By Samit Shah, MD
Faculty Peer Reviewed
‘Tis the season to be merry and enjoy all the wonderful aspects of the holidays, such as shopping, bright lights, holiday music, family, friends and of course food! As the festive season approaches, our natural inclinations for indulgent behaviors often go unchecked, leading us to do some damage on our waistlines. Fortunately, Primecuts has arrived in the nick of time to report some developments in our battle against obesity.
Traditionally, weight-loss surgery has been recommended for people who have been unable to lose weight through diet and exercise, have a body mass index (BMI) above 40, or above 35 if they have risk factors. Recently, the New York Times reported on a Food and Drug Administration (FDA) advisory panel’s recommendation to expand the use of Lap-Band (a stomach-restricting device that limits the quantity of food ingested and leads to early satiety) to patients who are less than severely obese, those with a BMI of 30 to 35 [1]. This new recommendation by the panel comes on the heels of a New England Journal of Medicine (NEJM) study [2] which examined the relationship between BMI and all-cause mortality in a pooled analysis of 19 prospective studies encompassing 1.46 million Caucasian adults. Investigators used Cox regression analysis to estimate an association between BMI and all-cause mortality, using BMI of 22.5 to 24.9 as the reference category, and found a hazard ratio of 1.44 (p=0.04) for BMI of 30 to 34.9 for healthy subjects who never smoked. The hazard-ratio for death from cardiovascular disease in these patients was 2.04. This data certainly is striking and should prompt primary care physicians to be more vigilant in helping patients achieve an ideal BMI through various means. Whether weight-loss surgery should be considered for patients with BMI 30 to 35 remains to be seen, as further studies are needed to assess its risks and benefits in this group.
With an increasing shift in healthcare towards prevention, perhaps more focus should be placed on curbing the epidemic of obesity and its related risks in adolescence. However, the utility of BMI in such an age group may not be ideal as changes may reflect lean mass, rather than fat mass. In a BMJ prospective study [3], 5235 children were followed from ages 9-12 until ages 15-16 to examine prospective associations between BMI, waist circumference and fat mass (using DEXA) in childhood and cardiovascular risk factors. Outcomes measured were systolic and diastolic blood pressure, fasting glucose concentrations, insulin, triglycerides, LDL and HDL at the age of 15-16. All three adiposity measures were shown to be positively associated with increased odds of adverse levels for each outcome measure in both genders, with the exception of glucose concentrations, which was found to be higher in males. BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94). In addition, girls who were overweight/obese at age 9-12 but were normal weight by 15-16 demonstrated similar odds of adverse levels of risk factors to those who were normal at both time points. The male cohort, however, demonstrated intermediate odds of adverse levels compared to those who were normal and those who were obese at both time points. This data is reassuring in showing that reversing obesity during early stages of adolescence is associated with better risk profiles than in those who stay overweight. Since the outcomes measured are not clinical outcomes, but rather surrogates of cardiovascular risk, long-term follow-up of these cohorts may be interesting.
With all this discussion about obesity, let’s discuss some emerging therapies designed to combat deep vein thrombosis (DVT), a known complication of obesity. Until recently, our options for oral antithrombotics have been limited to warfarin, which requires frequent laboratory monitoring and dose adjustments. With recent FDA approval for dabigatran, a direct thrombin inhibitor, for prevention of stroke and systemic embolism in patients with atrial fibrillation, here comes another contender to depose warfarin: rivaroxoban.
A NEJM study [4] evaluated the use of rivaroxaban, an oral factor Xa inhibitor in treating acute DVT (Acute DVT Study), as well as for continued treatment after patients completed therapy for venous thromboembolism (Continued Treatment Study). The primary outcomes in both sub-studies were recurrent venous thromboembolism.
The Acute DVT Study was a randomized, open-label study comparing efficacy and safety of rivaroxaban with standard therapy that consisted of enoxaparin and a vitamin K antagonist (VKA) in patients with acute DVTs. Patients enrolled in the study had symptomatic, objectively confirmed DVTs without symptomatic pulmonary embolism. Important exclusion criteria to be mindful of were receipt of some form of therapy prior to randomization, contraindication to VKA or enoxaparin, a creatinine clearance below 30 ml per minute, significant liver disease, or pregnancy. In this study, 3449 patients were randomized: 1731 patients were given rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) and 1718 were given enoxaparin plus VKA. The treating physician determined treatment duration. Rivaroxaban was shown to be non-inferior to enoxaparin with respect to the primary outcome (2.1% versus 3% with enoxaparin-VKA; p<0.001) with similar primary safety outcomes, defined as first major or clinically relevant non-major bleeding (8.1% in each group; HR 0.97; p=0.77).
The Continued Treatment Study was a double-blinded, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism, given the purported risk of recurrence of 5-10% during the first year after treatment. In this study, 1197 patients underwent randomization: 602 to rivaroxaban and 595 to placebo. Rivaroxaban had superior efficacy in preventing thromboembolism (8 events [1.3%] versus 42 [7.1%] with placebo; HR 0.18; p<0.001), with an insignificant risk of bleeding compared to placebo (p=0.11).
The above results provide good reason for excitement for physicians and patients alike. The option of rivaroxaban as a single-drug therapy without laboratory monitoring requirements can potentially increase compliance, reduce hospitalization and related expenditures, and improve outcomes. However, a cost-effectiveness analysis would be necessary to see how rivaroxaban compares to warfarin, which is available as a generic.
In related news, MedPage reported on a preliminary study of rivaroxaban in patients with atrial fibrillation in prevention of embolic stroke [5]. The ROCKET-AF (so aptly named) trial was presented at the recent American Heart Association scientific meeting. The investigators randomized 7111 patients to rivaroxaban 20 mg daily and 7125 patients to warfarin. Interestingly, the average CHAD score of patients in this trial was 3.5, indicating a fairly high-risk population. Preliminary data showed that the rate of stroke (per 100 patient-years) was 2.12 in the rivaroxaban arm compared with 2.42 in the warfarin arm (P<0.001 for noninferiority). Until we see the data published in a peer-reviewed journal, we can only speculate on its use in this patient population.
That’s all for this week’s edition of Primecuts. Here’s wishing you and your loved ones a safe and enjoyable holiday season!
Dr. Shah is a second-year resident at NYU Langone Medical Center
Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
References;
[1] Pollack, A. Panel Votes to Expand Surgery for Less Obese. New York Times. [Internet] December 3, 2010. http://www.nytimes.com/2010/12/04/business/04obese.html?ref=health
[2] Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-Mass Index and Mortality among 1.46 Million White Adults. NEJM. (363): 2211-2219. December 2, 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa1000367
[3] Lawlor D, Benfield L, Logue J, et al. Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study. BMJ. (341): 6224. November 25, 2010. http://www.bmj.com/content/341/bmj.c6224.abstract
[4] EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. NEJM. [Internet] December 4, 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa1007903
[5] Peck, P. AHA: ROCKET-AF May Launch Rivaroxaban Approval. MedPage Today. [Internet] November 15, 2010. http://www.medpagetoday.com/MeetingCoverage/AHA/23346
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