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  • 26 Sep 2019 2:06 PM | Mandy Garion (Administrator)

    Authors: Shu-wen Tran, B.S., UMKC PharmD Candidate 2020 and Diana Tamer, B.S., Pharm.D., BCOP

    How is it possible that patients with certain metastatic cancers are still treated with traditional chemotherapy when targeted precision medicine is available for them as first line agents? While sequencing the whole genome led to having technologies today to sequence each patient’s tumor DNA, and finding targeted therapies for tumorigenesis driving mutations; these therapies are costly and not affordable to most patients—even those with insurance coverage. Is there any way to drive down the cost of oncolytic agents? Let’s explore some avenues.

    Targeted therapy, otherwise known as precision medicine, are medications designed to specifically target driving mutation(s) that is/are causing the cancer type. Targeted therapy differs from traditional therapy in that they act on a specific pathway or gene mutation related to the cancer type instead of acting systemically, affecting all normal and abnormal cells. Over the past 10 years, the FDA has approved more than 80 targeted oncolytic therapies, with more than half of them approved for oral administration.1 It is important to understand that traditional chemotherapies remain the standard of care in early stages of cancer, while targeted drug therapies are options for patients with metastatic disease—if they harbor a particular mutation.  That is also partly because as new drugs are studied in clinical trials for cancer patients, they start testing them in patients that have no other options and are at more advanced stages of their disease. That being said, as these drugs gain approval, clinical trials in earlier stages of the disease are underway; which will lead to maybe more use of these agents at all stages of cancer.

    Disparities in insurance plan coverage for cancer treatment is one of the most challenging aspects patients are facing. Patients are faced with a financial burden when their plan coverage diverges (medical versus pharmacy benefit), and their oral cancer drug therapy treatment is submitted through their pharmacy benefit, instead of their medical benefit. Often times a set-back in cancer treatment occurs because they are unable to afford therapy. So why is this happening?

    “Medical benefits often require patients to pay a flat copayment (perhaps $20 to $50 per visit) for care in an outpatient setting, which can include administration of intravenous medications. Pharmacy benefits, by contrast, often have a tiered copayment structure and other provisions that increase cost sharing for more expensive medications. Pharmacy benefits may include coinsurance (in which patients are responsible for a percentage of the medication cost), high overall deductibles, and caps on annual drug benefits.”2 Most insurance plans place oral cancer agents into a “specialty tier” or “fourth tier,” which may require a cost-sharing responsibility for the patient of anywhere from 25 to 33 percent of the cost of the drug, leading to copays which can range from$150-$7,000 per month. And these medications are taken chronically, typically on a daily basis, until disease progression, unacceptable toxicity, or death. And a common question that patient ask in clinic is: “What would I do when I can no longer afford this treatment?”

    In 2013, the Cancer Drug Parity Act3 was first introduced to Congress. The purpose of this bill is to help ensure that patients will not pay more for oral chemotherapy agents under their pharmacy benefit than they would for an intravenous chemotherapy agent under their medical benefit. One might wonder, don’t we have something like this in effect? Well, yes—in 43 states. Since 2007, many states have passed their own oral parity law, but it only applies to state health plans, leaving out patients under self-funded and fully insured health plans. If Congress approves this bill, the new federal legislation will require all health plans, including the remaining seven states to adopt this cancer drug parity act. Currently, seven states have yet to adopt this cancer drug parity act: Alabama, Idaho, Michigan, Montana, North Carolina, South Carolina, and Tennessee4.

    In a retrospective claims analysis published by Dr. Dusetzina and colleagues5, authors found that oral chemotherapy parity laws showed only “modest” financial benefit for patients. Their analysis encompassed 63,780 patients from three nationwide insurers (Aetna, Humana, and UnitedHealthcare), comparing effects before and after oral chemotherapy parity laws. Patients that were studied lived in one of 16 states that had implemented oral chemotherapy parity laws from July 2008 to July 2012, and who were receiving chemotherapy treatment. Results showed an increase in patient out-of-pocket (OOP) spend of more than $100 per month in plans subject to parity versus a slight decline in plans not subject to parity (8.4% to 11.1% vs. 12.0% to 11.7%, p=0.004). Monthly patient OOP spend on oral chemotherapy agents showed a decline in plans subject to parity in the 25th-, 50th-, and 75th percentile ($19.44, $32.13, $10.83, p<0.001), but saw an increase at the 90th- and 95th percentile ($37.19, $143.25, p<0.001). Dr. Dusetzina and colleagues conclude that “these laws alone may be insufficient to ensure that patients are protected from high out-of-pocket costs.”

    So what should we do? As more and more precision, targeted therapies are being pumped into the market, cancer patients should not have to pay any less for their oral cancer drug treatment under their pharmacy benefit than they would under their medical benefit. It is currently unclear exactly how many patients will benefit from this bill. This federal act is a start to help patients gain access to precision medicine. The underlying issue may be the price of the agents themselves. But that’s another article for another time.

    References:

    1. Abramson, R. “Overview of Targeted Therapies for Cancer”. My Cancer Genome 2018. Available from: https://www.mycancergenome.org/content/molecular-medicine/overview-of-targeted-therapies-for-cancer/ (Updated May 25).
    2. Wang B, Joffe S, Kesselheim AS et al. Chemotherapy parity laws: a remedy for high drug costs?. JAMA Internal Medicine 2014. 174(11):1721-1722. Available from: https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/1907003
    3. Cancer Drug Parity Act of 2019, H.R. 1730, 116th Cong. (2019). Available from: https://www.congress.gov/bill/116th-congress/house-bill/1730/text
    4. “Oral anti-cancer therapy access legislative landscape-2018”. Patients Equal Access Coalition, 2018. Available from: http://peac.myeloma.org/oral-chemo-access-map/
    5. Dusetzina SB, Huskamp HA, Winn AN et al. Out-of-pocket and healthcare spending changes for patients using orally administered anti-cancer therapy after adoption of state parity laws. JAMA Oncology 2018. 4(6):e173598. Available from: https://jamanetwork.com/journals/jamaoncology/article-abstract/2661763


  • 26 Sep 2019 2:01 PM | Mandy Garion (Administrator)

    Authors: Marissa Chow, Pharm.D. Candidate Class of 2021 and
    Emily Shor, Pharm. D.

    Patients with malignancies have a 20% to 30% increased risk for venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE), due to their hypercoagulable state.1-3 Additionally, a VTE at the time of or within one year of cancer diagnosis is correlated with more advanced stages of cancer and increased risk of death.4 The 2019 NCCN and 2016 CHEST guidelines recommend that patients with a cancer associated VTE be anticoagulated for at least three months or indefinitely while cancer is active, patient is undergoing treatment, or risk factors remain present.2-3,5 However, the NCCN guidelines do not provide recommendations regarding routine VTE prophylaxis in ambulatory cancer patients unless they have certain risk factors, such as certain cancer types and/or chemotherapy agents. 2 Managing cancer-associated thrombosis (CAT) must balance both a patient’s increased risk of recurrent VTE patients alongside risks of bleeding. 

    The CLOT trial established low-molecular-weight heparin (LMWH) as first line therapy for chronic anticoagulation therapy in patients with metastatic disease with acute VTE.6 Despite frequent self-injections, which can affect patient adherence, LMWHs have a faster onset and reaches steady state more quickly than vitamin K antagonists.7 Moreover,  dalteparin significantly decreased risk of recurrent VTE compared to oral anticoagulants.6 While warfarin offers an oral alternative, it can be difficult to maintain a therapeutic INR due to frequent follow-up, drug-drug interactions with chemotherapy agents, malnutrition, and possible liver dysfunction.   

    Since their development, utilization of direct oral anticoagulants (DOACs) has greatly increased as their efficacy and safety were established in the setting of VTE treatment within the general population in various landmark trials. DOACs do not require frequent lab monitoring and have few drug-food interactions. However, until recently, the role of DOACs in CAT has been unclear due to limited evidence from subgroup analyses of cancer patients in each DOAC’s landmark trials. Although DOACs offer more convenient administration, further investigation of the role of DOACs as effective and safe agents in the prophylaxis and treatment of VTE in cancer patients is needed. This article will review the recently published literature regarding the use of DOACs in cancer patients. 

    VTE Treatment in Cancer Patients 

    The studies assessing the efficacy and safety of DOACs for VTE treatment in the general population had limited enrollment of cancer patients, ranging from 3% to 9%.8-11 Subgroup analyses of these patients show promising results, but the enrolled cancer patients likely had a lower risk profile. Randomized trials have recently assessed the role of apixaban, rivaroxaban, and edoxaban in CAT treatment as compared to the efficacy and safety of utilizing therapeutic dosing of a LMWH, dalteparin.

    Apixaban: ADAM VTE12 

    The ADAM VTE Trial, a multicenter, open-label trial, randomized patients with cancer-associated acute VTE to receive dalteparin or apixaban (10 mg twice daily for seven days followed by 5 mg twice daily). The most frequent types of cancer were colorectal, lung, pancreas, and breast cancers, and 65.5% of patients had metastatic disease. In the apixaban group (n=145), no major bleeding events occurred within six months compared to three major bleeding events (2.1%) in the dalteparin group (n=142) (p=0.9956). Recurrent VTE occurred in five patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (HR [hazard ratio]: 1.36; 95% CI [confidence interval]: 0.79-2.35). Monthly quality of life surveys regarding concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction (p<0.05) also favored apixaban. Thus, data from this trial supports oral apixaban therapy as it was associated with low rates of bleeding and significantly lower VTE recurrence rates.  However, full results of this study have not been published yet.

    Rivaroxaban: SELECT-D13 

    The SELECT-D Trial was a multicenter, open-label pilot study that assessed the safety and efficacy of rivaroxaban for treatment of active VTE in patients with cancer.  Patients with an active VTE were randomized to receive dalteparin or rivaroxaban (15 mg BID for three weeks, followed by 20 mg daily for a total of six months). The most prevalent primary tumors included colorectal cancer and lung cancer. The primary efficacy endpoint (VTE recurrence at 6 months) occurred in 18 (8.9%) of 203 dalteparin patients and eight (3.9%) of 203 rivaroxaban patients, resulting in a cumulate VTE recurrence rate at six months of 11% for patients receiving dalteparin and 4% for those receiving rivaroxaban (HR: 0.43; 95% CI: 0.19-0.99). The primary safety endpoint of major bleeding occurred in six patients (3.0%) receiving dalteparin and 11 patients (5.4%) receiving rivaroxaban, resulting in a cumulative major bleeding rate of 4% for the dalteparin group and 6% for rivaroxaban group (HR: 1.83; 95% CI: 0.68-4.96). Major bleeding events most commonly occurred within the gastrointestinal tract, and there were no identified CNS bleeds. Clinically relevant non-major bleeding (CRNMB) during the six-month period occurred in 4% of dalteparin patients and 13% of rivaroxaban patients (HR: 3.76; 95% CI: 1.63-8.69), indicating that although rivaroxaban and dalteparin have similar rates of major bleeding, patients receiving rivaroxaban experienced higher rates of CRNMB. Most CRNMB occurred within gastrointestinal or urologic systems. Overall, patients with esophageal/gastroesophageal cancer experienced more bleeding compared to other cancer types, which may be related to the site of action of rivaroxaban. Ultimately, this trial suggests that rivaroxaban may be a viable alternate VTE treatment option to LMWH in cancer patients. However, results of this trial cannot be translated to longer treatment due to the short follow up period.

    Edoxaban: Hokusai VTE Cancer 14

    The Hokusai VTE Cancer trial was an open-label, noninferiority trial that assessed the role of edoxaban for CAT treatment. Adult patients with active cancer and VTE were randomized and stratified to receive either dalteparin or edoxaban 60 mg daily after receiving a LMWH for five days. The edoxaban dose was adjusted based on renal function (CrCl 30-50 mL/min), body weight (< 60 kg), or use of concomitant potent P-glycoprotein inhibitors. Colorectal, lung, genitourinary, and breast cancer were the most common cancer types included. Patients were treated for six to 12 months as determined by the treating physician. The primary outcome (composite of recurrent VTE or major bleeding after 12 months) occurred in 67 of 522 edoxaban patients (12.8%) and 71 of 524 dalteparin patients (13.5%) (HR: 0.97; 95% CI: 0.70-1.36; p=0.006 for noninferiority; p=0.87 superiority). Separately, recurrent VTE occurred in 41 patients (7.9%) in the edoxaban group and 59 patients (11.3%) in the dalteparin group (HR: 0.71; 95% CI: 0.48-1.06; p = 0.09) while major bleeding occurred in 36 (6.9%) and 21 (4.0%) in the edoxaban and dalteparin group, respectively (HR: 1.77; 95% CI: 1.03-3.04; P = 0.04). Most major bleeding events in the edoxaban arm occurred as gastrointestinal bleeding in the setting of gastrointestinal cancer. Ultimately, edoxaban was found to be noninferior to dalteparin in regard to the primary composite outcome, but it is important to consider the patient’s risk for bleeding, particularly based on cancer type. However, the study was underpowered to determine a difference in major bleeding based on cancer site in order to determine if solely patients with gastrointestinal cancer had an increased risk of bleeding compared to other cancer types. Additionally, similar to the ADAM VTE and SELECT-D studies, the ideal duration of anticoagulation treatment remains unclear as patients received anticoagulation for up to 12 months.

    Conclusions

    Based on the available literature, rivaroxaban, edoxaban, and apixaban appear to be well-tolerated and efficacious in the treatment of CAT. However, a patient-specific approach that takes into consideration a patient’s type of cancer, renal function, hepatic function, and adherence should be utilized. A recent consensus statement from the International Society of Thrombosis and Haemostasis Scientific and Standardization Committee recommends DOACs as first-line options in cancer patients if they have a low bleeding risk, and there are no drug-drug interactions.15 Remaining patients should continue to receive LMWH, especially if they have a high risk of bleeding. In particular, DOACs appear to consistently be associated with increased bleeding risk in patients with gastrointestinal or genitourinary cancers, so DOACs should be avoided in these populations. In accordance, the NCCN guidelines caution the use of DOACs in patients with cancer and urinary or GI tract lesions, pathology, or instrumentation as noted in the SELECT-D and Hokusai VTE Cancer studies.3,13-14 At this time, it is difficult to make direct comparisons between DOACs in regard to their efficacy and safety due to the trial designs only comparing each DOAC to LMWH, but, most notably, rivaroxaban and edoxaban were found to have a statistically significant increased risk of CRNMB and major bleeding, respectively. Thus, patient specific factors, such as renal function, hepatic function, cancer type, and bleeding risk, should be considered when selection anticoagulation therapy.

    VTE Prophylaxis in Ambulatory Cancer Patients 

    A cancer patient’s risk of CAT is strongly associated with the type of cancer. Currently, thromboprophylaxis in ambulatory cancer patients is not routinely recommended but has been considered in high risk patients, such as those with a high Khorana Risk Score (> 3 points indicates high risk). The Khorana score assess the patient’s cancer diagnosis, body mass index, and CBC. DOACs offer a convenient alternative for VTE prophylaxis to LMWH.16 Recently, apixaban and rivaroxaban have been assessed in trials to be utilized in this setting.

    Apixaban: AVERT Trial17

    The AVERT Trial was a placebo-controlled, double-blind trial that assessed the role of apixaban compared to placebo for thromboprophylaxis in intermediate-to-high risk (Khorana score >2) ambulatory patients with cancer and initiating chemotherapy. Patients were randomized to initiate apixaban 2.5 mg twice daily or placebo within 24 hours of chemotherapy initiation for a treatment period of 180 days. The most common types of primary cancer included gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%) cancers.  The primary efficacy outcome (first episode of objectively documented major VTE (proximal DVT or PE) within 180 days) occurred in 12 of 288 patients (4.2%) in the apixaban group and 28 of 275 patients (10.2%) in the placebo group (HR: 0.41; 95% CI: 0.26-0.65; p<0.001), indicating a significantly lower risk of VTE in patients treated with apixaban, which was primarily driven by a lower rate of PE in the apixaban group. However, a statistically significant increase in major bleeding episodes was found in the apixaban group. Major bleeding events occurred in 10 of 288 patients (3.5%) in the apixaban group and five of 275 patients (1.8%) in the placebo group (HR: 2.0; 95% CI: 1.01-3.95; p=0.046). The major bleeding events were primarily associated with gastrointestinal bleeding, hematuria, and gynecologic bleeding with apixaban, and major bleeding most commonly occurred in patients with cancer of gastrointestinal or gynecologic nature. Overall, this trial displayed that there was no difference in survival between the apixaban and placebo groups; however, most of the patients in the trial had advanced stages of cancer.  The study consisted of limited types of cancers, so it is difficult to make conclusions regarding apixaban’s safety and efficacy in other cancer types; however, most commonly, included patients had cancers that significantly increased their risk for thrombosis events. Additionally, this study had a limited population with reduced renal function, a population at an increased risk of bleeding.   

    Rivaroxaban: CASSINI Trial18

    The CASSINI Trial was a double-blind, multi-centered, placebo-controlled trial. This study randomized patients with a solid tumor or lymphoma initiating a new cancer regimen and a Khorana score of at least two to receive rivaroxaban 10 mg or placebo daily for up to 180 days. Patients were screened every eight weeks for the development of the efficacy and safety endpoints. The most common types of primary cancer included pancreatic cancer (32.6%) and gastric/gastroesophageal junctional cancer (20.9%). Of patients with a solid tumor, 54.5% had metastatic disease. Of note, more patients with a history of VTE were randomly assigned to the rivaroxaban group compared to the placebo group (2.6% v. 0.5%). Additionally, 43.7% of patients in the rivaroxaban group and 50.2% of patients in the placebo group discontinued therapy prematurely. The mean intervention period (time period from the first dose of either drug through the last dose plus two days) was 4.3 months. The primary efficacy endpoint (development of DVT or PE) occurred in 11 (2.6%) of 420 rivaroxaban patients compared to 27 (6.4%) of 421 placebo patients during the intervention period (HR: 0.40; 95% CI: 0.20-0.80). However, during the period up to day 180, the primary efficacy composite endpoint occurred in 25 (6.0%) of the rivaroxaban patients compared to 37 (8.8%) of the 421 placebo patients (HR: 0.66; 95% CI: 0.40-1.09). The primary safety endpoint (major bleeding) occurred in 8 (2.0%) of the 405 rivaroxaban patients and 4 (1.0%) patients in the placebo arm (HR: 1.96; 95% CI: 0.59-6.49; p=0.26). Ultimately, in this population, low-dose rivaroxaban did not result in a statistically significant reduction in VTE at 180 days when compared to placebo, but, in the pre-specified intervention period, there was a 3.6% absolute reduction in thromboembolism with rivaroxaban, which may be hypothesis generating as this time period could be subject to bias. These findings are consistent with results of previous trials assessing rivaroxaban for thromboprophylaxis in cancer patients, such as the PROTECHT and SAVE-ONCO trials. However, the CASSINI trial included a higher-risk population. Additionally, an overall discontinuation rate of approximately 47% may be a limitation due to the inability to fully depict the bleeding and VTE occurrence. Overall, the role of rivaroxaban as thromboprophylaxis in this patient population remains promising.             

    Conclusions  

    Apixaban and rivaroxaban have both been shown to be noninferior to current standard therapy placebo. Current recommendation for anticoagulation therapy for ambulating cancer patients suggest that no further anticoagulation is needed. However, these studies show that DOACs may be used as primary prophylaxis in high-risk patients. Most notably, both studies showed an increased risk of bleeding, which must be considered and evaluated for each patient. Further research is needed in order to determine optimal anticoagulation in ambulating cancer patients with less advanced stages of cancer.  Additionally, the optimal timing and duration of thromboprophylaxis as well as the impact of thromboprophylaxis on cancer prognosis remain unclear.  

    References 

    1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. Available at http://doi.org/10.1182/blood-2013-04-460121 
    2. Kearon C., Akl EA., Ornelas J, et al. Antithrombotic theraoy for VTE disease: CHEST guidelines and expert panel report. Chest. 2016; 149 (2): 315-352. DOI: 10.1016/j.chest.2015.11.026.  
    3. Streiff MB, Holmstrom B, Angelini D, et al. NCCN clinical practice guidelines in oncology: cancer-associated venous thromboembolic disease: Version 1.2019. htpps://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Published February 28, 2019. Accessed September 4, 2019.  
    4. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. Engl J Med. 2000; 343: 1846-1850.  
    5. Kuderer NM, Francis CW, Culakova E, et al. Venous thromboembolism and all-cause mortality in cancer patients receiving chemotherapy. J Clin Oncol. Published 12 Dec 2016. DOI: 10.1200/jco.2008/26/15_suppl/9521.  
    6. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. Engl J Med. 2003; 349: 146-153. DOI: 10.1056/NEJMoa025313.  
    7. Khorana AA, Yannicelli D, McCrae KR, et al. Evaluation of US prescription patterns: Are treatment guidelines for cancer-associated venous thromboembolism being followed? Throm Res. DOI: 10.1016/j.thromres.2016.07.013.  
    8. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361:2342–2352.
    9. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013; 369:1406–1415,
    10. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism, N Engl J Med. 2013: 369;799–808
    11. EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism, N Engl J Med. 2013:366; 1287–1297,
    12. McBane II RD, Wysokinski WE, Le-Rademacher J, et al. Apixaban, dalteparin, in cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018; 132(1): 421.  
    13. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018; 36(20): 2017-2023.  
    14. Raskob GE, Van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. Engl J Med. 2018; 378(7): 615-624.  
    15. Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018; 16(8): 1891-1894.
    16. Choudury A, Balakrishnam A, Thai C, et al. Validation of the Khorana score in a large cohort of cancer patients with venous thromboembolism. Blood. 2016; 128(22):879.
    17. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. Engl J Med. 2019; 380:711-719.  
    18. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. Engl J Med. 2019; 380: 720-738.


  • 26 Sep 2019 1:55 PM | Mandy Garion (Administrator)

    Authors: Nicholas Pauley, PharmD Candidate 2020 and
    Mallory Crain, PharmD

    Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults.1 The average age at diagnosis is 69 years with a 5-year survival rate of 28.3%.2 A key determinant for increased survival is the patient’s ability to undergo intense induction chemotherapeutic regimens. However, intensive therapies are not always an option since some patients are unable to tolerate these treatments due to age and comorbidities. Fortunately, targeted therapies have expanded treatment options for these patients.

    Targeting specific genetic mutations in AML has become a large area of research in recent years.  Specifically, isocitrate dehydrogenase (IDH) 1 or 2 mutations are present in approximately 20% (IDH1: 7-14%, IDH2: 8-19%) of newly diagnosed patients with AML.3 Until recently, there were no specific therapies for patients with these mutations.  Two IDH inhibitors, enasidenib and ivosidenib, were FDA approved in August 2017 and July 2018, respectively. Both agents increase myeloid differentiation through inhibition of the IDH enzymes.4,5

    Enasidenib is currently FDA approved at a dose of 100 mg by mouth once daily for the treatment of relapsed/refractory AML in patients with an IDH2 mutation.4 Although enasidenib is only FDA approved for relapsed/refractory patients, the NCCN guidelines also recommend enasidenib as an option for older patients who are unfit for intensive therapy.6 No significant drug interactions requiring dose adjustments have been identified.4

    A phase 1, dose escalation and expansion study evaluated AML patients with an IDH2 mutation who were treated with enasidenib.  A total of 109 patients in the study had relapsed/refractory AML.  The median age was 67 years, and most patients received at least two prior therapies.  The overall response rate (ORR) was 38.5% with a complete remission (CR) of 20.2%.  The median overall survival (OS) was 9.3 months.  Of note, the median time to first response was 1.9 months.7 This study also evaluated 29 newly diagnosed patients who were deemed unfit for standard regimens. The ORR was 30.8% with a CR of 18%.  The estimated median OS was 11.3 months.8

    Ivosidenib is FDA approved at a dose of 500 mg for patients with an IDH1 mutation who have relapsed/refractory AML or are > 75 years with newly diagnosed AML (or those who cannot tolerate intensive induction chemotherapy). Dose adjustments for ivosidenib are recommended if it is given with strong CYP3A4 inhibitors since ivosidenib is a major CYP3A4 substrate. Induction of CYP3A4 has also been reported.5

    A phase 1, dose escalation and expansion study evaluated AML patients with an IDH1 mutation who were treated with ivosidenib.  A total of 179 patients had relapsed/refractory AML with a median age of 68 years. The ORR was 41.6% with a CR of 21.6%.  The median OS in the primary efficacy group was 8.8 months.  Similar to enasidenib, the median time to response was 1.9 months.  This study also included 34 patients with untreated AML (median age: 76.5 years).  The ORR was 58.8% with a CR of 26.5%. Survival data was not published for these patients.9

    In regard to safety, both agents have a similar adverse effect profile.  The most common adverse events observed in clinical trials were diarrhea, nausea, leukocytosis, febrile neutropenia, and anemia.  In addition, 38% of patients treated with enasidenib had indirect hyperbilirubinemia, and 24.6% of patients who received ivosidenib had a prolonged QTc interval.  Both agents caused differentiation syndrome in approximately 5% of patients, which is a serious complication that can become life-threatening. Therefore, it is imperative that clinicians are able to identify and treat differentiation syndrome when it occurs.7,10,13

    Differentiation syndrome results from rapid proliferation and differentiation of myeloid cells leading to cytokine imbalance and inflammation throughout the body.  It can present as a fever, cough, dyspnea, hypoxia, pleural effusions, pulmonary infiltrates, or organ dysfunction of unknown cause.  The median onset was 29 days (range 5 to 59) for ivosidenib and 48 days (range 10 to 340) for enasidenib in the phase 1 trials.7,9 Patients who experience differentiation syndrome should be initiated on dexamethasone 10 mg IV every 12 hours for a minimum of 3 days or until symptoms resolve.  If patients also develop leukocytosis, initiation of hydroxyurea may be considered.  Ivosidenib and enasidenib should only be discontinued if severe symptoms persist for more than 48 hours after the start of dexamethasone.4,5

    Within recent years, several new agents, including targeted therapy, have emerged as treatment options for AML.  In a disease state with previously limited options, having additional lines of therapy potentially allows for increased survival compared to historical treatment options. While intensive induction therapy is still the standard of care for those who can tolerate it, it is not an option for every patient. IDH inhibitors provide another treatment option for relapsed/refractory AML patients as well as those who cannot tolerate intensive induction therapy. In addition, an oral medication taken at home may be more convenient or desirable for some patients. When comparing these agents to traditional chemotherapy, one important factor to consider is the longer expected time to response.  The median time to response with IDH inhibitors is 1.9 months compared to an expected response within 30 days with traditional chemotherapy. Although long-term efficacy data is not yet available, the IDH inhibitor phase 1 trials show similar results compared to other standard treatment options given in the relapsed/refractory and newly diagnosed settings.6-9,11 Overall, both of these agents have proven efficacy in AML patients with an IDH mutation, and it is likely that use of IDH inhibitors for the treatment of AML will only continue to grow.

    References

    1. Sant M, Allemani C, Teareanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of HAEMECARE project. Blood. 2010;116(19):3724-34.
    2. SEER Cancer Stat Facts: Acute Myeloid Leukemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/amyl.html. Accessed August 20, 2019.
    3. Medeiros BC, Fathi AT, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;(31):272-281. 
    4. IDHIFA [package insert]. Summit, NJ: Celgene Corporation; (2017).
    5. TIBSOVO [package insert]. Cambridge, MA: Agios Pharmaceuticals; 2018.
    6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Published May 5, 2019. Accessed June 26, 2019.
    7. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
    8. Pollyea DA, Tallman MS, deBotton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019.
    9. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study. Blood. 2018;(132):561.
    10. Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777-2782.
    11. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
    12. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916-24.
    13. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015; 373: 1136–1152.
    14. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53-61.


  • 26 Sep 2019 1:52 PM | Mandy Garion (Administrator)

    Authors: Avatar Patel, PharmD Candidate 2020; Marissa Olson, PharmD, BCOP and Kristan Augustin, PharmD, BCOP

    Cytomegalovirus (CMV) is the largest β-herpesvirus transmitted by direct contact with infectious body fluids and is prevalent in over half of adults by the age of 40 years.1 CMV infection and disease are often characterized together, although they are not synonymous. CMV infection refers to the detection of viral antigens in tested bodily fluid or tissue, while CMV disease refers to symptomatic end-organ disease.2 While most individuals do not have signs or symptoms associated with CMV infection, primary infection leads to life-long latency. Reactivation of CMV infection occurs in 50-60% of patients after hematopoietic stem cell transplantation (HSCT) due to decreased CD4+ and CD8+ lymphocytes and represents the most common infection in HSCT.2 CMV reactivation is associated with increased morbidity and mortality post-HSCT. Common complications include pneumonia, colitis, and hepatitis. Risks for CMV reactivation include recipient and donor CMV seropositivity, transplant modality, and recipient’s age. Infection risk in HSCT patients can be broken down into three phases which include early phase (day 0 to day 30), intermediate phase (day 31 to day 100), and late phase (day 101 and after) post-transplant. Although CMV reactivation in HSCT patients can occur at any time, most reactivation is seen during the intermediate phase. Without prophylaxis, 80% of CMV-seropositive patients undergoing HSCT will have CMV reactivation.4

    Prevention of CMV complications in HSCT patients can be approached by primary prophylaxis or preemptive therapy. Primary prophylaxis includes treating high risk patients, defined as recipients who are CMV-seropositive, during the first 100 days after transplant. Preemptive therapy is defined as the initiation of therapy after the detection of CMV viremia. Current National Comprehensive Cancer Network (NCCN) guidelines for preemptive therapy recommend valganciclovir or ganciclovir as first-line agents for the treatment of CMV viremia. Foscarnet or cidofovir are recommended as second-line agents for resistant CMV or for patients unable to tolerate first line therapy.5 The major limitations of preemptive therapy include weekly clinical follow-up and lack of protection against early CMV reactivation, which can lead to complications. While primary prophylaxis reduces early CMV reactivation, it does not prevent late onset reactivation, and use of antiviral therapies may be associated with significant adverse events such as myelosuppression and nephrotoxicity.6

    Letermovir (PrevymisTM) was approved by the Food and Drug Administration (FDA) in November 2017 for CMV prophylaxis in HSCT CMV-seropositive recipients. Letermovir is the first non-nucleoside 3,4 dihydroquinazoline, reversible viral terminase inhibitor. It acts on the late stages of viral replication by inhibiting viral terminase at UL56 subunit which prevents viral DNA cleavage and results in inhibition of viral replication.6 Letermovir differs from other antiviral agents with CMV activity, such as ganciclovir, valganciclovir and foscarnet, in that it does not target UL54. Rather, it has a unique binding domain on UL56, which prevents cross-resistance with other agents.5 It is available as both an immediate-release tablet and intravenous formulation. It is initiated at 480 mg once daily beginning between day 0 and day 28 posttransplant and continued through day 100. Letermovir is eliminated via hepatic uptake OATP1B1/3 with a half-life of 12 hours.

    In addition, letermovir is also a substrate of P-glycoprotein and a moderate inhibitor of CYP3A and CYP2C8 which can lead to drug-drug interactions. Trials have shown letermovir reduces the AUC of voriconazole by 50% and increases the AUC and Tmax of atorvastatin.2 Dosage should be decreased to 240 mg once daily in patients receiving concomitant therapy with cyclosporine as cyclosporine-mediated OTAP1B1/3 inhibition has been shown to double the AUC of letermovir.7 There are no dose adjustments recommended for creatinine clearance > 10 ml/min and mild or moderate hepatic impairment (Child Pugh class A or B). Letermovir is also not recommended in patients with severe hepatic impairment (Child Pugh class C) due to increased exposure.

    NCCN guidelines updated in early 2019 added letermovir as a first-line agent for CMV prophylaxis in CMV-seropositive allogeneic HSCT recipients based on the results of a phase III study. The trial randomized 545 subjects in a 2:1 ratio to receive letermovir or placebo daily through week 14. The primary end point was the proportion of subjects with clinically significant CMV infection, defined as > 300 copies/ml via PCR testing, through week 24. Patients were stratified based on CMV disease risk and were eligible if they were CMV-seropositive and had an undetectable level of CMV DNA within 5 days of randomization. A decrease in clinically significant CMV infection at week 24 was observed in the letermovir group compared to the placebo group (37.5% vs. 60.6%, p < 0.001). In addition, all-cause mortality was lower at week 24 for patients receiving letermovir (10.2% vs. 15.9%, p < 0.03). Patients being treated for graft versus host disease (GvHD) or those with T-cell depleted grafts were found to have the greatest benefit from letermovir prophylaxis. However, the trial did show a rise in CMV infection when letermovir was discontinued after 100 days which may suggest the reduced benefit of letermovir prophylaxis when discontinued. There were no statistical significant differences in adverse effects between the two treatment groups.7

    Letermovir has proven efficacy when used as CMV prophylaxis in HSCT CMV-seropositive recipients. It offers clinicians a therapeutic option without the significant toxicities seen with other antiviral treatments. Although the phase III trial showed a significant decline in rates of CMV infection and all-cause mortality at 24 weeks, there are still unanswered questions. Upon discontinuation of letermovir, high risk patients were more likely to have CMV reactivation. In addition, while this trial only evaluated letermovir for prevention of CMV in HSCT patients, future trials may assess the potential option to use letermovir as a treatment option due to the minimal adverse effect profile.

    References

    1. Centers for Disease Control and Prevention. Cytomegalovirus (CMV) and Congenital CMV Infection. www.cdc.gov/cmv/overview (accessed 2019 June 6).

    2. Ljungman P, Boeckh M, Hirsch HH et al. Definitions of Cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2016;1(1):87-91.

    3. Deleenheer B, Spriet I, Maertens J. Pharmacokinetic drug evaluation of letermovir prophylaxis for cytomegalovirus in hematopoietic stem cell transplantation. Expert Opinion on Drug Metabolism & Toxicology. 2018;14(12):1197-1207.

    4. Styczynski J. Who is the patient at risk of CMV recurrence: A review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;7:1-16.

    5. National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections (updated 2019). www.nccn.org/professionals/physician_gls/pdf/infections.pdf (accessed 2019 Jul 18).

    6. Razonable RR. Role of letermovir for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Curr Opin Infect Dis. 2018;31:286-291.

    7. Foolad F, Aitken SL, Chemaly RF. Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients. Expert Review of Clinical Pharmacology. 2018;11(10):931-941.

    8. Marty FM, Ljungman P, Chemaly RF et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444. 


  • 26 Sep 2019 1:46 PM | Mandy Garion (Administrator)

    Authors: Betsy Abraham, PharmD: PGY-1 Pharmacy Resident, NorthShore University HealthSystem
    Katie Lentz, PharmD, BCOP: Oncology Clinical Pharmacy Specialist, Barnes-Jewish Hospital

    Nausea and vomiting are common in patients who are on chemotherapy. A recent analysis of 991 patients receiving chemotherapy showed an incidence of anticipatory nausea of 8 to 14%, with rates increasing with each subsequent cycle.1  Patients beginning a cancer treatment consistently list chemotherapy-induced nausea and vomiting (CINV) as one of their greatest fears.2 Patient factors which increase the risk of nausea and vomiting include: female gender, age less than 50 years, dehydration, history of motion sickness, prior history of nausea and vomiting with chemotherapeutic agents, receiving chemotherapy outpatient, dose and emetogenicity of chemotherapy, no history of alcohol consumption and radiation (whole body or upper abdomen). Inadequately controlled emesis decreases the quality of life for patients, increases the use of healthcare resources, and can impair a patient from completing chemotherapy.3-4 However, new insights into the pathophysiology of CINV and a better understanding of the risk for these effects have helped clinicians better treat and prevent CINV. 

    There are three subtypes of CINV which include: acute, delayed and anticipatory (see Table 1 for list of available agents). Acute CINV occurs within 24 hours after chemotherapy. Patients who are at greater risk for anticipatory CINV include those who have any of the patient factors which increase the risk of nausea and vomiting. The neurotransmitter responsible for anticipatory CINV is serotonin (5HT3). Therefore, treatment of CINV is with 5HT3 receptor antagonists (5HT3-RA) such as ondansetron (Zofran®). On the other hand, delayed CINV occurs 1 to 7 days after chemotherapy. The chemotherapeutic classes/agents which increase the risk for delayed CINV are ones of high emetic risk (> 90% of patients experience CINV without appropriate prophylaxis) which include, but are not limited to: anthracyclines, platinum analogs, cyclophosphamide (Cytoxan®), and ifosfamide (Ifex®).5 The neurotransmitter believed to primarily be responsible for delayed CINV is Substance P. However, delayed CINV is treated with a combination of antiemetics which include Neurokinin-1 receptor antagonists (NK1-RA) such as aprepitant (Emend®) and fosaprepitant intravenous (Emend®), corticosteroids, and the 5HT3-RA palonosetron (Aloxi®) (see Table 2 for list of combinations).6-7 Finally, anticipatory CINV happens prior to receiving a chemotherapeutic agent and is seen in patients with a history of CINV with prior use of chemotherapeutic agents. Treatment of anticipatory CINV is with benzodiazepines, specifically lorazepam (Ativan®).

    Despite receiving antiemetic prophylaxis for acute and/or delayed CINV, some patients may experience breakthrough nausea and vomiting. Various antiemetics may be used during this time, including 5HT3-RAs, dopamine receptor antagonists, and cannabinoids. 5HT3-RAs such as ondansetron, palonosetron, granisetron (Kytril®) and dolasetron (Anzemet®) are usually well-tolerated by most patients and have constipation and migraine-like headaches as its side effects. Dopamine receptor antagonists such as prochlorperazine (Compazine®), promethazine (Phenergan®), and metoclopramide (Reglan®) are commonly prescribed; however, these agents carry unpleasant side effects such as extrapyramidal symptoms such as acute dystonia as well as sedation.6-7 Patients who develop acute dystonic reactions are treated with anticholinergics: benztropine (Cogentin®) and diphenhydramine (Benadryl®). Furthermore, cannabinoids, like dronabinol (Marinol®) and nabilone (Cesamet®) can be used second line for breakthrough CINV. These are synthetic analogs of delta-9-tetrahydrocannabinol, a naturally occurring component of Cannabis sativa. Cannabinoids carry side effects such as increased appetite, sedation, dysphoria, or euphoria. Therefore, these agents are prescribed only when patients have CINV with the preferred agents.6-8

    Additionally, one agent that has recently come to prominence for CINV is the second-generation anti-psychotic olanzapine (Zyprexa®) typically used for the treatment of bipolar I disorder and schizophrenia. A randomized, double-blind phase 3 trial compared olanzapine with placebo in combination with dexamethasone (Decadron®), aprepitant or fosaprepitant, and a 5HT3-RA. The study revealed that the anti-emetic combination with olanzapine, as compared with placebo, had a lower proportion of patients with no CINV in the first 24 hours (74% vs. 45%, p = 0.002), the period from 25 to

    120 hours after chemotherapy (42% vs. 25%, p = 0.002), and the overall 120-hour period (37% vs. 22%, P=0.002).9 Moreover, complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (p < 0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001).9 Dosed at 5-10 mg by mouth daily, olanzapine has become a novel agent used in combination with dexamethasone and palonosetron in patients with moderate to high emetogenic potential.

    The goal for each patient is to prevent CINV and to start antiemetics prior to chemotherapy. The risk of nausea and vomiting can persist for up to 3 days after receiving the last dose of high emetic potential agents and for up to 2 days with moderate emetic potential agents.  CINV is a fear of patients who are starting chemotherapy or already receiving chemotherapy. Over the past two decades, more effective and better tolerated pharmacologic agents have been developed to prevent CINV. Currently, 5HT3-RAs, NK1-RAs, and corticosteroids are the most effective therapeutic agents to help prevent and control CINV. Despite the use of these therapeutic agents, uncontrolled vomiting and inadequately controlled nausea remain a problem in patients. Nevertheless, complete remission from CINV should be a goal for each patient with the hopes that patients can receive chemotherapy without having the fear of CINV.

    References

    1. Aapro M. CINV: still troubling patients after all these years. Supportive Care in Cancer. 2018;26(1):55-59.
    2. de Boer-Dennert M, de Wit R, Scmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997;76:1055-1061.
    3. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol 2006;24:4472-4478.
    4. Farrell C, Brearley SG, Pilling M, et al. The impact of chemotherapy-related nausea on patients' nutritional status, psychological distress and quality of life. Support Care Cancer 2013;21(1): 59-66.
    5. National Comprehensive Cancer Network/ Anti-Emesis Guidelines. Version 2.2017. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
    6. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2492.
    7. Navari R, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-1367.
    8. Hesketh PJ, Kris GM, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:3240-3261.
    9. Navari R, Qin R, Ruddy JK, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):137-142.


  • 26 Sep 2019 1:31 PM | Mandy Garion (Administrator)

    Authors: Justice Oehlert, PharmD Candidate 2020 and
    Kathryn Lincoln, PharmD, BCPS, BCIDP, Clinical Pharmacist – Infectious Diseases, Olathe Medical Center

    Learning Objectives:

    1. Describe the magnitude of the problem of multi-drug resistant gram negative bacteria
    2. Identify the bacteria that pose the most risk in the United States and globally
    3. Describe mechanisms of resistance for selected bacteria against antibiotic agents
    4. Evaluate the use of novel antibiotic agents against multi-drug resistant bacteria

    Background

    The discovery of antibiotics in the 20th century ushered in a golden age of medicine. Before the discovery of penicillin in 1928 and its subsequent wide-spread use, bacterial infections were much more deadly. The introduction of antimicrobial therapies markedly increased the average life expectancy and drastically reduced the mortality rate of communicable diseases. Over the next several decades many new classes of antibiotics were discovered and marketed. As we entered the 21st century, the discovery of new antibiotic classes plateaued, and newly approved agents had been limited to classes that were already established. Bacterial resistance to antibiotics has steadily followed the introduction of new agents. As soon as an agent is used in clinical practice, populations of bacteria that are exposed begin selecting individuals that harbor genetic mechanisms of resistance. Furthermore, resistance mechanisms often render the pathogen resistant to multiple, if not all, agents in a given class of antibiotics. Due to the costly development process and low rate of return on investment, pharmaceutical companies have had little incentive to perform research and development on new antimicrobial agents. Thus, we are currently seeing higher rates of resistance to our commonly employed antibiotics. Agents that had typically been reserved due to toxicity or low resistance, such as colistin, tigecycline or carbapenems, are being forcibly employed. As a result, resistance to these agents is increasing at an alarming rate. Pairing this resistance with a lack of viable antibiotic treatment options leads to a global crisis. The 2014 study commissioned by the UK government used predictive modeling to demonstrate that, in a worst case scenario, by 2050, the death rate from resistant bacteria could be as high as 10 million individuals per year, surpassing the current death rate of cancer.1

    Pathogenic bacteria in humans are acquiring resistance at an alarming rate, often to many different available antibiotics. Multi-drug resistant (MDR) bacteria are non-susceptible to at least one agent in three or more antimicrobial classes, extensively-drug resistant (XDR) are non-susceptible to at least one agent in all but two or fewer classes, and pandrug-resistant bacteria are non-susceptible to all available agents.2 Some of the most concerning organisms to consider are gram negative bacilli (GNB), which are responsible for 45-70% of ventilator-associated pneumonia cases (VAP), 20-30% of catheter-related bloodstream infections, and commonly cause sepsis related to urinary tract infections (UTI) or surgical site infections.3 Gram-negative bacteria are often intrinsically more resistant to common antibiotics due to their additional lipopolysaccharide membrane, which serves as a permeability barrier to many drugs.2 Additionally, gram-negative bacteria can acquire resistance through mutations as well as horizontally transfer resistance genes through transformation, transduction, and conjugation both within and between species. Bacteria introduced into humans via consumption of livestock is potentially able to transfer resistance, having been demonstrated with extended spectrum beta-lactamase (ESBL) and the colistin resistance gene mcr-1 in GNR.2

    The most relevant MDR gram-negative pathogens in humans are members of Enterobacteriaceae, such as Escherichia coli, Citrobacter spp., Enterobacter spp., Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter spp. In the latest antibiotic resistance report released by the CDC in 2013, carbapenem-resistant Enterobacteriaceae (CRE) account for approximately 9,000 infections and 600 deaths per year.10

    Several studies have been performed to evaluate resistance rates of GNB in institutional settings. The INICC, SENTRY, ANSRPRG, and EARS-NET analyzed data in a multitude of countries and in both ICU and non-ICU settings. Results demonstrated Enterobacteriaceae resistance to fluoroquinolones from 0-70%, 3rd generation cephalosporins 0-72%, and carbapenems 0-59%, depending on the study. Pseudomonas aeruginosa was 0-53% resistant to fluoroquinolones, 0-51% resistant to aminoglycosides, 0-55% resistant to piperacillin/tazobactam, 0-44% resistant to ceftazidime, and 3-60% resistant to carbapenems. The resistance variability between study sites reiterates the importance of generating local antibiograms to help guide empiric therapy for bacterial infections.

    Resistance Mechanisms

    For Enterobacteriaceae, the primary mechanism of resistance to beta-lactams is the production of beta-lactamases, which are enzymes that hydrolyze the beta-lactam ring of these agents and render them unable to bind to penicillin-binding protein (PBP). Additionally, AmpC, an inducible beta-lactamase, can confer further resistance to 2nd and 3rd generation cephalosporins in Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii, and others. Exposure to penicillins and 1st-3rd generation cephalosporins can cause the AmpC gene to become de-repressed and resistance can evolve quickly. Additionally, plasmid-borne beta-lactamases of the ESBL variety confer resistance to all cephalosporins. Finally, strains which carry plasmid-borne carbapenemases that inactivate carbapenems have rapidly spread.3

    While all Enterobacteriaceae are naturally susceptible to fluoroquinolones, chromosomal mutations in DNA gyrase and topoisomerase IV genes modify the binding affinity and raise the MIC for specific agents. Additionally, mutations may lead to decreased permeability into the cytoplasm or increased drug efflux. Plasmid-borne mechanisms of resistance have also been observed, and are frequently associated with ESBL producing strains.3

    Pseudomonas aeruginosa, like the Enterobacteriaceae, also carry an inducible AmpC cephalosporinase that confer resistance to 3rd generation cephalosporins. Wild-type strains are intrinsically resistant to amoxicillin, amoxicillin/clavulanate, 1st and 2nd generation cephalosporins, cefotaxime, ceftriaxone, and ertapenem. They are susceptible to piperacillin, ceftazidime, cefepime, imipenem, meropenem, and doripenem. Mutations in efflux transporters rendering them overexpressed confers resistance to aztreonam, cefepime, and meropenem. Fluoroquinolone resistance results from mutations in topoisomerase-encoding genes and/or hyperactive efflux systems. Finally, colistin resistance has been well documented in regards to selection of mutants. More recently, transferable resistance has been described in Pseudomonas harboring mcr-5, a variant of the gene discussed previously.3,11

    The newest advancement in the bacterial arms race is the emergence of resistance to colistin. Certain species are intrinsically resistant, such as Proteus spp., Providencia spp., Serratia spp., and Morganella spp. Naturally, MDR strains of these organisms are concerning due to the lack of susceptibility to colistin, which is currently the last resort agent for CRE. Until recently, transferable resistance to colistin had not been observed. The plasmid-borne mcr-1 gene confers resistance to colistin and was described in farm animals in several countries, including the U.S. In China, the mcr-1 gene has been found in humans, livestock, and food products.2,3

    Novel Agents

    Ceftolozane/tazobactam (TOL/TAZ) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for the treatment of complicated intra-abdominal infections (cIAIs), in combination with metronidazole, and complicated urinary tract infections (cUTIs), including pyelonephritis. TOL/TAZ demonstrated superiority to levofloxacin in the outcomes of composite cure and microbiological eradication in cUTI. It was non-inferior to meropenem in the outcome of clinical cure of cIAI.5 It is highly potent against P. aeruginosa, most Enterobacteriaceae and also ESBL-producing GNB, but provides little activity against Acinetobacter baumannii.5,7 Common mechanisms of resistance in P. aeruginosa are ineffective against ceftolozane/tazobactam. TOL/TAZ provides most of its utility in practice towards treating Pseudomonas and ESBL producing GNB infections while sparing carbapenems. It has been referred to as the most potent antibiotic against Pseudomonas.7

    Ceftazidime/avibactam (TAZ/AVI) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for cUTI, cIAI (in combination with metronidazole), healthcare-associated pneumonia (HAP) and VAP.7 The addition of avibactam restores activity of ceftazidime to a variety of organisms, including ESBL producing GNB and some, but not all, carbapenemase producing GNB, including Pseudomonas aeruginosa.4,5,7 In comparison to TOL/TAZ, the presence of avibactam leads to retention of activity against GNB that produce Klebsiella pneumoniae carbapenemases (KPC).6 In clinical trials, TAZ/AVI plus metronidazole was compared with meropenem in patients with cIAIs and nosocomial pneumonia, and proved non-inferiority. An open-label trial comparing TAZ/AVI to best available therapy in cUTI or cIAI caused by ceftazidime-resistant Enterobacteriaceae or P. aeruginosa showed utility as an alternative to carbapenems.7 The Consortium of Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) database demonstrated that therapy for CRE infection with TAZ/AVI had significantly lower mortality than therapy with colistin. Current data does not support the use of TAZ/AVI as monotherapy when MDR GNB are suspected. Use of local antibiograms should be employed to pair its use with an aminoglycoside, fosfomycin, tigecycline, or colistin.7

    Meropenem/vaborbactam is the first carbapenem/beta-lactamase inhibitor combination product available. Addition of vaborbactam restores activity of meropenem against some, but not all, carbapenemase producing GNB.7 It was FDA approved for cUTI, including acute pyelonephritis, after demonstrating non-inferiority to piperacillin/tazobactam.4,7 On a negative note, one study found that the addition of vaborbactam did not increase in vitro activity against P. aeruginosa or Acinetobacter spp. in comparison to meropenem alone.4 Real-life clinical data is lacking at this point, which will be necessary to define its place in clinical practice.7

    Plazomicin is the newest agent in the aminoglycoside class and is active against MDR Enterobacteriaceae due to its stability against AMEs.4,7 Plazomicin spectrum of activity includes Enterobacteriaceae (including CRE, ESBL, and MDR isolates) as well as methicillin-resistant Staphylococcus aureus (MRSA) irrespective of resistance to currently available aminoglycosides. Moreover, plazomicin has demonstrated favorable in vitro activity against polymyxin-resistant Enterobacteriaceae, including mcr-1 producing isolates.4,9 FDA approval was achieved for cUTI based on comparisons of plazomicin with meropenem or colistin with concurrent tigecycline or meropenem, in which non-inferiority was demonstrated. Favorable lung penetration, in comparison to colistin, may hold some promise as to future adjunctive therapy for VAP. Plazomicin potentially has utility as part of combination therapy for XDR GNB along with novel beta-lactams.7

    Eravacycline, a synthetic fluorocycline with similarities to tigecycline, has activity against GNB and gram positive cocci. It inhibits peptide elongation by binding to the 30s subunit of the bacterial ribosome and inhibiting addition of amino acids to the growing peptide chain. Many mechanisms of resistance, such as ESBL production, do not affect the activity of eravacycline. While it does not inhibit P. aeruginosa, it is active against MRSA and vancomycin-resistant enterococcus (VRE). Its advantages over tigecycline include more potent in vitro activity, excellent oral bioavailability, lower potential for drug interactions, and greater activity in biofilms. Of note, it extensively concentrates in alveolar macrophages, indicating potential utility in pneumonias caused by MDR bacteria. It is the most potent antibiotic against carbapenem resistant A. baumannii. Eravacycline is FDA approved for cIAI based on 2 clinical trials that demonstrated non-inferiority to ertapenem and meropenem.

    Omadacycline is a semisynthetic derivative of minocycline within the tetracycline class. It is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) as well as community-acquired pneumonia (CAP). Coverage includes gram-positive, including MRSA and VRE, gram-negative, anaerobic and atypical pathogens. FDA approval was obtained for ABSSSIs based on the results of 2 trials demonstrating non-inferiority to linezolid. Approval for CAP was obtained based on a trial comparing omadacycline to moxifloxacin, in which omadacycline demonstrated non-inferiority.8

    Imipenem/cilastatin/relebactam (IMI/REL) is a carbapenem/beta-lactamase inhibitor that gained FDA approval in July 2019 for complicated UTIs, including pyelonephritis, and cIAIs, both due to a set of susceptible organisms. The addition of relebactam restores activity against KPC type carbapenemases, but not the other carbapenemases. IMI/REL was compared to imipenem alone in patients with cIAIs and cUTIs and demonstrated non-inferiority, but the trials were not selective for MDR infections. It is expected that IMI/REL will provide an additional therapeutic option against KPC producing GNB.4 In vitro analysis show that 32% of imipenem non-susceptible P. aeruginosa strains from the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program remain resistant with the addition of relebactam.12 A trial comparing IMI/REL to piperacillin/tazobactam in patients with pneumonia has been completed, but the results are not currently available.

    Conclusions

    While the rapid development of resistance, particularly in gram-negative bacteria, is concerning, the development of novel agents and their appropriate use has the potential to spare us from a global crisis. Antimicrobial stewardship will be critical to ensure that these agents remain active against MDR bacteria in the future. Clinicians should be well aware of their local antibiograms to help guide empiric antimicrobial therapy. While these newer agents have been able to overcome many modalities of bacterial resistance, no single agent can be employed that will be active against all MDR GNB. Table 1 shows the activity of these new agents against several types of resistance. Of note is that no single agent can work against all types of CRE. Additionally, MDR Acinetobacter poses a significant problem as no agent can be considered a “drug of choice” due to its extensive list of resistance mechanisms. Real-world data will become available as these agents are used in practice, and this data will help illuminate the niche uses that each agent likely possesses. 

    Figure 1.

    Ruppé E. Ann. Intensive Care. 2015; 5:21.

    Table 1.

    References

    1. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014
    2. Exner M, Bhattacharya S, Christiansen B, et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hyg Infect Control. 2017;12:Doc05. doi: 10.3205/dgkh000290
    3. Ruppé E, Woerther P, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann. Intensive Care. 2015; 5:21. doi: 10.1186/s13613-015-0061-0
    4. Petty LA, Henig O, Patel TS, et al. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect Drug Resist. 2018;11: 1461-1472. doi: 10.2147/IDR.S150447
    5. Toussaint KA, Gallagher JC. β-Lactam/β-Lactamase Inhibitor Combinations: From Then to Now. Ann Pharmacother. 2015; 49(1): 86-98. doi: 10.1177/1060028014556652
    6. Van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63(2):234–41. doi: 10.1093/cid/ciw243
    7. Karaiskos I, Lagou S, Pontikis K, et al. The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front. Public Health. 2019; 7(151).  doi: 10.3389/fpubh.2019.00151
    8. Baker DE. Omadacycline. Hosp Pharm. 2019;54(2):80-87. doi: 10.1177/0018578718823730
    9. Denervaud-Tendon V, Poirel L, Connolly LE, et al. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017; 72: 2787–2791 doi:10.1093/jac/dkx239
    10. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed July 11, 2019.
    11. Snesrud E, Maybank R, Kwak YI, et al. Chromosomally encoded mcr-5 in colistin nonsusceptible Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62(8). doi: 10.1128/AAC.00679-18.
    12. Young K, Painter RE, Raghoobar SL, et al. In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa. BMC Microbiol. 2019; 19(150). doi: 10.1186/s12866-019-1522-7 

    Submit for CE

  • 26 Sep 2019 1:16 PM | Mandy Garion (Administrator)

    Author: Christopher Clayton, PharmD
    Preceptor: Jacob Kettle, PharmD, BCOP

    Learning Objectives

    1. Describe the general principles of CAR T-cell therapy
    2. Summarize literature supporting CAR T-therapy for diffuse large B-cell lymphoma and acute lymphocytic leukemia
    3. Describe the common adverse effects of CAR T-cell treatment and their management
    4. Discuss the current state and future directions of CAR T-therapy

    Introduction

    The human immune system possesses essential and sophisticated mechanisms capable of recognizing, attacking, and ultimately causing lysis of tumor cells.1,2 The efficacy of these processes is unfortunately limited due to insufficient numbers of T-cells specific for tumor antigens, blunted T-cell activation resulting from immune checkpoints, and an immunosuppressive tumor microenvironment.3 The principle theory behind CAR-T (chimeric antigen receptor T-cell) therapy is to overcome the shortcomings of the human immune system through the laboratory design and development of immune cells which specifically target cancer in sufficient abundance to yield a tumor response.4

    CAR-T therapy is produced through a complex manufacturing process that generally takes several weeks to complete. The process begins with T-cell extraction from the patient through leukapheresis. A CAR is then introduced ex vivo to the T-cells via viral transfer vector.3,5 The CAR T-cells then undergo expansion to produce enough cells to provide an adequate dose before they can be administered to the patient. Following administration, the modified T-cells will presumably recognize the target on tumor cells and initiate an immune cascade to destroy the malignant cells.3,6,7 Due to the length of time needed to both develop a therapy and for the immune system to illicit a response after administration, the use of conventional cytotoxic chemotherapy is a necessary component of CAR-T therapy.5

    Access to CAR-T is currently limited to a relatively small number of institutions owing to the complexity of CAR T-cell manufacture and administration. Further, the immense financial burden (up to $475,000 for the drug cost alone) creates additional logistical barriers to implementation.

    Overview of Evidence                                    



    While CAR-T only has FDA approval for DLBCL and ALL, researchers are actively striving to identify more uses for CARs in other types of malignancy as research is underway in numerous solid tumors and hematological malignancies.14,15,16 For instance, CARs have been designed to target B-cell maturation antigen (BCMA) for treatment of multiple myeloma, type 1 insulin-like growth factor receptor (IGF1R) and receptor tyrosine kinase-like orphan receptor (ROR1) for sarcoma, and the L1-cell adhesion molecule (L1-CAM) for ovarian cancer.14,15 The greatest challenge in developing new therapy appears to be establishing targets on the cancer cells that are not routinely expressed on normal tissue.14

    Adverse Effects

    Treatment with CAR-T is associated with considerable risks. The most common serious complication of CAR-T therapy is cytokine release syndrome (CRS), a phenomenon caused by the rapid release of inflammatory cytokines and chemokines.17 CRS generally occurs 2-3 days following administration and is characterized by fever, hypotension, hypoxia, tachycardia, and cardiac, renal, or hepatic dysfunction.16 Reported frequency of CRS ranges from 57% to 93% of patients with many experiencing a severe and potentially life-threatening reaction.10,11,13 Management of CRS revolves around initiation of immune suppression (i.e. corticosteroids) and supportive care measures to support end organ function.16 Tocilizumab, an anti-IL-6 monoclonal antibody, is also an effective component of proper management.17,18 Beyond CRS, neurotoxicity is also a common and severe adverse effect of CAR-T. As many as 40% of patients will experience neurologic symptoms, including encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, anxiety, autonomic neuropathy, agitation, and psychosis.13,17 Symptoms tend to occur 4-10 days following treatment and persist for up to two weeks or longer.13,17 Seizures and life-threatening cerebral edema may also occur.17 Likewise, it is recommended to initiate one month of seizure prophylaxis beginning on the day of treatment.17 Less severe and more persistent chronic side effects of CAR-T therapy include infections, blood dyscrasias, acute kidney injury, and increased hepatic enzyme levels among others.6,7 Many of these effects could occur for up to 8 weeks following treatment.


    Conclusion

    CAR-T therapy has demonstrated efficacy in the treatment of patients with relapsed or refractory DLBCL or ALL, both of which are historically challenging disease states. Further, the potential for customization suggests CAR-T may become an important treatment modality in additional tumor types in the future. Despite the promise, CAR-T is associated with frequent and potentially life-threatening adverse events as well as financial and logistical barriers due to the complexity of this type of therapy. Assuming the current trajectory holds and use of CAR-T becomes more widespread in the future, it will become increasingly more important for pharmacists in all practice settings to become familiar with this emerging cancer treatment. 

    Submit for CE


    References

    1. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335-3337.
    2. Khalil DN, Smith EL, Brentjens RJ, et al. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273-290.
    3. Roberts ZJ, Better M, Bot A, Roberts MR, Ribas A. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL. Leuk Lymphoma. 2018;59(8):1785-96.
    4. Sadelain M, Brentjens RJ, Riviere I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009;21:215-23.
    5. Davila ML, Brentjens R, Wang X, Riviere I, Sadelain M. How do CARs work? Early insights from recent clinical studies targeting CD19. OncoImmunology. 2012;1(9):1577-1583.
    6. Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2018.
    7. Yescarta (axicabtagene ciloleucel) [prescribing information]. Santa Monica, CA: Kite Pharma, Inc; received May 2019.
    8. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-91.
    9. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-90.
    10. Neelapu SS, Locke FL, Bartlett LJ, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-44.
    11. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-54.
    12. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-47.
    13. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-48.
    14. Yong CSM, Dardalhon V, Devaud C, et al. CAR T-cell therapy of solid tumors. Immunol Cell Biol. 2017;95:356-63.
    15. Hamieh M, Sadelain M. Insights into chimeric antigen receptor therapy for chronic lymphoblastic leukemia. Trends Mol Med. 2018;24(9):729-31.
    16. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18)1726-37.
    17. National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities (Version 2.2019). http://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed June 5, 2019.
    18. Actemra (tocilizumab) [product information]. South San Francisco, CA: Genentech Inc; April 2019.
  • 26 Sep 2019 1:08 PM | Mandy Garion (Administrator)

    Authors: Borden Edgar, UMKC PharmD Candidate 2019 and 
    Sarah Cox, PharmD, MS

    Medicinal marijuana is a growing topic being discussed in Missouri. Recently, Missouri passed Amendment 2, which enacted a new section to be known as Section 1 of Article XVI of the Missouri Constitution1. This change allowed the use of medical marijuana for certain medical conditions. However, marijuana is classified as a schedule I controlled substance by the Drug Enforcement Agency (DEA)2. This may pose a challenge to health-systems when caring for patients licensed and legally using medical marijuana under state law. According to the Missouri Department of Health and Senior Services (DHSS), patients could begin applying to receive a medical marijuana card on the 28th of June. For an additional $100 fee, a patient may grow up to six flowering plants1.

    With the foreseeable increase in the use of medical marijuana and its derivatives, hospitals must be prepared for managing these patients and pharmacy must be at the forefront of these decisions. Fortunately, many states have legalized the use of medical marijuana and have shared recommendations or guidance for health-system policies. Minnesota and Washington were among the first to pilot successful policy guidelines with other states following similar principles3-6. In addition, the Missouri Hospital Association (MHA) recently released model medical marijuana staff bylaws and policy templates7. A description of each policy guideline is provided below.

    Minnesota

    Medical marijuana was passed in the state of Minnesota in 2014. The Minnesota Hospital Association released a recommendation for policies that gave three options for pharmacies to consider when creating their own policy.

    1. To not allow the use of medical marijuana in the hospital.
    2. Patient directed medical marijuana therapy, which removes medical marijuana from the list of medication use policies and procedures within the hospital. With this policy, the physician verifies the patient has an active medical marijuana card and that the medical marijuana is brought in from an approved dispensary.  The health care team will not hold, handle, or dispense medical marijuana to the patient. The patient or the patients designated caregiver take all responsibility with the medical marijuana.
    3. Medical marijuana implemented into the patient medication process. In this policy, the provider determines appropriateness of therapy, the hospital stores the patient’s home supply, and the nurse dispenses and documents each dose. The physician is also expected to discuss the continuing use with the patient, however, is not obligated to discuss continuing use upon discharge5.

    Missouri

    The Missouri Hospital Association model medical marijuana staff bylaws and policy templates closely resembled the previously discussed policies provided by the Minnesota Hospital Association. The policy templates and model medical staff bylaws can be found at the following link: https://web.mhanet.com/medical-marijuana.aspx7.

    Washington

    Washington state legalized medical marijuana in 1998. The Washington Health Care Association released model guidelines for the recommendation of medical marijuana in long term care settings. The recommendation is for medical marijuana to be allowed but for it to be handled by the patient. The facility should verify that the patient has all required documentation and has brought their own legitimate supply of medical marijuana. The patient is then responsible for identifying a designated provider that is not affiliated with the long-term care facility. Each patient can only identify one provider and each provider can only assist one patient. This provider is responsible for checking in with the medical marijuana, dispensing it to the patient, and checking out with any leftover medical marijuana6.

    Since the legalization of medical marijuana in Missouri, many health-systems have been discussing policies and procedures to put in place. And many health-systems have looked to pharmacy for the answer. Use these guidelines as blueprints to be tweaked based on individual health-system need.

    References

    1. Medical Marijuana Regulation. (n.d.). Retrieved July 10, 2019/ https://health.mo.gov/safety/medical-marijuana/index.php
    2. The Controlled Substance Act. (1970). Drug Enforcement Agency. Retrieved July 24, 2019. https://www.dea.gov/controlled-substances-act.
    3. 2018-2019 Pennsylvania Medical Society Policy Compendium Medical Society,18-19. Retrieved July 20, 2019. https://www.pamedsoc.org/docs/librariesprovider2/pamed-documents/advocacy-priorities/policycompendium17-18.pdf?sfvrsn=410d9b00_6.
    4. Medical Marijuana Medication Standards. (2016). Strong Memorial Hospital Policy. Retrieved July 20, 2019. https://www.urmc.rochester.edu/MediaLibraries/URMCMedia/quality/Medical-Marijuana.pdf.
    5. Medical Cannabis Template Policy. (2015). Minnesota Hospital Association. Retrieved July 10, 2019. https://www.mnhospitals.org/Portals/0/Documents/patientsafety/MedCannabis/Medical Cannabis Documentation.pdf
    6. Medical Marijuana Policy. (2016). Washington Healthcare Association. Retrieved July 10, 2019, from https://www.whca.org/files/2013/04/sample-medical-marijuana-policy.pdf.
      Medical Marijuana Guidance. (2019). Retreived July 24, 2019. https://web.mhanet.com/medical-marijuana.aspx
    7. Medical Marijuana Guidance. (2019). Retreived July 24, 2019. https://web.mhanet.com/medical-marijuana.aspx
  • 18 Jul 2019 10:02 AM | Mandy Garion (Administrator)

    Authors: Peggy Pace, RPh, BCGP, BCPS and
    Chelsea Meczkowski, PharmD
    Christian Hospital- St. Louis

    Background

    HMG CoA reductase inhibitors, or “statins”, soon became the mainstay of treatment for secondary prevention in atherosclerotic cardiovascular disease (ASCVD) after their introduction to the prescription market in 1987. Their benefit has been primarily attributed to the reduction of blood cholesterol, specifically the LDL-C component, though other mechanisms have been proposed and are being investigated.1 After the publication in 2008 of Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), primary prevention was added as an indication for the first time.2

    As the US population ages, statin use is expected to increase among elders. In fact, from 1999-2011, statin use in patients older than 80 years increased nearly four-fold.3 This article will evaluate current evidence on the safety and effectiveness of these agents in patients > 75 years when used for primary prevention. Their use for secondary prevention will not be evaluated.

    Determining Risk

    There are several tools available online to estimate risk of ASCVD in patients without known heart or vascular disease. Commonly used tools are the ACC/AHA ASCVD Risk Estimator Plus and the Pooled Cohort Equations to estimate 10-year risk for ASCVD events.4,5 The outcome of these estimators is heavily dependent on age, such that all patients > 75 are advised to start statin therapy if LDL-C is 70 mg/dL or greater. A caveat is that these tools should not be used to seek therapy advice for patients older than 79 years. The American Board of Internal Medicine acknowledges these estimators’ weakness for use in the elderly with advice at “Choosing Wisely”, a campaign aimed at reduction of medication, testing, and procedure overuse. The advice to older patients states in part: “Many older adults have high cholesterol. Their doctors usually prescribe statins to prevent heart disease. But for older people, there is no clear evidence that high cholesterol leads to heart disease or death. In fact, some studies show the opposite—that older people with the lowest cholesterol levels have the highest risk of death.”6 Similarly, the American College of Cardiology 2018 Guideline on the Management of Blood Cholesterol says that for patients older than 75, statins should be started only after a clinical assessment and a discussion of risk.7 Risk for ASCVD increases with age, so why the caution when adding a statin to drug regimens of older patients?

    Cautions

    Additions to medication regimens should be made when benefits clearly outweigh risks, and only after discussion with the patient and/or their caregiver. Reasons for caution when adding a statin include comorbidities, complicating existing drug regimens, increased expense, the potential for drug interactions with existing medications, and of course potential side effects such as myopathy, impaired cognition, and new onset diabetes.

    The likelihood of drug interactions is increased in elders because the oxidative capacity of the liver decreases with age. Any medications metabolized by oxidation are more likely to accumulate.8 Statins are metabolized to varying degrees by cytochrome P450 (CYP) enzymes, an oxidative pathway.9 Medications that induce, inhibit, or compete for the CYP enzymes will require careful monitoring. These interactions could result in reduced levels/ineffectiveness (i.e., atorvastatin + rifampin) or increased levels/side effects (i.e., simvastatin + verapamil) of the statin.10,11

    Myopathy, a known side effect of statin therapy, can lead to sedentary behavior resulting in increased frailty and falls. This side effect is hotly debated among experts but remains a complaint in about 1 in 5 patients.12 Avoiding movement due to muscle pain can worsen frailty and lead to weakness. A fall can be disastrous in an elder, especially if it results in a fracture requiring surgery. In addition to surgical risks, post-op complications, delayed healing, and months of physical therapy could result in loss of independence.

    Cognitive impairment has been recognized with these agents, though the mechanism is not understood. Statins are thought to be protective of cognition in some conditions, but cause impairment in other patients.13 If it occurs, it is generally reversible with drug discontinuation.13 Cognitive side effects could easily be overlooked or attributed to something else, and elders themselves may be unwilling to report these symptoms.

    The risk of new onset diabetes is increased with the use of statins.14 This may take years to manifest, so it may seem to be less of a concern in a person with a limited life expectancy. However, CDC reports that a person who has survived to age 75 in 2016 is expected to live on average another 12.3 years.15

    Risk vs. Benefits: the Actual Numbers

    The World Health Organization has requested that study results be reported in Absolute Risk Reduction (ARR) or Number Needed to Treat (NNT), rather than Relative Risk Reduction (RRR), as these convey a clearer picture of expected benefit.16 This has mostly been ignored, making it difficult to determine if a perceived benefit is worth the associated risks.17 Relative risk gives risk of occurrence of an event in the experimental group relative to the control group. Absolute risk tells us the number of events in the experimental group versus the number in the control group in absolute terms. The number needed to treat tells us how many patients have to receive a treatment for one patient to benefit.

    For example, if the risk of developing a disease or condition is 20% and an intervention can reduce that risk to 15%, it is correct to say the intervention showed a RRR of 25%  [(20%-15%)/20%], which sounds more significant than the ARR of 5% (20%-15%).  The NNT is the inverse of the ARR, or 1/0.5=20 patients need to be treated for one to realize a benefit in this example.18  The more impressive sounding 20% RRR might persuade patients and providers to accept the risks associated with treatment, while the 5% ARR might not offer a benefit they think is worth those risks. For this reason, it is helpful to convert reported RRR to ARR or NNT for patients up front when discussing whether to start a new therapy.

    JUPITER was said to prove the benefit of taking rosuvastatin for primary prevention, reporting a 43% reduction of risk, according to the trial authors.2 How did they arrive at these figures? In the placebo group the rate of a negative outcome was 1.36% while in the rosuvastatin group the rate was 0.77%. The ARR was 1.36%-0.77%=0.59%.2 Stated as RRR, this figure is (1.36-0.77)/1.36 or 43%.2 So the ARR is less than 1%, but the over 40% RRR was the figure the study authors chose to report, and what readers remember. The NNT in JUPITER is 1/0.0059= 170 patients for one year for one patient to realize a benefit.

    Pravastatin in elderly individuals at risk of vascular disease (PROSPER), which enrolled patients aged 70-82, reported that the primary composite endpoint at 3 years (CHD-related death, nonfatal MI, and stroke) in the placebo group was 16.2% vs. 14.1% in the pravastatin group.19 This is an ARR = 2.1%, but is reported as a relative risk reduction of 13%.19 This corresponds to 48 patients treated for 3 years for one patient to realize a benefit. PROSPER was not exclusively a primary prevention trial, but analysis of the primary prevention subgroup showed no benefit with the statin.19

    The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT-LLT) trial concluded there was no significant difference in outcomes when pravastatin vs. placebo was used for primary prevention in adults older than 65.20 The Third Heart Outcomes Prevention Evaluation(HOPE-3) trial also looked at statin use for primary prevention.21 Refreshingly, HOPE-3 reported the ARR and NNT in the published trial. The ARR was 1.1%, corresponding to 91 patients needing to be treated for 5.6 years for one patient to benefit.21 These stastistics are summarized in the table below.

    Studies Evaluating Statin Use for Primary Prevention in the Elderly

    A new study, Statin therapy for reducing events in the elderly (STAREE) is currently recruiting with an estimated study completion in 2033.22 Until then, we have precious few trials that include the elderly to assist in making decisions on whether to start or continue statins in patients over 75 with no evidence of ASCVD.

    Conclusion

    ASCVD increases with age so it seems reasonable that lipid lowering therapy provides a benefit in older adults, but this assumption does not always hold up to scrutiny. There are numerous other risk reduction strategies with proven benefit that should be considered besides reducing cholesterol, such as blood pressure control and lifestyle modifications.23 Shared decision making should be used to elicit patients’ values and goals of care to be sure therapies are aligned with expressed wishes.24 In addition, factors such as life expectancy, time to benefit, current comorbidities, costs, and risks of therapy must be included in frank discussions with patients and/or caregivers before agreeing on the best course of treatment for older adults.

    REFERENCE LIST:

    1. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5(4):378-387. doi:10.1111/j.1582-4934.2001.tb00172.x
    2. Ridker P, Danielson E, Fonseca FA, Genest J, Gotto Jr A, Kastenlein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med. 2008;359:2195-2207. doi: 10.1056/NEJMoa0807646
    3. Johansen ME, Green LA. Statin use in very elderly individuals, 1999-2012. JAMA Intern Med. 2015;175(10):1715–1716. doi:10.1001/jamainternmed.2015.4302
    4. Project Risk Reduction by Therapy. ASCVD Risk Estimator. http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/. Accessed June 5, 2019.
    5. Pooled Cohort Risk Assessment Equations. https://clincalc.com/cardiology/ascvd/pooledcohort.aspx. Accessed June 5, 2019.
    6. Cholesterol Drugs for People 75 and Older. Choosing Wisely – promoting conversations between providers and patients. https://www.choosingwisely.org/patient-resources/cholesterol-drugs-for-people-75-and-older/. Accessed June 6, 2019.
    7. Grundy SM, Stone NJ, Bailey AL, et al. CLINICAL PRACTICE GUIDELINE 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003
    8. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions*. Clin Pharmacol Ther. 1997;61(3):331-339. doi:10.1016/s0009-9236(97)90166-1
    9. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11. doi:10.1016/j.phrs.2014.03.002
    10. Lipitor (atorvastatin) [package insert]. New York, NY: Parke-Davis; 2009.
    11. Zocor (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2010.
    12. Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy: a common dilemma not reflected in clinical trials. Clev Clin J Med. 2011;78(6):393-403. doi:10.3949/ccjm.78a.10073
    13. Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener. 2018;7(1). doi:10.1186/s40035-018-0110-3
    14. FDA Drug Safety Communication. Published Feb 28, 2012. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-label-changes-cholesterol-lowering-statin-drugs. Accessed June 7, 2019.
    15. Deaths: final data for 2016. National Vital Statistics Reports. 2018;67(5):1-76. https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_05.pdf. Accessed June 5, 2019.
    16. Campaigning for a fact-based approach to health journalism. Bull World Health Organ. 2017;95(4):248-249. doi:10.2471/blt.17.030417
    17. Nuovo J, Melnikow J, Chang D. Reporting number needed to treat and absolute risk reduction in randomized controlled trials. JAMA. 2002;287(21):2813. doi:10.1001/jama.287.21.2813
    18. BMJ best practice: how to calculate risk. https://bestpractice.bmj.com/info/us/toolkit/learn-ebm/how-to-calculate-risk/. Accessed June 6, 2019.
    19. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. The Lancet. 2002;360(9346):1623-1630. doi:10.1016/s0140-6736(02)11600-x
    20. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA. 2002;288(23):2998-3007. doi:10.1001/jama.288.23.2998.
    21. Yusuf S, Phil D, Bosch J, Dagenais G, Zhu J, Xavier D, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2021-2031. doi:10.1056/NEJMoa1600176
    22. A clinical trial of statin therapy for reducing events in the elderly (STAREE). https://clinicaltrials.gov/ct2/show/NCT02099123. Accessed June 29, 2019.
    23. Alfaddagh A, Arps K, Blumenthal RS, Martin SS. The ABCs of primary cardiovascular prevention:2019 update. Am Coll Cardiol. 2019. https://www.acc.org/latest-in-cardiology/articles/2019/03/21/14/39/abcs-of-primary-cv-prevention-2019-update-gl-prevention. Published March 21, 2019. Accessed May 31, 2019.
    24. Grad R, Légaré F, Bell NR, Dickinson JA, Singh H, Moore AE, et al. Shared decision making in preventive health care: what it is; what it is not. Can Fam Physician. 2017;63(9):682–684. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597010/. Accessed June 1, 2019.
  • 18 Jul 2019 9:54 AM | Mandy Garion (Administrator)

    Author:  Hunter Ragan, PharmD Candidate 2020; SIUE School of Pharmacy
    Mentor: Sarah Cook PharmD, BCPS; SSM Health St. Joseph Hospital – St. Charles

    Introduction

    Cardiovascular Disease (CVD) is the leading cause of death for adults in the United States, with approximately 610,000 deaths due to CVD per year.1  Patients with hyperlipidemia are at roughly twice the risk of developing CVD compared to those with normal cholesterol levels.2  Over 95 million adults aged 20 or older in the United States have hyperlipidemia with total cholesterol greater than 200 mg/dL.3 

    Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are the newest class of cholesterol-lowering medications and have been shown to reduce LDL-C by up to 70%.  There are currently two PCSK9 inhibitors approved by the FDA: alirocumab (Praluent) and evolocumab (Repatha).  They are fully human monoclonal antibodies that bind in a 1:1 ratio to circulating PCSK9, which normally binds to low-density lipoprotein receptors (LDLR) on the surface of hepatocytes and promotes their degradation.  LDLR are the primary receptors responsible for removing LDL-C from the blood.  Thus, PCSK9 inhibitors increase clearance of LDL-C from the blood by increasing the number of LDLR on hepatocytes.4,5

    Alirocumab (Praluent)

    Alirocumab was the first FDA-approved PCSK9 inhibitor in July 2015 with an indication of primary hyperlipidemia; an additional indication of secondary prevention of myocardial infarction (MI), stroke, and unstable angina (UA) requiring hospitalization was recently added in April 2019.6  The ODYSSEY Phase III Program which led to alirocumab’s initial FDA approval consisted of multiple studies enrolling more than 23,000 patients.  These studies showed statistically significant improvement in LDL-C levels, but CVD benefit was not assessed in these trials.  The ODYSSEY OUTCOMES trial was undertaken to assess the impact of alirocumab on CVD.7

    The ODYSSEY OUTCOMES trial was a multicenter, randomized, double-blind, placebo-controlled trial that consisted of more than 18,000 patients in 57 countries.  Eligible patients were 40 years of age or older with elevated LDL-C (≥70 mg/dL) or elevated non-HDL-C (≥100 mg/dL) despite high-intensity or maximally tolerated statin therapy that experienced acute coronary syndrome (ACS) within 1-12 months prior to enrollment.  The primary end point was a composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and UA requiring hospitalization. The targeted LDL-C value was 25-50 mg/dL and median follow up was 2.8 years.  Baseline median LDL-C was 87 mg/dL in both treatment and placebo groups, and alirocumab resulted in 54.7% lower LDL-C at 2 years compared to placebo.  Alirocumab also resulted in a 15% reduction in the composite primary endpoint compared to placebo (95% CI 0.78-0.93; p=0.0003).  Additionally, alirocumab was associated with a 15% reduction in the secondary endpoint of all-cause mortality compared to placebo, with an incidence of 3.5% in the alirocumab group and 4.1% in the placebo group (95% CI 0.73-0.98; p=0.026). However, the difference in mortality due to coronary heart disease alone was not found to be statistically significant.  Subgroup analysis of the ODYSSEY OUTCOMES trial found that patients with baseline LDL-C values higher than 100 mg/dL experienced a greater benefit with alirocumab.  Additionally, patients achieving LDL-C levels of approximately 30 mg/dL at 4 months of treatment experienced lower all-cause mortality rates.8,9

    Alirocumab’s most common adverse effect seen in clinical trials was injection site reactions; flu-like symptoms, cough, and myalgias were also reported (all at rates < 10%).  Neutralizing antidrug antibodies to alirocumab were noted in clinical trials at a rate of approximately 1%, with even fewer patients having loss of efficacy due to their presence.10  A safety analysis of 5 placebo-controlled trials studying alirocumab found no statistical difference in new-onset of diabetes or worsening of diabetes, which was consistent with results seen in ODYSSEY OUTCOMES.  The most common side effects noted in this study were nasopharyngitis, upper respiratory infections, and injection site reactions.11

    Evolocumab (Repatha)

    Evolocumab was approved in August 2015 for primary hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and heterozygous familial hypercholesterolemia (HeFH); an additional indication of secondary risk reduction after MI, stroke, and coronary revascularization was approved in December 2017.12  Similar to the phase III trials leading to alirocumab’s initial FDA approval, studies of evolocumab showed significant reduction of LDL-C (approximately 54-77% reduction at 12 weeks compared to placebo) but did not assess clinical endpoints related directly to CVD morbidity or mortality.13 The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial assessed the impact of evolocumab on CVD, and was the first study to look at the impact of PCSK9 inhibitors on CVD outcomes.

    The FOURIER trial was a multinational, randomized, double-blind, placebo-controlled trial involving over 27,000 patients in 49 countries.  Eligible patients were between 40-85 years of age with clinically evident ASCVD with elevated LDL-C (≥70 mg/dL) or elevated non-HDL-C (≥100 mg/dL) despite maximally tolerated statin therapy (at least atorvastatin 20 mg daily or its equivalent) with or without ezetimibe. Patients with prevalent diabetes were excluded at the start of the trial. The primary endpoint was the composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization.  After a median follow-up of 2.2 years, the primary endpoint was experienced in 9.8% of the evolocumab group and in 11.3% of the placebo group (HR 0.85; 95%CI 0.79-0.92).  No significant difference in all-cause mortality or mortality due to coronary heart disease alone was noted. Both treatment and placebo groups had a median LCL-C of 92 mg/dL at baseline, and at 48 weeks, LDL-C was reduced to a median of 30 mg/dL in the evolocumab group.14  A secondary analysis of the FOURIER trial found that event rates for the primary outcome were lowest in patients who achieved the lowest LDL-C and highest in those with the highest LDL-C.15  The authors concluded that high-risk CVD patients may benefit from lowering LDL-C levels below current goals.14 

    The most commonly reported adverse effect from evolocumab is nasopharyngitis; additional side effects include injection site reactions, diabetes, and flu-like symptoms, and rarely neurocognitive effects.10  In the FOURIER trial, the number of patients with new-onset diabetes, neurocognitive effects, and muscle-related events were numerically higher, but these were not statistically significant.14  Additionally, an analysis of multiple placebo-controlled trials of evolocumab did not find the presence of anti-evolocumab antibodies in any of the trials analyzed.16

    Current Guideline Recommendations

    The 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association (AHA), American College of Cardiology (ACC), and others recommend high-intensity (or maximally tolerated) statin therapy as first line medication therapy in patients with clinical ASCVD (Class I recommendation).  In patients with LCL-C ≥ 70 mg/dL despite statin therapy, the addition of ezetimibe is reasonable (Class IIa recommendation for very high risk individuals, Class IIb recommendation for not very high risk individuals).  If LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL despite both therapies, a PCSK9 inhibitor may be reasonable in patients at very high risk (Class IIa recommendation).   PCSK9 inhibitors can also be considered prior to ezetimibe, but this is not preferred (Class I recommendation).  Very high risk individuals have multiple ASCVD events or 1 ASCVD event plus multiple other high risk conditions. PCSK9 inhibitors should also be considered in patients with HeFH when LDL-C ≥ 100 mg/dL despite treatment with a maximally tolerated statin and ezetimibe (Class IIb recommendation) as well as in patients with baseline LCL-C ≥ 220 mg/dL with an LDL-C ≥ 130 mg/dL despite being on a maximally tolerated statin and ezetimibe (Class IIb recommendation).  These guidelines do acknowledge that the cost-effectiveness of PCSK9 inhibitors is not well defined, particularly in patients without clinical ASCVD using PCSK9 inhibitors for primary prevention of CVD.17

    The 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease only mention the use of statins for cholesterol management based on a patient’s ASCVD risk score and risk enhancers such as family history, LDL-C > 160 mg/dL, chronic kidney disease, and others.18  However, these recommendations may change in the future based on the results of the VESALIUS-CV trial which was announced in March 2019.  This study will enroll a minimum of 13,000 patients from various countries and will evaluate primary prevention of CV events in patients with high CVD risk but no prior MI or stroke.  It will last a minimum of four years or until a sufficient number of patients experience the primary composite outcome of time to CVD death, MI, or ischemic stroke.  It will also evaluate time to CVD death, MI, ischemic stroke, or any ischemia driven arterial revascularization.19

    Conclusion

    Currently, PCSK9 inhibitors’ primary place in therapy is for secondary prevention of CVD in patients with LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL despite a maximally tolerated statin and ezetimibe therapy and for LDL-C lowering in patients with severe primary hyperlipidemia.  The FOURIER and ODYSSEY trials have shown promise with their use in preventing secondary ASCVD events.  Alirocumab also showed a decrease in all-cause mortality while evolocumab did not, which could potentially be due to the higher-risk population in ODYSSEY OUTCOMES compared to FOURIER.  Previous phase III trials of both PCSK9 inhibitors have already established their effectiveness in lowering LDL-C in patients with primary hyperlipidemia, but further trials are needed to establish their effectiveness for primary prevention of CVD.  Further research is also needed to establish the ideal LDL-C target.

    Overall, PCSK9 inhibitor’s clinical benefits related to lowering LDL-C and secondary prevention of CVD are evident, and their adverse events noted in clinical trials are minimal.  Long-term safety data is remains unknown due to their novelty.  Additionally, cost concerns and cost-effectiveness are still unclear, although the manufacturers have reduced pricing since their initial release to promote their use and garner more insurance approval.  Manufacturer websites can be consulted to find further information on payment assistance options that are available.

    References:

    1. Heart Disease Facts & Statistics | cdc.gov. https://www.cdc.gov/heartdisease/facts.htm. Published October 9, 2018. Accessed June 13, 2019.
    2. Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association | Circulation. https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000485?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&fbclid=IwAR3b93ou2NpHcmRM89PAYg5Edxya4i23Ho81PXUzba_rm6_nQE0FdlBLygY. Accessed June 13, 2019.
    3. CDC. High Cholesterol Facts. Centers for Disease Control and Prevention. https://www.cdc.gov/cholesterol/facts.htm. Published February 6, 2019. Accessed June 13, 2019.
    4. Learn About PCSK9 Inhibitor Mechanism of Action | Repatha® (evolocumab). https://www.repathahcp.com/about-repatha/. Accessed June 9, 2019.
    5. Mechanism of Action | PRALUENT® (alirocumab) Injection. home. https://www.praluenthcp.com/dosing-and-administration/mechanism-of-action. Accessed June 9, 2019.
    6. FDA approves Praluent® (alirocumab) to prevent heart attack, stroke and unstable angina requiring hospitalization. http://www.news.sanofi.us/2019-04-26-FDA-approves-Praluent-R-alirocumab-to-prevent-heart-attack-stroke-and-unstable-angina-requiring-hospitalization. Accessed June 9, 2019.
    7. Sanofi and Regeneron Announce FDA Approval of Praluent® (alirocumab) Injection, the First PCSK9 Inhibitor in the U.S., for the Treatment of High LDL Cholesterol in Adult Patients - Jul 24, 2015. http://www.news.sanofi.us/2015-07-24-Sanofi-and-Regeneron-Announce-FDA-Approval-of-Praluent-alirocumab-Injection-the-First-PCSK9-Inhibitor-in-the-U-S-for-the-Treatment-of-High-LDL-Cholesterol-in-Adult-Patients?fbclid=IwAR0tm70_yDB7VL5Opt2XrTc8jGQBZ1rl_2o0V9f6WkggrKibSdu5kpDcPyQ. Accessed June 26, 2019.
    8. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
    9. Steg Philippe Gabriel, Szarek Michael, Bhatt Deepak L., et al. Effect of Alirocumab on Mortality After Acute Coronary Syndromes: An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation. 0(0).
    10. Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. Accessed June 13, 2019.
    11. Ginsberg HN, Farnier M, Robinson JG, et al. Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies. Diabetes Ther Res Treat Educ Diabetes Relat Disord. 2018;9(3):1317-1334.
    12. FDA Approves Amgens Repatha evolocumab To Prevent Heart Attack And Stroke. https://www.amgen.com/media/news-releases/2017/12/fda-approves-amgens-repatha-evolocumab-to-prevent-heart-attack-and-stroke/. Accessed June 13, 2019.
    13. Amgen - Investors - Press Release. http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=2082837&fbclid=IwAR26MNAZQei9vrbMOv3rlvl65U6DAJ9OYcKDYr4qtky2nKGvTD7uCdde1hA. Accessed June 26, 2019.
    14. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.
    15. Giugliano RP, Pedersen TR, Park J, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017b;390:1962-71.
    16. Toth Peter P., Descamps Olivier, Genest Jacques, et al. Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies. Circulation. 2017;135(19):1819-1831.
    17. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. November 2018:25709.
    18. Arnett Donna K., Blumenthal Roger S., Albert Michelle A., et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 0(0):CIR.0000000000000678.
    19. Amgen Announces New Four Year Outcomes Study To Examine Long Term Effects Of Repatha evolocumab In High Risk Cardiovascular Disease CVD Patients Without Prior Heart Attack Or Stroke. https://www.amgen.com/media/news-releases/2019/03/amgen-announces-new-fouryear-outcomes-study-to-examine-longterm-effects-of-repatha-evolocumab-in-highrisk-cardiovascular-disease-cvd-patients-without-prior-heart-attack-or-stroke/. Accessed June 9, 2019.


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