Primecuts-This Week in the Journals

December 27, 2010

File:Blizzard2 - NOAA.jpgBy Ilya Lim, MD

As the New Year rolls around, many people are making New Year’s resolutions aimed at preventing weight gain, excessive spending, or indulging in other guilty pleasures.  Likewise, in this week’s medical literature, prevention is the recurring theme.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) remain significant preventable sources of morbidity and mortality.  Luckily, new tools in our arsenal against venous thromboembolic (VTE) disease such as specific factor Xa inhibitors continue to make splashes in the medical news. Unlike enoxaparin, which is injected subcutaneously, or warfarin which requires lab monitoring and dosing adjustments, the specific factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban, are orally dosed, of quick onset and require no lab monitoring.

Coming on the heels of an earlier study showing that oral treatment with rivaroxaban was as safe and effective as enoxaparin plus warfarin for acute DVT[1], a new study in the New England Journal of Medicine (NEJM) reveals the superiority of apixaban when compared to enoxaparin for thromboprophylaxis after hip replacement [2].  In this industry-sponsored double blind study, 5,407 patients undergoing total hip replacement were randomized to receive apixaban (2.5 mg orally twice daily, initiated 12 to 24 hours post-op) or enoxaparin (40 mg subcutaneously every 24 hours, initiated 12 hours pre-op) for 35 days, followed by bilateral venographic studies.  Apixaban was considerably more effective than enoxaparin for preventing the primary endpoints (asymptomatic or symptomatic DVT, PE, or death from any cause), 1.4% vs. 3.9%  (relative risk with apixaban 0.36; 95% confidence interval (CI), 0.22 to 0.54; P<0.001).  Apixaban was also more effective than enoxaparin for preventing major VTE events 0.5% vs. 1.1% (relative risk of 0.40; 95% confidence interval, 0.15 to 0.80; one sided P<0.001 for noninferiority and two sided P=0.01 for superiority). Number needed to treat (NNT) to prevent 1 primary endpoint was 40, and the NNT to prevent 1 major VTE event was 147.  There was no significant difference in the amount of major and clinically relevant nonmajor bleeding in the apixaban vs. the enoxaparin groups (4.8% vs. 5.0%).

This study is undoubtedly a breakthrough, adding to the growing body of data showing the efficacy of specific factor Xa inhibitors in the fight against VTE disease.  However, before generalizing the results of this study to your patient population, it must be noted that concomitant need for antiplatelet therapy was an exclusion criterion and that the patients in this study were relatively young (average age of 60 years old).  Current lack of reversibility of apixaban and its very high cost are the obvious drawbacks to widespread utilization.  These cautions will necessitate further studies, preferably not funded by the pharmaceutical companies making the drug.

While we’re on the topic of prevention, aspirin has recently been shown to prevent colon cancer.  A recent study published in Lancet aimed to determine whether low dose aspirin is equivalent to high dose aspirin for colon cancer prevention [3]. Using national registries of the United Kingdom and Sweden, researchers examined data among more than 14,000 patients who participated in four large[4-7] randomized trials of high dose and low dose daily aspirin vs. control, and one study comparing different doses of aspirin to each other[8]. The goal of this analysis was to establish the effect of aspirin on risk of colorectal cancer over a 20-year period.  Aspirin doses of at least 75 mg daily reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0.76, CI 0.60-0.96, p=0.02; mortality HR 0.65, 0.48-0.88, p=0.005).Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0.45, 0.28-0.74, p=0.001; 0.34, 0.18-0.66, p=0.001), but not the distal colon (1.10, 0.73-1.64, p=0.66; 1.21, 0.66-2.24, p=0.54; for incidence difference p=0.04, for mortality difference p=0.01). There was no increase in benefit at doses of aspirin greater than 75 mg daily. However, very low doses of 30 mg daily had no significant affect on colorectal cancer incidence or mortality.  Additionally, reduction in cancer incidence and mortality correlated with the duration of aspirin use.  Thus, there appears to be growing evidence that low dose aspirin is as efficacious as high dose aspirin, with the presumed benefit of an improved side effect profile.

Let’s switch gears and discuss influenza now that the flu season is in full swing.  How can we address our patients’ lingering concerns regarding prevention of swine flu and the efficacy & safety of the swine flu vaccine?  A recent NEJM article by Wu et. al. presents data demonstrating the safety and efficacy of the 2009 H1N1 vaccine[9].  After the first monovalent 2009 pandemic influenza A (H1N1) vaccine became available in September 2009, Chinese officials in Beijing conducted a 5-day mass vaccination program of 95,244 children and adults.  All participants were subject to passive surveillance. Participants were given diary cards to complete and telephone interviews were conducted to document adverse events.  Adverse event severity was graded on a four point scale, and severe adverse events (grade 3 and 4) were investigated by specially trained personnel. Adverse events were reported through passive surveillance in 193 vaccine recipients (0.2%).  Of these adverse events the most common systemic symptom was fever, and the most commonly reported injection site symptom was pain. When all telephone calls and diary cards were considered, a projected 12% of vaccinated participants had a local or systemic symptom.  Through hospital-based citywide active surveillance within the10 weeks after the mass vaccination, not a single case of Guillain-Barre or other neurologic disease was identified in the vaccine recipients (although 27 cases of Guillain-Barre were incidentally identified in unvaccinated individuals).  In a comparison of vaccinated vs. unvaccinated schoolchildren the estimated effectiveness of the vaccine was 87.3%(CI 95%, 75.4%-93.4%).  The lack of neurologic side effects in this enormous cohort study should diminish safety concerns that may be an obstacle to the acceptance of the influenza vaccine.

We cannot conclude this edition of primecuts without mentioning the breakthroughs from our basic science colleagues working tirelessly in the lab.  A European team published a recent article in Nature detailing a promising novel approach to reduce already deposited amyloid plaques in a murine model of systemic amyloidosis.  Amyloid deposits have been notoriously difficult to target because of the different misfolding patterns of the various amyloid proteins.  Because all amyloid deposits include the non-fibrillar plasma glycoprotein, serum amyloid P (SAP); by targeting SAP, a new gateway to eliminate already deposited amyloid plaques has been unleashed.  First, the team created a murine model of systemic amyloidosis by inducing chronic inflammation in mice that were engineered to produce human SAP.  The team subsequently developed a molecule with high affinity for circulating human SAP inducing its hepatic clearance.  Once the circulating SAP was depleted, the only SAP remaining was inside the amyloid plaque deposits.  At this point the team infused anti-human-SAP antibody, stimulating the endogenous phagocytic clearance mechanisms.  As one would hope, the plaque burden was significantly reduced, and there were no clinical or biochemical adverse effects.  This form of tertiary prevention is unique because to date, there has been no therapy that eliminates amyloid deposits.  This research is still in its infancy.  We are yet to see if this approach will pan out in humans and what the adverse effect profile would be.  Nonetheless, as we sit on the edge of our seats waiting to see what direction this research will take, one can only wonder how this methodology can be applied to plaque deposition in Alzheimer’s disease.

That is all for this edition of primecuts. Have a happy and healthy New Year and join us next week for more exciting medical news!

Dr. Ilya Lim is a first year internal medicine resident at NYU Langone Medical Center.

Peer reviewed by Neil Shapiro MD, Editor-in-Chief, Clinical Correlations

Image:  Standing tall on North Dakota snow; A March blizzard nearly buried utility poles. Caption jokingly read “I believe there is a train under here somewhere!” Jamestown, North Dakota March 9, 1966, courtesy of Wikimedia Commons.

References

[1] EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. NEJM. [Internet] 2010 December 4.  http://www.nejm.org/doi/full/10.1056/NEJMoa1007903

[2]Lassen MR et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. NEJM 2010 Dec 23;363(26):2487-98. http://www.nejm.org/doi/full/10.1056/NEJMoa1006885

[3] Rothwell PM et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet. 2010 Nov 20;376(9754):1741-50. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961543-7/fulltext#article_upsell

[4] Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet. 1998 Jan 24;351(9098):233-41. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2897%2911475-1/abstract

[5] The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet. 1991 Nov 30;338(8779):1345-9. http://www.thelancet.com/journals/lancet/article/PII0140-6736(91)92233-R/abstract

[6]B Farrell, J Godwin, S Richards and C Warlow. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991 Dec;54(12):1044-54. http://jnnp.bmj.com/content/54/12/1044.abstract?sid=84bdc6e2-1b61-4983-bd3c-b21e1b72fc05

[7] R Peto, R Gray and R Collins et al., Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed). 1988 Jan 30;296(6618):313-6. http://eresources.library.mssm.edu:2060/pmc/articles/PMC2544821/pdf/bmj00270-0009.pdf

[8] The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. NEJM. 1991 Oct 31;325(18):1261-6. http://www.nejm.org/doi/pdf/10.1056/NEJM199110313251801

[9]Wu J et al. Safety and effectiveness of a 2009 H1N1 vaccine in Beijing. N Engl J Med. 2010 Dec 16;363(25):2416-23. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1006736

[10] Bodin K et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010 Nov 4;468(7320):93-7. http://www.nature.com/nature/journal/v468/n7320/full/nature09494.html

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