March 2016 FAQs

What data support selexipag and initial ambrisentan/tadalafil therapy for pulmonary arterial hypertension?

Introduction

In December 2015, the Food and Drug Administration (FDA) approved selexipag for the treatment of pulmonary arterial hypertension (PAH).¹ The approval was based on the GRIPHON trial which demonstrated that selexipag reduces hospitalization and delays disease progression compared to placebo. Additionally, the FDA approved initial treatment combination of ambrisentan and tadalafil in October 2015.² This approval was based on positive results reported in the AMBITION trial. This document reviews the evidence behind these new approvals and their potential place in therapy.

Pulmonary arterial hypertension

Pulmonary hypertension (PH) describes elevated pulmonary arterial pressure; however this condition is caused by a diverse group of disorders.³ The World Health Organization (WHO) has classified PH into 5 categories based on the pathophysiology causing hypertension and hemodynamic changes. Pulmonary arterial hypertension is classified as Group 1 in this system. The WHO groups 2-5 for PH are based on the underlying etiology which include left heart disease, chronic lung disease and/or hypoxia, chronic thromboembolic PH, and PH due to multifactorial mechanisms, respectively. The PAH group characterizes those with a mean pulmonary arterial  pressure ≥ 25 mm Hg, a pulmonary artery wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance > 3 Wood units.⁴ There are a variety of underlying etiologies that cause PAH including idiopathic disease, hereditary, drug- and toxin- induced, and disease-associated (e.g., connective tissue disease) PAH.³

Despite the varied etiologies, PAH patients have a similar pathophysiology.⁵ Shared mechanisms contributing to progressive vascular disease include endothelial cell dysfunction, smooth muscle cell dysfunction, inflammation, and procoagulant states. Due to the progressive nature of this disease, the signs and symptoms can vary. The WHO has a classification system to categorize patients based on symptoms.  Class I represents patients without limitations of usual physical activity and Class IV represents patients who cannot perform physical activity and may have signs of right ventricular failure. This classification system helps assist clinicians in choosing appropriate treatment options; although other patient-specific characteristics, such as exercise capacity, right ventricular function, hemodynamics, and patient preferences, also must be considered.⁶

Treatment options

There are 3 pathogenic pathways that are targeted in PAH, the endothelin, nitric oxide, and prostacyclin pathways.^6,7  Endothelin receptor antagonists (ERA) include ambrisentan, bosentan, and macitentan. Pulmonary arterial hypertension-specific therapies that target the nitric oxide pathway include phosphodiesterase-5 (PDE-5) inhibitors and riociguat, a soluble guanylate cyclase stimulator. Sildenafil and tadalafil are the 2 FDA-approved PDE-5 inhibitors for treatment of PAH. Until the recent approval of selexipag, the synthetic prostacyclins (epoprostenol, treprostinil, and iloprost) were the only treatment options available that targeted the prostacyclin pathway. Of these agents, only treprostinil has an orally available dosage form. Selexipag represents an additional oral option for targeting the prostacyclin pathway by acting as a selective prostacyclin IP receptor agonist.⁷ Current US guidelines recommend initial monotherapy for patients with PAH without a preference for targeting a specific pathway.^6,7 Combination therapy is recommended when a patient does not attain an adequate clinical response to initial monotherapy.  However, the American College of Cardiology Foundation guideline and the  American College of Chest Physicians guideline were published prior to the results of the GRIPHON and AMBITION trials.

Selexipag

The GRIPHON trial was a phase 3, multicenter, double-blind, placebo-controlled, event-driven randomized controlled trial that evaluated selexipag in the treatment of PAH.⁸ Patients between 18 and 75 years old with PAH who were previously untreated or were on stable treatment (≥ 3 months) with an ERA and/or a PDE-5 inhibitor were eligible for the trial. Diagnosis of PAH was confirmed via right heart catheterization (confirming pulmonary vascular resistance ≥ 5 Wood units) and performance on 6-minute walk distance (6MWD; distance between 50 and 450 m).  Enrolled patients had any previous PAH-specific medication discontinued and were randomized to receive either selexipag or placebo in a double-blinded manner. Selexipag was initiated at 200 mcg twice daily and increased to the maximum tolerated dose (up to 1600 mcg twice daily) during the first 12 weeks of the trial. The primary outcome of the trial was a composite of death or PAH-related complication. Disease progression (as measured by 6MWD or WHO functional class), worsening of PAH resulting in hospitalization, initiation of parenteral prostanoid or long-term oxygen therapy, or referral to lung transplantation or balloon atrial septostomy were defined as PAH-related complications.

A total of 1156 patients were randomized to selexipag (n=574) or placebo (n=582).⁸ The majority of patients had idiopathic disease (56.1%) and were classified as WHO functional class II or III (98.3%). Prior to enrollment, approximately 20% of patients had previously not received treatment for PAH; while one-third of patients had previously received combination therapy with ERA plus a PDE-5 inhibitor. Patients remained on selexipag and placebo for a median of 70.7 weeks and 63.7 weeks, respectively. Selexipag therapy was successful in reducing the percentage of patients who experienced a primary endpoint compared to placebo (27% vs 41.6%, respectively; hazard ratio [HR] 0.60; 99% confidence interval [CI] 0.46 to 0.78; p<0.001). This result was primarily driven by a reduction in disease progression and worsening of PAH resulting in hospitalization. Table 1 summarizes results of the primary endpoint and its individual components. Selexipag did not result in more adverse events or serious adverse events compared to placebo. However, there were more discontinuations of the study drug due to adverse events in the selexipag group compared to placebo (14.3% vs 7.1%). The most common adverse events in the selexipag group included headache (65.2%), diarrhea (42.4%), nausea (33.6%), and jaw pain (25.7%).

Table 1. GRIPHON study primary endpoint results.⁸

Ambrisentan/tadalafil combination

The AMBITION trial was a phase 3/4, multicenter, double-blind, event-driven randomized controlled trial that sought to investigate whether initial combination therapy with ambrisentan and tadalafil can provide additional benefits compared to monotherapy with either agent.⁹ Patients between 18 and 75 years old with PAH and WHO function class II or III symptoms were eligible for the trial. All patients were previously untreated or received a PAH-approved treatment for less than 14 days and not within 7 days of enrollment. After 6 months, based on the high number of patients enrolled with risk factors for left ventricular diastolic dysfunction, the protocol was amended to exclude those with 3 or more risk factors (body mass index ≥ 30, history of essential hypertension, diabetes mellitus, and history of significant coronary artery disease). Patients were randomized to receive ambrisentan/tadalafil, ambrisentan/placebo, or tadalafil/placebo in a 2:1:1 ratio. Ambrisentan and tadalafil were titrated to a target dose of 10 mg and 40 mg, respectively. The primary outcome of the trial was a composite of death, worsening PAH resulting in hospitalization, disease progression, or unsatisfactory long-term clinical response. Disease progression and unsatisfactory long-term clinical response were evaluated based on deterioration of 6MWD times from baseline and changes in WHO functional class.

A total of 605 patients were randomized to combination therapy (n=302), ambrisentan monotherapy (n=152), or tadalafil monotherapy (n=151).⁹ However, only 500 patients were included in the primary analysis due to the amended inclusion criteria. The majority of the study population had either idiopathic PAH (53%) or PAH associated with connective tissue disease (37.4%). Ninety-five percent had not previously received PAH-specific therapy and received the first dose of the study drug a median of 29 days after diagnosis. The median duration of study treatment was 73.9 weeks. Initial combination therapy was associated with a reduction in the primary endpoint compared to the pooled monotherapy group (18% vs 31%, respectively; HR 0.50, 95% CI 0.35 to 0.72; p<0.001). This result was primarily driven by a reduction in hospitalization from worsening PAH. Table 2 summarizes results of the primary endpoint and its individual components. Combination therapy did not result in more serious adverse events or adverse events leading to discontinuations compared to monotherapy. However, combination therapy was associated with a higher incidence of peripheral edema (45%), headache (42%), nasal congestion (21%), and anemia (15%) compared to monotherapy.

Table 2. AMBITION study primary endpoint results.⁹

The AMBITION trial established initial combination therapy with ambrisentan and tadalafil as a viable treatment option in PAH patients with WHO functional class II or III symptoms.⁹ Additionally, a small open-label trial of 24 patients with scleroderma-associated PAH was also recently published that demonstrated that initial therapy with ambrisentan and tadalafil was associated with a reduction in right ventricular mass and median pulmonary vascular resistance after 36 weeks of treatment.¹⁰ While this trial had several limitations including a lack of a placebo group, use of surrogate markers, and limited external validity to other PAH groups, it did provide complementary results to the AMBITION trial.

Incorporation of new data into treatment recommendations

Both the GRIPHON and AMBITION trial provide additional understanding in how to optimally treat patients with PAH. While the GRIPHON trial did not provide a head-to-head comparison, it was the landmark trial that established selexipag’s efficacy and safety in PAH, particularly in WHO functional class II and III.⁸ Selexipag represents a new oral treatment option that can target the prostacyclin pathway. The AMBITION trial established initial combination therapy as potential first-line option in patients with WHO functional class II or III symptoms.⁹ The 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines on the treatment of PAH have incorporated both trials into their current recommendations.¹¹ This guideline recommends that patients with WHO functional II or III symptoms can be treated initially with either monotherapy or oral combination therapy. For initial monotherapy, there is no recommended first-line agent, but instead route of administration, adverse effect and drug interaction profiles, patient preferences, comorbidities, physician experience, and cost should direct the choice of therapy. For initial combination therapy, ambrisentan and tadalafil combination received the highest grade of recommendation based on the AMBITION data. For patients with WHO functional class IV symptoms, initial combination therapy, including a prostacyclin analogue, is recommended. A brief overview of the current ESC/ERS recommendations is available in Table 3. Overall, the GRIPHON and AMBITION trial results have reshaped the approach to treating PAH. However, additional studies are needed to further elucidate the optimal therapy for these patients.

Table 3. ESC/ERS treatment guideline recommendations for pulmonary arterial hypertension.¹¹

References

1.      FDA approves new orphan drug to treat pulmonary arterial hypertension. Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm478599.htm. Accessed February 3, 2016.

2.      Semedo D. FDA approves combination therapy of Gilead’s Letairis plus Eli Lilly’s Adcirca for patients with pulmonary arterial hypertension. Lung disease news website. http://lungdiseasenews.com/2015/10/05/fda-approves-combination-therapy-gileads-letairis-plus-eli-lillys-adcirca-patients-pulmonary-arterial-hypertension/. Accessed February 3, 2016.

3.      Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41.

4.      Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42-D50.

5.      Attridge RL, Moote R, Levine DJ. Pulmonary arterial hypertension. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 9^th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Section id=48811465. Accessed February 3, 2016.

6.      Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2):449-475.

7.      Galiè N, Corris PA, Frost A. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-D72.

8.      Sitbon O, Channick R, Chin KM, et al; GRIPHON Investigators. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522-2533.

9.      Galiè N, Barberà JA, Frost AE, et al; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844.

10.  Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(9):1102-1110.

11.  Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177.

March 2016

The information presented is current as February 3, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What information is available on Zika virus infection?

Introduction

A recent outbreak of the Zika virus in South America, Central America, and the Caribbean has led the World Health Organization (WHO) to declare a public health emergency due to potential fetal and neurologic complications that may be associated with the infection.¹ Zika virus belongs to the Flavivirus genus similar to dengue, yellow fever, chikungunya and West Nile virus. It is primarily transmitted by bites from tropical Aedes mosquitoes but can also occur from Aedes mosquitoes found in temperate climates. Breeding of these mosquitoes occurs in standing water and bites can occur during daylight or twilight.   Maternal-fetal, perinatal, sexual and blood transfusion transmission may also occur as the virus has been detected in blood, semen, and amniotic fluid.  

Epidemiology

Although Zika virus was first isolated in Uganda in the late 1940s, the first outbreak did not occur until 2007 in Micronesia followed by a second outbreak from 2013 to 2014 in French Polynesia.^1,2  More recently, Zika virus infection was reported on Easter Island in Chile from February to June 2014 and in May 2015, infection was confirmed in Brazil and by December 2015, over 56,000 cases of Zika infection were reported.  As of February 1, 2016, Zika-virus infected mosquitoes have spread to 32 countries in Africa, Asia, South America, the Caribbean, Puerto Rico, US Virgin Islands and American Samoa. The WHO estimation is that between 500,000 and 1.5 million people have been infected with Zika virus.  Although Zika-infected mosquitoes have not been identified in the US, there have been reports of imported Zika infections by US travelers from over 25 states. ³

Symptoms/Complications

Infection with Zika virus may not lead to symptoms in all patients and may not occur for up to 14 days after exposure.^1,2 Only 20% of people who are infected develop symptoms including fever, rash, joint pain, headache, myalgia, eye pain, asthenia and conjunctivitis.  Rare occurrences of gastrointestinal symptoms (pain, nausea, and diarrhea) and pruritus have been reported.  Resolution of symptoms can be expected within 2 to 7 days. Although hospitalization and mortality rates are low, the major complications that may be associated with Zika virus infection are congenital microcephaly, fetal loss in infected pregnant women, and Guillain-Barre syndrome (GBS).

Fetal complications

Microcephaly is a condition in which full development of the head and brain has not occurred in a newborn. This can lead to developmental delays, epilepsy, hearing and vision impairment in some, but not all, children.⁴  In Brazil, over 5000 cases of newborns with congenital microcephaly have been documented from March 2015 to February 2016.² Fetal loss was reported in 91 cases.  Of the cases investigated thus far, 462 have been confirmed as microcephaly of unknown etiology of which 41 cases have laboratory confirmed Zika virus infection.  Investigation into the rest of these cases to determine presence of Zika infection is ongoing.  The presence of Zika virus has been confirmed in 4 cases of congenital malformation in Brazil. Although a causal association between Zika virus infection and microcephaly or congenital malformations has not been proven, pregnant women should follow preventative measures, including delaying travel to areas with Zika virus circulation.¹ It has been suggested that infection in the first trimester of pregnancy is associated with the highest risk of fetal complication.

Neurologic complications

Guillan-Barre syndrome is an autoimmune disorder that causes inflammation of the peripheral nerves.⁵ Symptoms usually develop 1 to 4 weeks after a viral or bacterial infection and include muscle weakness, pain, facial paralysis, and tingling in the extremities.   Although recovery from GBS does occur, residual weakness can become permanent. Additionally, weakness of respiratory muscles can cause serious complications requiring hospitalization and intubation in about 25% of patients. The incidence of death associated with GBS ranges from 3% to 5%.⁶

The possible association of Zika virus infection with GBS was first made during the 2013 outbreak in French Polynesia during which there was a 20-fold increase in the incidence of GBS compared to previous years.^2,6 A causal link, however, could not be established to Zika virus infection as some cases had documented dengue infection as well.   Subsequently, over 1700 cases of GBS have been reported in Brazil between January 2015 and January 2016 which coincides with outbreaks of Zika, dengue, and chikungunya infection.  During the 2015-2016 outbreak, an increase in the incidence of GBS has been reported in 8 countries all of which have documented Zika virus circulation. Despite the coinciding occurrences of GBS and Zika infection, further evaluation into a causal link is underway.  It has been suggested that the development of GBS may be due to sequential or co-infection with multiple flaviviruses. ² Interim guidance from the WHO suggests use of intravenous immunoglobulin (IVIG) or therapeutic plasma exchange for patients with GBS with rapidly progressive symptoms who are unable to walk.⁶

Treatment

To date, there is no treatment or vaccine for Zika virus infection.^1,7   Acetaminophen can be used to control fever and pain. The use of aspirin and NSAIDs should be avoided as use of these agents in patients co-infected with dengue virus can cause hemorrhage.  Additionally, aspirin should be avoided in children with viral illness due to the risk of Reye’s syndrome. Non-pharmacologic interventions of regular fluid intake and rest are also recommended. In order to limit further transmission, patients with Zika virus should take measures to prevent future mosquito bites. (see Table below)

According to the Centers for Disease Control and Prevention (CDC) guideline on management of Zika virus exposure during pregnancy, women who develop symptoms within 2 weeks of travel to an area with Zika virus transmission should have RNA virus and/or serologic testing performed.⁸ Pregnant women with confirmed or inconclusive test results should have routine ultrasound every 3 to 4 weeks and referred to a maternal-fetal medicine specialist.  At birth, testing of amniotic, placental, and cord tissue is recommended even in cases of fetal loss.  Infants who acquire Zika infection in utero or during delivery also can be tested if there are signs of abnormal development at birth or during fetal ultrasound. Two reports of perinatal transmission indicated no effects on the infant in one case but thrombocytopenia and rash in the second case.⁹ Reports in children have indicated mild symptoms similar to adults.

Women infected with Zika virus should continue to breastfeed. ¹⁰ Although Zika virus RNA has been detected in breastmilk, the active virus has not been detected. Currently, WHO states that the benefit of breastfeeding outweighs the potential risk of transmitting Zika virus through breastmilk.  

Prevention

Pregnant women in any trimester should consider postponing travel to areas with Zika virus circulation.¹¹  Women and their male partners who are trying to get pregnant should either reconsider travel or follow all preventive measures to avoid Zika infection.

Preventative measures for travelers visiting areas with Zika virus circulation are summarized in the Table below.  Mosquito repellants registered with the EPA are considered safe to use during pregnancy and lactation as well as in children over the age of 2 months.¹²  Babies 2 months or younger should be protected with clothing that covers arms and legs and a mosquito net over the crib and stroller. 

Table.  CDC Recommendations for Prevention of Mosquito Bites ^2,12

Sexual transmission of Zika virus has been demonstrated and presence of the virus in semen appears to be longer than in blood.¹³ Men who are infected with Zika virus can ensure the virus is not transmitted by abstaining from sex. The use of condoms can also help reduce the risk of Zika transmission. 

Two cases of Zika virus infection from blood transfusion have been reported in Brazil.¹⁴  In order to maintain a safe blood supply in unaffected areas, blood donors who have visited affected areas may be requested to delay donation for at least 28 days after their visit.  In affected regions, donations from blood donors with recent symptoms, confirmed infection, or sexual contact with an infected individual should be postponed until 28 days after resolution of symptoms or last sexual contact.  Additionally, donors should inform authorities if they develop symptoms or have a confirmed Zika infection within 14 days after a blood donation.

Conclusion

The recent outbreak of Zika virus infection transmitted primarily by tropical mosquitoes with a concomitant increase in congenital microcephaly and GBS has led to widespread measures to prevent further transmission, educate citizens and travelers, and research methods to prevent complications.  Results of research efforts and updates on Zika virus are available at the CDC and WHO websites.

References

1. Sexton DJ. Zika virus infection. In: Baron EL, ed.  UpToDate, Waltham, MA;2016. Accessed on February 23, 2016.
2. Garcia E, Yactayo S, Nishino K, et al. Zika virus infection: global update on epidemiology and potentially associated clinical manifestations. Weekly Epidemiological Record. 2016;91(7):73-88. http://www.who.int/wer/2016/wer9107/en/. Accessed February 29, 2016.
3. Centers for Disease Control and Prevention.  Zika virus disease in the United States, 2015-2016. http://www.cdc.gov/zika/geo/united-states.html. Accessed February 29, 2016.
4. World Health Organization. Assessment of infants with microcephaly in the context of Zika virus- interim guidance. http://apps.who.int/iris/bitstream/10665/204475/1/WHO_ZIKV_MOC_16.3_eng.pdf?ua=1. Accessed February 29, 2016.
5. Ferri FF. Guillain-Barre syndrome. In: Ferri FF, ed. 2016 Ferri’s Clinical Advisor. Philadelphia, PA: Elsevier;2016. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323280471003371. Accessed February 22, 2016.
6. World Health Organization. Identification and management of Guillain-Barre syndrome in the context of Zika virus. http://apps.who.int/iris/bitstream/10665/204475/1/WHO_ZIKV_MOC_16.3_eng.pdf?ua=1. Accessed February 29, 2016.
7. Centers for Disease Control and Prevention. Clinical evaluation and disease. http://www.cdc.gov/zika/hc-providers/clinicalevaluation.html. Accessed February 29, 2016.
8. Centers for Disease Control and Prevention. Update: interim guidance for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure-United States, 2016.  http://www.cdc.gov/mmwr/volumes/65/wr/mm6505e2.htm. Accessed February 29, 2016.
9. Centers for Disease Control and Prevention. Update: interim guidance for health care providers caring for infants and children with possible Zika virus exposure-United States, 2016. http://www.cdc.gov/mmwr/volumes/65/wr/mm6507e1.htm. Accessed February 29, 2016.
10. World Health Organization. Breastfeeding in the context of Zika virus- interim guidance. http://apps.who.int/iris/bitstream/10665/204473/1/WHO_ZIKV_MOC_16.5_eng.pdf?ua=1. Accessed February 29, 2016.
11. Centers for Disease Control and Prevention. Questions and answers. Zika virus infection and pregnancy: travel. http://www.cdc.gov/zika/pregnancy/question-answers.html. Accessed February 29, 2016.
12. Centers for Disease Control and Prevention. Mosquito bite prevention for travelers. http://www.cdc.gov/chikungunya/pdfs/fs_mosquito_bite_prevention_travelers.pdf. Accessed February 29, 2016.
13. Centers for Disease Control and Prevention. Interim guidelines for prevention of sexual transmission of Zika virus-United States, 2016. http://www.cdc.gov/mmwr/volumes/65/wr/mm6505e1.htm. Accessed February 29, 2016.
14. World Health Organization. Zika virus and safe blood supply: questions and answers. http://www.who.int/features/qa/zika-safe-blood/en/. Accessed February 29, 2016.

March 2016

The information presented is current as of February 29, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What are the major drug-related changes to the 2016 update of the CHEST Guideline for Antithrombotic Therapy for VTE Disease?

Introduction

Venous thromboembolism (VTE) is widely recognized as a serious health concern and encompasses patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ While the overall incidence of VTE in the United States is difficult to define because no nationwide surveillance program exists, risk factors for VTE such as advanced age, immobility, surgery, and obesity continue to become more prevalent. Patients who present with a VTE are subject to increased rates of morbidity and mortality, with an estimated 30-day mortality rate of 10% to 30%.

For years, anticoagulation with parenteral low molecular weight heparin (LMWH) transitioned to an oral vitamin K antagonist (VKA; eg, warfarin) was used routinely in the treatment of VTE.² Recommendations concerning the appropriate anticoagulant agent, duration of therapy, monitoring parameters, and secondary prevention measures are periodically updated in CHEST guidelines from the American College of Chest Physicians (ACCP). The 9^th edition Antithrombotic Therapy for VTE Disease (AT9) was published by ACCP in February 2012. At the time of AT9 publication, there were limited data on the treatment of VTE with dabigatran and rivaroxaban, the direct oral anticoagulants (DOACs) that were then approved by the Food and Drug Administration (FDA).^3,4 The DOACs offer greater convenience in administration compared to VKAs because routine testing is not required. However, because of the lack of data at the time of AT9 publication, dabigatran and rivaroxaban were not recommended as first-line therapy for VTE treatment, and a VKA or a LMWH remained the anticoagulants of choice. Additionally, the 2012 guideline made no recommendations concerning the use of aspirin for secondary prevention of VTE.

Since the publication of the AT9 guideline, the FDA has approved two additional DOACs (apixaban and edoxaban), and further studies of this drug class have been performed for VTE treatment. These events led to a guideline update (AT10) released in January 2016.⁵ Important drug-related updates in the current AT10 guideline for the treatment of VTE, including the use of DOACs and aspirin, are addressed in this review.

DOACs preferred over VKAs in non-cancer VTE

A notable change in the updated AT10 guideline is the recommended use of dabigatran, rivaroxaban, apixaban, or edoxaban over VKA therapy in patients with DVT of the leg or PE who do not have cancer as long-term (first 3 months) anticoagulant therapy.⁵

At the time of AT9 publication, strong literature supporting the safety and efficacy of DOACs for VTE treatment was lacking. ² Only dabigatran and rivaroxaban had been compared to VKA therapy for VTE treatment in well-designed randomized controlled trials (RCTs), and long-term safety and efficacy data were unavailable.^5-7 Since that time, RCTs have found each available DOAC to be similar to warfarin in safety and efficacy for acute and long-term VTE treatment, and all DOACs received FDA approval for treatment of VTE.^3,4,8-13

Additionally, a 2014 meta-analysis of 45 trials evaluated the safety and efficacy of all FDA-approved DOACs in the treatment of VTE compared with other anticoagulants, including LMWH-VKA combinations.¹⁴ Results showed that DOACs were associated with similar clinical outcomes as the more traditional LMWH-VKA combination. An additional finding was the reduced risk of major bleeding episodes with apixaban and rivaroxaban compared to the LMWH-VKA combination. Apixaban also had significantly reduced rates of major bleeding compared with all of the other DOACs and LMWH alone.

Despite the preference of DOACs as a class over VKAs, AT10 does not recommend one DOAC agent over another.⁵ However, AT10 does provide limited guidance to the selection of an anticoagulant based on patient-specific drug-disease interactions and preferences (Table). Additionally, factors such as medication compliance and cost should be considered when determining the appropriate anticoagulant. Lastly, the AT10 guideline states that unless a patient’s circumstances or preferences change during therapy, there is no need to change the anticoagulant after the first 3 months in patients who receive extended therapy.

Table. Factors influencing preferential selection of DOACs.⁵

Finally, the risk of major bleeding becoming fatal appears to be similar with the DOACs and VKA therapy despite the concern by many healthcare providers that some DOACs lack a reversal agent.^5,15  However, this concern may be diminishing because idarucizumab (Praxbind), a reversal agent for dabigatran, was approved by the FDA in late 2015.¹⁶ Similarly, andexanet alfa, a reversal agent for factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), has been shown to be effective in healthy volunteers and is currently being studied in phase III trials of acute major bleeding episodes.¹⁷ Based on the results of the current literature, AT10 now makes the recommendation to support DOACs over VKA therapy due to equivalent efficacy, less bleeding, and greater convenience for both patients and healthcare providers. ⁵ Future developments in DOAC reversal agents may further strengthen this recommendation.

DOACs and VKAs recommended equally as second-line VTE treatment in patients with cancer

For cancer patients with DVT of the leg,  the previous AT9 guideline recommended LMWH as initial treatment, followed by a recommendation for preference of VKA therapy over dabigatran or rivaroxaban.² Due to recently published evidence to support the use of DOACs in cancer patients, this recommendation has been updated to reflect no preference to either VKA or DOAC therapy as second-line therapy to a LMWH.⁵ The agent of choice for VTE treatment in patients with cancer has been LMWH due to the available literature that suggests that the risk reduction for recurrent VTE is greater with LMWH than with VKA therapy. Additionally, oral therapy may be difficult to tolerate in these patients and LMWH is easier to withhold or adjust if invasive interruptions are needed.

Vitamin K antagonist therapy was recommended over DOAC therapy in the AT9 guideline due to limited available data of DOACs in cancer patients.² Since 2012, the same evidence that supports the use of DOACs in non-cancer patients also analyzed the risk of VTE recurrence in patients with cancer, and indicates that the risk reduction is similar with VKA and DOAC therapy.^8-11 There has been no direct assessment of VTE risk reduction with a LMWH and DOACs in cancer patients, but indirect comparisons show that, compared to VKAs, LMWH significantly reduced this risk (relative risk, 0.52; 95% confidence interval [CI], 0.36 to 0.74) while DOACs did not.^5,18

In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy, aspirin may be used to prevent recurrent VTE

The previous AT9 guideline recommended that patients without a high risk for bleeding should be considered for indefinite anticoagulation after an unprovoked proximal DVT or PE.² However, AT9 made no recommendations concerning aspirin for secondary prevention of VTE. Recommendations are now included in AT10 based on new data.

Since the publication of AT9, two randomized trials have compared aspirin to placebo for the prevention of recurrent VTE.^19,20 Both studies included patients who had received initial anticoagulation after an unprovoked VTE but had discontinued anticoagulation despite being deemed at low bleeding risk. Patients were randomly assigned to receive aspirin 100 mg daily or placebo for 2 years.

In one trial, investigators found no statistically significant difference in the primary outcome of VTE recurrence.¹⁹ However, there were significant reductions in the annual rate of two secondary composite outcomes –  VTE, myocardial infarction (MI), stroke, or cardiovascular death (34% reduction), and the annual rate of VTE, MI, stroke, major bleeding, or death from any cause (33% reduction). There were no significant differences in rates of major or clinically relevant non-major bleeding or serious adverse events. In another trial, the incidence of VTE recurrence was 6.6% vs 11.2% in patients who were randomized to aspirin and placebo, respectively (hazard ratio, 0.58; 95% CI, 0.36 to 0.93).²⁰ One patient in each treatment group had a major bleeding episode and there were no differences in rates of adverse events.

Based on findings of these two studies, the AT10 guideline concludes that extended aspirin therapy reduces the risk of recurrent VTE by about one third.⁵ Although no direct comparison trials exist, this benefit is believed to be substantially lower than the benefit provided by extended therapy with a VKA or DOAC. For this reason, the recommendation for aspirin as secondary prevention of an unprovoked DVT or PE is limited to patients who wish to stop anticoagulation and do not have a contraindication to aspirin. Aspirin is not an alternative for patients wishing to receive extended anticoagulant therapy.

Conclusion

With the growing prevalence of VTE in the United States, new treatment options that provide a better safety profile, sustained efficacy, and improved ease of use continue to accrue data supporting their use. The DOACs have largely provided these benefits to patients, prompting changes in the AT10 guideline that recommend the use of DOACs over VKAs as first-line therapy for VTE in non-cancer patients, as well as no preference between the use of VKAs and DOACs for cancer patients as second-line therapy.  Additionally, AT10 is the first update to provide recommendations concerning the use of aspirin for secondary prevention of VTE in select patients who are not candidates for anticoagulation, but who would benefit from continued therapy.

The new recommendation favoring DOACs over VKA as first-line VTE treatment may be one that requires the greatest overall change in clinical practice. Careful consideration of patient specific-factors will be necessary to ensure appropriate attention is made to the choice of anticoagulant agent. Further studies are needed to directly compare DOACs to provide greater clarity on their comparative risks and benefits. Until then, DOAC selection in treatment of VTE is largely based on cost, accessibility, and comorbidities.

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Prepared by,
Maggie Guinta, PharmD
PGY1 Pharmacy Resident
College of Pharmacy
University of Illinois at Chicago

March 2016

The information presented is current as of January 15, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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