Status Update on the National Cardiovascular Prevention Guidelines - JNC 8, ATP 4, and Obesity 2

TABLE OF CONTENTS Status Update on the National Cardiovascular Prevention Guidelines 1 Drosperinone-Containing Oral Contraceptives and Venous Thromboembolism Risk 1-4 P&T Committee Formulary Action 5 Status Update on the National Cardiovascular Prevention Guidelines - JNC 8, ATP 4, and Obesity 2 The National Heart, Lung, and Blood Institute (NHLBI) has been in the process of updating national hyperlipidemia, hypertension, and obesity guidelines for many years. The process has been painstakingly slow with many clinicians currently expressing concern over the reasons given for holding back the new guidelines and the impact these delays may be having on patient care. The last set of NHLBI guidelines for these disease states were issued in: 2001, with a 2004 update, for the Adult Treatment Panel Detection, Evaluation, and Treatment of High Blood Cholesterol (ATP III) guidelines; 2003 for the Seventh Edition of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines; 1998 for the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. At the recent 2011 American Heart Association (AHA) meeting, long-awaited key details from the new guidelines were to be presented; however, attendees at the spotlight session were merely treated to an explanation of the delayed process as well as an overview of critical questions being addressed for all 3 guidelines. The main factor behind the slow down in guideline development was the release of a March 2011 Institute of Medicine report entitled Clinical Practice Guidelines We Can Trust. This report contained 8 standards for developing rigorous, trustworthy clinical practice guidelines. These standards were incorporated into the national cardiovascular prevention guidelines development process thereby delaying completion, with the end result hopefully being an improvement in the overall quality of the guidelines. In addition, these new guidelines incorporate a vast amount of clinical data. For the JNC 8 guidelines alone, the expert committee performed a literature review back to 1966. Across all 3 guidelines, approximately 39,000 papers were screened, graded, and abstracted. At the AHA meeting, expert panel members presented critical questions that will be used as the basis for recommendations within each guideline. These are presented in Table 1. During the AHA presentation, it was noted that all 3 guidelines should be released sometime in 2012, potentially within the first 6 months. In addition, the NHLBI announced that an expert panel will be working towards development of an integrated guideline that incorporates information from the hyperlipidemia, hypertension, and obesity reports. This integrated guideline may potentially be completed in 2 years. Drosperinone-Containing Oral Contraceptives and Venous Thromboembolism Risk Drospirenone, a unique fourth generation progestogen, has been approved by the Food and Drug Administration (FDA) for the prevention of pregnancy in combination with ethinyl estradiol (EE) since May 2001. Drospirenone, an analogue of spironolactone, displays antimineralocorticoid activity due to increasing sodium and water excretion, and antiandrogenic activity by blocking androgen receptors in skin. Its proposed benefits include reducing problems with weight gain, acne, hirsutism, as well as having a more favorable effect on the lipid profile when compared with older progestogens. Yaz and Yasmin, drospirenone-containing oral contraceptives (OCs), have consistently been among the top 200 drugs in the country. Shortly after approval, reports of venous thromboembolism (VTE) began to surface among users of OCs containing drospirenone. As of the middle of 2002, 40 cases of VTE had been reported in European women receiving OCs containing drospirenone and 30 mcg of EE. 1

Table 1. Critical Questions to be Addressed by National Cardiovascular Prevention Guidelines. Guideline Critical Questions Comments ATP 4 JNC 8 Obesity 2 1. What evidence supports LDL-C goals for secondary prevention? 2. What evidence supports LDL-C goals for primary prevention? 3. What is the impact of the major cholesterol medications on efficacy and safety? 1. Does initiating antihypertensive drug therapy at specific blood pressure thresholds improve outcomes? When should treatment be initiated? 2. Does treatment with antihypertensive drug therapy to a specified blood pressure goal lead to improvements in outcomes? How low should you go? 3. Do various antihypertensive drugs or drug classes differ in comparative benefits and harms for specific outcomes? How do you get there? 1. What are the benefits of weight loss? 2. What are the risks of being overweight? 3. What is the efficacy of different diet strategies? 4. What is the role of a comprehensive lifestyle intervention (diet plus exercise plus behavioral therapy) in achieving and maintaining weight loss? 5. What are the benefits and risks of various bariatric procedures? The impact of diet/exercise is being evaluated in a separate lifestyle working group. Randomized controlled trials and high-quallity meta-analyses were considered in this guideline. These guidelines only considered evidence from randomized controlled trials. Pharmacologic interventions will not be included in this guideline due to a lack of sufficient evidence. Several studies have been conducted to evaluate and quantify the risk of VTE with drospirenone-containing OCs. No increase in VTE risk with drosperinone-containing OCs as compared to other OCs was observed in the results of 2 cohort studies published in 2007- one involving women 10 to 59 years of age from a U.S. health insurer database (United Healthcare) and the other involving women with mean ages of 25 to 27 years from 7 European countries (the European Active Surveillance [EURAS] study). In contrast, in 2009, results from a cohort study conducted in women age 15 to 49 years using various types of OCs from 4 national Danish registries between 1995 and 2005, and a case-control study conducted in the Netherlands (women 18 to 50 years of age) found a 1.5- to 2-fold higher VTE risk in drospirenone recipients compared to women receiving levonorgestrel. Based on results from the 4 studies mentioned above, FDA alerted the public about the potential increased risk of VTE in women using drospirenone-containing OCs on May 31, 2011. At the time of this initial safety announcement, FDA stated that it was continuing to review the data and would communicate additional information when available. The safety announcement was updated on September 26, 2011 coinciding with publication of 2 additional cohort studies, which are described in the next sections. Recent Literature 2011 U.S. Data The first study was conducted in the U.S. to assess the risk of non-fatal idiopathic VTE in women receiving drospirenone-containing OCs compared with those receiving levonorgestrel-containing OCs. Participant data were collected from claims paid by managed care plans in the PharMetrics database, a database containing prescription drug claims, medical diagnoses, procedures, and demographic information on 55 million people. The investigator included data for women 15 to 44 years of age who received either drospirenone or levonorgestrelcontaining OCs after January 1, 2002 (current users). Cases were defined as women receiving the study OCs who had medical history in the database for at least 6 months before their first-time claim for deep vein thrombosis (DVT) or pulmonary embolism (PE) who subsequently received anticoagulation therapy. Women who had documentation of any VTE risk factors within 90 days before the index date were excluded from the study in order to focus on women with idiopathic VTE. Controls were matched to each case by age (4:1). A nested case-control design was used to determine the impact of confounding variables such as age, duration of OC use, obesity, and emergency department visits on the results of the study. Conditional logistic 2

regression was used to analyze the matched case-control data. Controlled variables were age and date of diagnosis. Data were analyzed to estimate the incidence rate and 95% confidence intervals (CIs). The study population consisted of 186 cases and 681 controls. When compared with control, cases had a higher percentage of obesity (13% vs. 6%) and emergency department visits (9% vs. 3%). Women using drospirenone were younger (higher percentage in <30 years of age group), had a shorter duration of OC use, and were more likely to have a history of menstrual disorders. Among cases with idiopathic VTE, 121 (65%) were using drospirenonecontaining OCs, and 65 (35%) were taking a levonorgestrelcontaining agent. Among the control group, 313 (46%) were receiving drospirenone compared to 368 (54%) using levonorgestrel-containing OCs. The unadjusted matched odd ratio (OR) for VTE with drospirenone-containing OCs compared to those containing levonorgestrel was 2.3 (95% CI 1.6 to 3.2). Among women younger than 30 years of age, those who used drospirenone-containing OCs had a higher risk of VTE (OR 3.7, 95% CI 2.0 to 6.9) than younger women using levonorgestrel-containing OCs. The incidence rates of VTE in women receiving drospirenone and levonorgestrelcontaining OCs were 30.8 (95% CI 25.6 to 36.8) and 12.5 (95% CI 9.61 to 15.9) per 100,000 woman years, respectively. The incidence of VTE increased with increasing age for both types of OCs. The authors concluded that risk of VTE in women receiving drospirenone-containing OCs was about double the risk of their counterparts receiving a levonorgestrel-containing OC. UK Data The second nested case-control study was conducted in the UK to examine the risk of non-fatal idiopathic VTE in current users of OCs containing drospirenone compared to those using levonorgestrel. Overall study design was similar to the U.S. study. Women from the UK General Practice Research Database 15 to 44 years of age who received either drospirenone or levonorgestrel-containing OCs between May 1, 2002 and September 30, 2009 were included to the study. Included cases were those who had a medical history recorded in the database for at least 1 year and were diagnosed with either DVT or PE with subsequent anticoagulation therapy in the absence of history or risk factors for VTE. Controls were matched to each case (up to 4 per case) by year of birth (within 2 years), number of years of recorded date, and general practice. Conditional logistic regression was used to compute OR and 95% CI in this case-control analysis. Potential confounding factors were body mass index (BMI), history of varicose veins, smoking status, and antidepressant use. The study population included 61 cases and 215 controls. Seventeen (28%) cases and 26 (12%) controls were users of drospirenone-containing OCs (unadjusted OR 3.2, 95% CI 1.5 to 7). The mean age of cases and controls was similar (32.2 vs. 31.8 years of age). Cases had a higher proportion of women with BMI 25 than controls (61% vs. 31%); OR adjusted for BMI was 3.3 (95% CI 1.4 to 7.6). Further adjustment for confounding factors (BMI, history of varicose veins, smoking status, and antidepressant use) showed results similar to the unadjusted analysis (OR 3.1, 95% CI 1.3 to 7.5). The investigators also found that differences in age (<35 years, and 35 years), duration of OC use, and history of OC use before the current episode (no previous use vs. at least 1 previous episode of use) did not significantly affect the excess risk of VTE in users of drospirenone-containing OCs. The unadjusted incidence rates of VTE for current users of drospirenone and levonorgestrel-containing OCs were 23 (95% CI 13.4 to 36.9) and 9.1 (95% CI 6.6 to 12.2) per 100,000 woman years, respectively. The incidence rate ratio adjusted for age was 2.7 (95% CI 1.5 to 4.7). The authors concluded that drospirenone-containing OCs cause a higher risk of VTE compared to levonorgestrel-containing OCs. FDA Safety Announcement September 26, 2011 and Literature Update Although the results of the 2 most recently published studies showed an increased risk of VTE in women using OCs containing drospirenone compared with levonorgestrel, the FDA stated that further review of the data is warranted. The agency has scheduled a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee for December 8, 2011 to discuss the risk of VTE with drospirenone-containing OCs. In the meantime, the FDA has suggested the following for healthcare professionals (http://www.fda.gov/ Drugs/DrugSafety/ucm273021.htm): Consider the risks and benefits of OCs containing drospirenone prior to prescribing with consideration for the individual patient s risk for developing VTE. Some risk factors for VTE include smoking, obesity, and family history of VTE. Counsel patients about the current information on the risk of VTE with OCs containing drospirenone compared with levonorgestrel. The studies assessing risk of VTE have only evaluated the OC containing drospirenone and 30 mcg EE, so these results might not apply to other drospirenone-containing products with a lower dose of EE. Report adverse events involving OCs to FDA Med- Watch (https://www.accessdata.fda.gov/scripts/medwatch/ medwatch-online.htm). In addition to the results of the recently published studies, the safety announcement also mentioned preliminary data from an FDA-funded epidemiologic study that found a 1.5 times increased risk of VTE in users of OCs containing drospirenone compared to other OCs. Recently, the final report of the study has been published on the FDA s website (http://www.fda.gov/downloads/drugs/drugsafety/ UCM277384.pdf). 3

The study was conducted to assess the risk of VTE in women 10 to 55 years of age using newer combined hormonal contraceptives including the drospirenone and EE OC, the norelgestromin (third generation) and EE transdermal patch, and the etonogestrel (third generation) and estradiol vaginal ring compared with those using standard OCs with low estrogen levels from 4 U.S. health plan databases between January 1, 2001 and December 31, 2007. The standard comparator OCs included: 0.10 mg levonorgestrel + 20 mcg EE 0.15 mg levonorgestrel + 30 mcg EE 1 mg norethindrone acetate + 20 mcg EE 0.18 0.25 mg norgestimate + 35 mcg EE There were 835,826 women with 898,251 person-years of combined hormonal contraceptive use included in the study. The final cohort contained 189,210 person-years of drospirenone use, 67,865 person-years of norelgestromin use, 23,910 person-years of etonogestrel use, and 617,265 person-years of the standard combined OCs (comparator) use. Key results showed a significantly increased risk of VTE in users of drospirenone and EE tablet, norelgestromin and EE transdermal patch, and etonogestrel and estradiol vaginal ring with adjusted relative risk (RR) of VTE of 1.74 (95% CI 1.42 to 2.14), 1.55 (95% CI 1.17 to 2.07), and 1.56 (95% CI 1.02 to 2.37), respectively compared to standard therapy. The analysis was restricted to new users, and only the drospirenone-containing regimen was associated with a higher risk of VTE (RR 1.77, 95% CI 1.33 to 2.35) and arterial thrombotic events (RR 2.01, 95% CI 1.06 to 3.81). Another analysis focused on duration of exposure. Increased risk of VTE was found with drospirenone use for less than 3 months (RR 1.93, 95% CI 1.24 to 3.00) and 6 to 12 months (RR 2.80, 95% CI 1.48 to 5.29) relative to comparators. The norelgestromin patch had a higher risk of VTE with more than 12 months of exposure (RR 3.05, 95% CI 1.23 to 7.53). The conclusion of this FDA analysis was that drospirenone, norelgestromin transdermal patch, and etonogestrel vaginal ring were associated with a higher risk of VTE compared with the standard, low-dose, estrogen-containing OCs. Following the FDA safety announcement, another study was published in the British Medical Journal online October 25, 2011. This study was an extension of the Danish study published in 2009, and the objective was to assess the risk of VTE in users of combined OCs according to progestogen type and estrogen dose. Participants were women 15 to 49 years of age without history of or risk factors for VTE from Danish registries. Data were analyzed by multiple Poisson regression, and RR was adjusted for age, calendar year, level of education, and duration of OC use; smoking data were not available. Never-users and former-users, collectively defined as non-users, of all types of hormonal contraception methods were used as the reference group for RR analysis. There were 1,296,120 women and 4307 first-time VTE events included in the analysis, and a total of 2847 (67%) of VTE events were confirmed. The incidence rate of VTE in non-users of hormonal contraception was 3.7 per 10,000 woman years. All users of combined OCs had a significantly increased risk of VTE, while users of progestogen-only contraceptives did not compared to non-users. The highest adjusted RR of VTE was seen in users of the OCs containing norethisterone and 50 µg EE (5.66, 95% CI 3.12 to 10.3), and the lowest adjusted RR of VTE was seen in users of OCs containing norethisterone and 30 to 40 mcg EE (1.57, 95% CI 0.84 to 2.92). The adjusted RR of VTE in users of OCs with levonorgestrel and 30 mcg EE and users of OCP with drospirenone and 30 µg EE were 2.19 (95% CI 1.74 to 2.75) and 4.47 (95% CI 3.91 to 5.11), respectively. The adjusted RR in drospirenone users was a bit higher (4.84, 95% CI 3.19 to 7.33) when using the lower estrogen dose (20 mcg) formulation. In the analysis of the confirmed VTE cases, adjusted rate ratio of VTE risk of drospirenone users relative to levonorgestrel users was 2.12 (95% CI 1.68 to 2.66). Similar rate ratios of VTE risk, relative to levonorgestrel users, were also seen in users of OCP containing desogestrel (2.20, 95% CI 1.74 to 2.77), and gestodene (2.07, 95% CI 1.70 to 2.52). Further adjustment for duration of OC use did not change the increased risk of VTE in drospirenone users, but decreased the risk in gestodene users. The investigators also conducted sensitivity analyses, but no substantial changes were observed. The authors concluded that the risk of VTE among users of OCs containing drospirenone, desogestrel, or gestodene was at least twice that compared to users of OCs containing levonorgestrel. Summary Recent literature consistently supports an increased risk for VTE among woman taking drospirenone-containing OCs compared to women using levonorgestrel-containing products. This risk has been shown even in women with shortterm use of drospirenone (<3 months). A joint meeting of 2 FDA advisory committees will occur in early December 2011 to discuss the risks and benefits of drospirenone-containing OCs. In the meantime, healthcare providers are encouraged to carefully assess risk factors for VTE prior to prescribing OCs, notably drospirenone-containing regimens. Although the fourth generation progestin may offer some benefits in terms of its antimineralocorticoid activity, it is unclear if the potential benefits outweigh the established risk for VTE. 4

P&T Formulary Committee Action* *The P&T Committee actions are effective when formulary changes have been implemented in the Cerner System. Additions - Losartan - Atorvastatin - formulary use restriction removed Deletions - Valsartan - Telmisartan - Simavastatin - Drotrecogin alfa - Mebendazole Authors: Michael Gabay PharmD, JD, BCPS Amy Lodolce PharmD, BCPS Suputat Chumnumwat PharmD candidate Editor: Michael Gabay PharmD, JD, BCPS 5