patients not refilling their prescriptions, you have the opportunity to point out the benefits of taking their medications regularly.

 If you detect frequent divergence from prescribed medication, it may warrant notification of the patient’s primary physician. Statins significantly reduce morbidity and mortality in coronary artery disease, but only if they are taken regularly.

 Benefits of statins are only seen after 1 to 2 years of continuous use.

Lifestyle modifications (primarily diet and exercise) are effective for reducing coronary heart disease, but are rarely adhered to despite being, safe, inexpensive, and helpful (Table

 Social support can decrease anxiety and promote the benefits of self-care.

 Pharmacists can also provide support by encouraging patients to care for themselves, promoting the benefits of self-care, and reducing anxiety and depression through counseling.

Table: Effects of Lifestyle on Heart Health Level

				Never smoked or quit more than a year ago

				• >4 servings of fruits and vegetables per day

				• 2 or more servings of fish per wk

				• ≤450 calories per week of sweets

				• ≥3 servings of whole grains per day

				Up to 49 min a week at moderate intensity

				≥150 min a week at moderate intensity

Articles

Patients with a new diagnosis of acute coronary syndrome often do not know a great deal about their disease, its treatment, or the lifestyle changes needed to prevent recurrence.

Acute Coronary Syndrome: How to Empower Patients

About 25 million Americans see a physician for an upper respiratory infection (URI) every year.

 There are more than 1 billion colds in the United States every year,

 as well, and 3 to 5 million individuals worldwide catch the flu, with more than 250,000 individuals dying from it each year.

Vaccination, the best preventive measure for the flu, which can be mild to severe,

 is very strongly encouraged for pregnant women and patients at high risk of complications due to other diseases, including asthma, diabetes, heart disease, and immunosuppression.

 The American Academy of Pediatrics even recommends universal use of trivalent or quadrivalent flu shots, with no preference given to either.

 Influenza A is subdivided by hemagglutinin (H protein) and neuraminidase (N protein), such as H1N1.

 Influenza B is named for where it was first identified (Victoria or Yamagata lineage).

 Influenza C causes milder illness and occurs less often, so it is not included in the seasonal flu shots.

Effective management of URIs depends on detection and differentiation within 48 hours of symptom onset—for efficacy, antivirals need to be started within these 48 hours5,6 (Online Table

). Roche’s new Liat PCR System is a pointof- care test that distinguishes between influenzas A and B, using a nasal swab specimen, in about 20 minutes.

 The test is 94% accurate, as well as extremely sensitive (it has a low limit of detection).

Antivirals are not a substitute for immunization, but can be used for treatment or prophylaxis.

 It is expected that this year’s flu viruses (ie, the 2015-2016 flu season) will be susceptible to all of the neuraminidase inhibitors.

 Therefore, consider early, empiric treatment of hospitalized and other high-risk patients with neuraminidase inhibitors.

 Amantadine and rimantadine are not recommended due to high resistance in the currently circulating flu virus.

For specific recommendations for your pediatric patients, check the American Academy of Pediatrics website (www.aapredbook.org/flu) for updated information when the flu season officially starts.

 Current pediatric guidelines recommend neuraminidase inhibitor antivirals (oseltamivir or zanamivir) for severe or progressive confirmed/highly suspected H1N1 infections.

 For H3N2, oseltamivir or zanamivir are recommended, while adamantanes (amantadine, rimantadine) are not recommended.9 For H5N1, oseltamivir and zanamivir are first-line treatment, with amantadine reserved for when neuraminidase inhibitors are not available.

Antivirals are not recommended for influenza-like syndrome: resistance to antivirals is emerging, and they do not seem to affect outcomes much.

 About 2% of flu samples (from the 2013 to 2014 flu season) were resistant to neuraminidase inhibitors, primarily oseltamivir.8 Neuraminidase inhibitors also should not be used in close timing with the flu shot, as they could decrease the vaccination’s effectiveness.

Using oseltamivir for the flu decreases the risk of lower respiratory tract complications and the need for antibiotics by 28%.

 Oseltamivir is recommended for postexposure prophylaxis in nonvaccinated, institutionalized people,

 as well as for uncomplicated influenza A and B.10 It can be used in renally impaired patients, including those on dialysis.

 Nausea and vomiting are the most common adverse effects (AEs).

 Therefore, oseltamivir should be taken with food to decrease stomach upset.

 Oseltamivir reduces flu symptoms by 1.5 days for pediatric patients, 1 day for geriatric patients, and 1.3 days for adolescents and adults.

 When used prophylactically, only 1% of patients got an influenza infection.

Zanamivir is inhaled, so it is not recommended for patients with airway diseases, as serious bronchospasm has occurred.

 It is given twice daily for 10 or 28 days (treatment and prophylaxis, respectively) and can be used to treat or prevent influenza A or B in patients, but is not proven effective in nursing home patients.

 AEs are similar to placebo in frequency.

 Using zanamivir for postexposure prophylaxis reduced the incidence of flu from 19% to 4.1% in infected households and from 6.1% to 2% in community outbreaks.

 Although zanamivir reduces flu symptoms by 1 to 1.5 days, patients with lower temperatures (100.94°F [38.3°C] or lower) and less severe symptoms benefit less.

Peramivir is a single-dose intravenous infusion neuraminidase inhibitor approved for flu treatment

 in adults; however, it did not help patients whose flu was so severe that they were hospitalized.

 Peramivir reduced flu symptoms by 21 hours.

Amantadine and rimantadine are used for both the treatment and prevention of influenza A (H1N1, H2N2, and H3N2), but have little to no effect on influenza B.

 Although amantadine is approved for the treatment and prevention of influenza A in adults and pediatric patients, rimantadine is approved just to treat influenza A in adults (but can be used for prophylaxis in both adults and children).

 When used for prophylaxis, either drug can be given with a flu shot while immunity develops.

 Common AEs of both drugs include nausea, dizziness, and insomnia.

 These drugs may be a less desirable treatment, as there are influenza A variants that are resistant to them.

 Amantadine is dosed orally once a day, but the dose can be divided if there are central nervous system effects.

 Rimantadine is dosed orally twice daily.

About 25 million Americans see a physician for an upper respiratory infection every year.

Upper Respiratory Infections: The Lowdown

If all individuals with diabetic retinopathy were treated in a timely manner, the incidence of blindness from diabetes could be decreased by 90%. Many factors that are completely within your own control have a notable impact on reducing your risk of diabetic retinopathy, including regulating blood sugar and blood pressure, and following recommended checkups.

Although some people may not feel they need eye care, most early eye disease has no signs or symptoms. Following recommended exam schedules detects and promotes treatment of diabetic eye disease and cuts the occurrence of severe vision loss by half or more,

 and early detection and treatment of diabetic retinopathy reduces vision loss by up to 60%.

 Half of adult patients with diabetes do not have annual eye care, however.

 The most common reasons for skipping eye care given by individuals are that they do not feel they need it or they cannot afford it.

Medicare covers a yearly exam for diabetic neuropathy, and many individuals now have vision coverage through their health insurance.

 Patients with health insurance are more likely to have recommended eye exams.

 Lack of insurance increases the probability of eye problems.

 Uninsured and lowincome individuals are the patients most likely to cite cost as a reason for not seeking care, but even without insurance, dilated eye exams have low upfront costs, reduce patients’ overall costs, and increase quality of life.

: it currently affects nearly 26 million Americans, or about 8% of the US population.

 The Centers for Disease Control and Prevention (CDC) recently reported that nearly 2 million individuals were newly diagnosed with diabetes in 2010.

 Of that group, 30% of adults had prediabetes (high blood glucose or glycosylated hemoglobin [A1C] level, but not high enough to be considered diabetic) and half of the elderly population was prediabetic.

 It is estimated there will be 366 million individuals with diabetes worldwide by 2030.

Diabetic retinopathy is a complication of diabetes and is the leading cause of new-onset blindness in US adults.

 Because vision decreases slowly with age, many patients do not even realize they have a problem.

 More than 33,000 new cases of diabetic macular edema and 86,000 cases of proliferative diabetic retinopathy are diagnosed every year in the United States, along with 12,000 to 14,000 new cases of blindness.

 In addition, within 3 years after a diagnosis of diabetes, 28% of adults will develop diabetic retinopathy and 4% will have advanced retinopathy, which can lead to vision loss.

Diabetic retinopathy happens in most patients with type 1 diabetes and is seen in over 77% of patients with type 2 diabetes within 20 years after receiving a diagnosis.

 The longer a person has had diabetes, the higher the chance of retinopathy and blindness.

 Therefore, the elderly are more affected by diabetic retinopathy, at a rate of 27% of individuals older than 65 years.

Treating diabetes can reduce the risk of diabetic retinopathy by 90%.

 The only ways to prevent diabetic retinopathy are by controlling blood sugar, blood pressure, and other factors.

 For example, intensive blood glucose control reduces diabetic retinopathy, even if your A1C level does not improve.

 In addition, hypertension worsens diabetic retinopathy, as do high cholesterol and high lipid levels.

 Losing weight, exercising, and improving nutrition can significantly improve your health and slow or prevent complications from diabetes.

 For instance, early use of antioxidants and zinc can reduce visionthreatening age-related macular degeneration by 25%.

Adhering to health checks (glucose, blood pressure, and cholesterol monitoring; eye and foot exams) recommended by your primary care practitioner (PCP) can reduce the likelihood of eye problems.

 Detecting and treating diabetic eye disease can reduce the rate of severe vision loss by half.

For most (65%) patients with diabetes, vision is adequately helped by glasses.

 If glasses and other self-care are not enough, you can talk to your PCP about the following treatments:

 more than halves vision loss from diabetic retinopathy, to less than 2%.1

 (removal of the clear gel that fills the eye between the lens and the retina) in patients with type 1 diabetes may reduce the amount of time they have poor vision after diabetic vitreous hemorrhage (bleeding).

 Early vitrectomy showed no advantage for type 2 diabetes.

Taking control of your eye health can have long-lasting benefits. Following recommended exam schedules has been shown to reduce eye problems in people with diabetes.

Debra Freiheit has been a practicing pharmacist and human services professional for over 25 years. Specializing in medical information, Debra has compiled a broad spectrum of experience obtained through research for companies including Cerner and PPD Inc. With an emphasis on clear and concise information transfer, Debra has built a career communicating data with medical professionals and patients. Education and knowledge have been her motivation for a rich career of caregiving through research. Debra’s current project involves the creation of a multinational database of drug information. 

Prevention of Blindness from Diabetes Mellitus: Report of a WHO Consultation in Geneva, Switzerland, 11 November, 2005

. Switzerland: World Health Organization; 2006. ISBN: 92 4 154712 X.

		Chou CF, Sherrod C, Zhang X, et al. Barriers to eye care among people aged 40 years and older with diagnosed diabetes, 2006-2010. 

. 2014;37(1):180-188. doi: 10.2337/dc13-1507.

		Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic neuropathy. Two-year results of a randomized trial. Diabetic Retinopathy Virectomy Study report 2. 

		Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. 

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		Your medicare coverage: is my test, item, or service covered? Medicare website. www.medicare.gov/coverage/yearly-eye-exam.html. Accessed September 9, 2015.

		Rein DB, Wittenborn JS, Zhang X, et al. The cost-effectiveness of welcome to medicare visual acuity screening and a possible alternative welcome to medicare eye evaluation among persons without diagnosed diabetes mellitus. 

2012;130(5):607-614. doi:10.1001/archopthalmol.2011.1921.

		National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Centers for Disease Control and Prevention website. www.familydocs.org/f/CDC%20Diabetes%20fact%20sheet-2011.pdf. Published 2011. Accessed September 1, 2015.

		Fout BT, Gilleskie DB. Does health insurance encourage or crowd out beneficial nonmedical care? A dynamic analysis of insurance, health inputs, and health production. 

		Diabetic Retinopathy Vitrectomy Study. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) report No. 1. 

If all individuals with diabetic retinopathy were treated in a timely manner, the incidence of blindness from diabetes could be decreased by 90%. 

Eye Health: Insights for Patients with Diabetes

Pulmonary arterial hypertension (PAH) affects between 15 and 50 million individuals.

 Remodeling of the pulmonary vasculature, thrombi, and increased vascular resistance and pulmonary arterial pressure (over 25 mm Hg) lead to right heart failure and death if not treated.

 PAH may be idiopathic or genetic, or caused by drugs and/or disease.1 The 3-year survival rate for idiopathic or heritable PAH is 74%.

World Health Organization (WHO) functional classes range from least (class I) to most affected (class IV) based on functional compromise (including shortness of breath, fatigue, chest pain, and dizziness); 75% of patients are WHO functional class III/IV at diagnosis.

 Clinical presentation is usually related to right heart failure symptoms.

 Medications developed specifically for PAH include prostanoids (epoprostenol, treprostinil, and iloprost) and endothelin receptor antagonists (ERAs) (bosentan and ambrisentan).

Prostanoids (Prostacyclin Vasodilators) Prostacyclin promotes vasodilation, but is decreased with PAH.

 Prostanoids are direct vasodilators that inhibit platelet aggregation, cause smooth muscle relaxation, and may affect pulmonary remodeling and reduce inflammation.

 Adverse effects (AEs) common to all prostanoids include headache, gastrointestinal disturbances, jaw pain, and flushing.

 Consider using inhaled formulations to reduce systemic AEs.

 This drug improves symptoms, exercise capacity, hemodynamics, and survival (possibly), but it is complex to administer.

 Because its short half-life (less than 6 minutes) necessitates an indwelling catheter for continuous infusion (increasing infection and thrombosis risk), pump failure could lead to deadly rebound pulmonary hypertension.

 Close observation is needed during initiation/ titration because of potentially fatal acute pulmonary edema.

Dosing starts at 2 ng/kg/min and increases to 10 to 16 ng/kg/min if tolerated.

 There are 2 formulations: the more stable (24 to 72 hours) arginine-mannitol excipient (Veletri) or the glycine-mannitol excipient (Flolan), which is only stable at room temperature for 8 hours (24 hours using cold packs).

Iloprost (Ventavis) is an inhaled prostanoid that improves exercise tolerance and symptoms, and slows deterioration.

 Although monotherapy works for about 17% of patients, over half lose efficacy within 1 year.

 Iloprost is dosed at 2.5 to 5 mcg inhaled 6 to 9 times a day (every 2 hours while awake).

 Hepatic impairment slows elimination, so dosing intervals may increase (eg, 3-4 hours) depending on response.

 Cough and insomnia are common AEs, and iloprost may interact with warfarin.

 Transitioning between inhaled iloprost and inhaled treprostinil appears safe and well tolerated.

 Treprostinil increases quality of life and improves pulmonary function, with a 68% survival rate at 4 years.

 It is available as an infusion, inhalation, or oral tablet.

 A half-life of about 4 hours reduces the dosing frequency.

Parenteral treprostinil (Remodulin) is given subcutaneously (SC) or intravenously (IV) with a pump.

 At room temperature, SC fluid is stable for 72 hours and the IV fluid for 48 hours.

 Dosing is started at 1.25 ng/kg/min (IV) or 2.5 ng/kg/min (SC). The average long-term doses are 26 and 42 ng/kg/min, respectively.

 Pump/tubing problems (30%), and edema are common AEs.

 Local pain and inflammation (SC infusion site pain 85%; not a problem with IV) is doselimiting or leads to discontinuation.

 Use of the same site for 4 or more weeks reduces pain peaks brought on by injection site changes.

 Bloodstream infections are less frequent with treprostinil than with epoprostenol (0.36 vs 0.12 infections/1000 treatment days).

Inhaled treprostinil (Tyvaso) is dosed 4 times a day, at least 4 hours apart.

 Dosing starts at 18 mcg (3 breaths/dose); full dose is 54 mcg (9 breaths/dose).

 Cough is very common (54%), as is dizziness and throat irritation.

 Triple therapy with sildenafil, bosentan, and inhaled treprostinil is associated with a 91% survival rate at 24 months.

Oral treprostinil (Orenitram) is a sustained- release (2 times/day) tablet.

 Oral bioavailability is low (17%). It is dosed with food to increase area under the concentration time curve, C

. Dosing starts at 0.25 mg, increasing to an average of 3.4 mg. Consider recommending 0.25 mg every 8 hours for tolerability, which limits the maximum oral dose. Severe hepatic impairment is a contraindication due to hepatic metabolism of the oral tablet and because the tablet shell does not dissolve. Use with caution in patients with diverticulitis because the tablet may lodge in the diverticulum.

ERAs mediate vasoconstriction, fibrosis, proliferation, inflammation, vascular hypertrophy, and organ damage.

 They counteract endothelin-mediated vasoconstriction and decrease smooth muscle proliferation and remodeling. Endothelin and its receptors are overactive in PAH, however,

Bosentan (Tracleer) is an oral medication that improves exercise capacity and functional status, delays clinical worsening, and maintains safety and efficacy up to 5 years.

 It is only available through a restricted access program due to its hepatotoxicity and teratogenicity risk; monthly monitoring is mandatory; pregnancy is contraindicated.

 Abnormal liver function tests occur in about 17% of patients, and most events resolve with discontinuation.

 Dosing starts at 62.5 mg twice daily, with or without food, increasing to 125 mg twice daily after 1 month.

 About 30% will need concomitant PAH medications (sildenafil, tadalafil, or prostanoids).

Ambrisentan (Letairis) is an oral, highly selective ERA that decreases pulmonary arterial pressure, improves lung function and hemodynamics, delays time to clinical worsening, and has a dose-dependent increase in exercise tolerance.

 AEs include peripheral edema, headache, and dose-dependent nasal congestion, but ambrisentan is well tolerated long term.

 Dosing starts at 5 mg daily, increasing to 10 mg daily if tolerated; monitor monthly for increased liver function and bilirubin.

 Hemoglobin and hematocrit reductions are possible: recommend baseline levels and periodic monitoring.

Macitentan (Opsumit) is an extendedrelease tablet (set dosing: 10 mg once daily) and has a high affinity for, and prolonged binding at, endothelin receptors.

 It is the first ERA with significantly decreased morbidity and mortality. The drug also causes dose-dependent decreases in mean arterial pressure, but does not affect heart rate or QTc, even at triple the approved dose. It has a black box warning regarding reproductive effects and hemoglobin decreases. Because of possible liver injury, it is not recommended for use in patients with severe hepatic impairment. Macitentan does not interact with warfarin or cyclosporine, it increases sildenafil exposure; ketoconazole doubles to triples macitentan exposure (but is still well tolerated); rifampin decreases macitentan concentrations 4-fold. Pharmacokinetics are not affected by age, sex, meals, ethnicity, or hepatic or renal impairment.

Currently, the preferred treatments for mild (WHO class II) PAH include phosphodiesterase inhibitors (sildenafil and tadalafil), riociguat, and ERAs (bosentan, ambrisentan, and macitentan).

 Moderate to severe PAH (WHO classes III and IV) usually require prostacyclin analogs (epoprostenol, iloprost, and treprostinil), which improve mortality, clinical worsening, exercise capacity, and hemodynamics.

 Combination therapy with medications with different mechanisms of action is an option; however, studies to date have shown limited improvement in efficacy with combinations tried.

 Several more therapeutic approaches are still under study for PAH.

 Nonpharmacologic treatments include balloon septostomy or lung transplantation (the treatment of choice when pharmacologic agents are insufficient).

Debra Freiheit has been a practicing pharmacist and human services professional for more than 25 years. Specializing in medical information, she has compiled a broad spectrum of experience obtained through research for companies including Cerner and PPD Inc. With an emphasis on clear and concise information transfer, Debra has built a career communicating data with medical professionals and patients. Education and knowledge have been the motivation of a rich career of caregiving through research. Debra’s current project involves the creation of a multinational database of drug information.

		Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. 

. 2015;54(5):457-471. doi: 10.1007/s40262-015-0255-5.

		LeVarge BL. Prostanoid therapies in the management of pulmonary arterial hypertension. 

. 2015;11:535-547. doi: 10.2147/TCRM.S75122.

		Simonneau G, Galie N, Jansa P, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. 

Remodeling of the pulmonary vasculature, thrombi, and increased vascular resistance and pulmonary arterial pressure lead to right heart failure and death if not treated.