Primecuts-This Week in the Journals

March 29, 2010

800px-matzoh-0851Kara Greenwald, MD

Faculty Peer Reviewed

The United States medical community, still reeling from an exciting debate in Congress, has revealed its cautiously optimistic side this week in the journals and press.  At once there is exciting news for liver disease,  a fresh look at the proton pump inhibitor (PPI) – clopidogrel interaction, an update on global MDR-TB[1] and XDR-TB, and from the FDA some news that may surprise you. The theme in medical news this week is “moving forward with an eye on the past.”

On Tuesday March 23rd President Obama signed his Health Reform Bill into law and then wrote on his Twitter© feed “Today, after almost a century of effort, health insurance reform has become law.” (1) There is still much debate about how this will affect the medical community and our patients.  Some changes, like preventing insurance companies from denying children with pre-existing conditions, are to take effect this year and others by 2019.  An overview as well as the text of the Senate bill and the revisions passed by the House of Representatives are available on the Whitehouse website .(2) Get ready for the questions from your patients!

Next up, the Food and Drug Administration (FDA) reacted to Bass and colleagues’ paper in the NEJM by approving Xifaxan (Salix Pharmaceuticals) for secondary prevention of hepatic encephalopathy (HE) in patients with recurrent HE (3).  Xifaxin, which is rifaximin, had been previously approved for treatment of traveler’s diarrhea (3). Bass and colleagues in a multicenter randomized double blind placebo controlled trial set out to evaluate if rifaximin is effective at decreasing the recurrence of hepatic encephalopathy.  They randomized 299 patients who had at least two previous episodes of hepatic encephalopathy to placebo or rifamixin groups.  The primary endpoint was time to hepatic encephalopathy (HE) and the secondary endpoint was time to hospitalization with HE.  For the Rifaximin group compared to placebo hazard ratios were 0.42 (95% CI 0.28-0.64) and 0.5 (95% CI 0.29-0.87) for the primary and secondary endpoints, respectively.  The absolute risk reduction(ARR) of rifaximin for having an episode of hepatic encephalopathy during the study time was 23.8% (45.9 % in placebo – 22.1% in rifaximin), and the  ARR for rifaximin for HE requiring hospitalization was 9% (22.65-13.6%).  Importantly 91.2% of the placebo group and 91.4% of the rifaximin group were using lactulose and compliance was 84.3 and 84.9%, respectively.  Their analysis was by intention-to-treat.  As a medication with minimal oral absorption/bioavailability, which also likely does not induce antimicrobial resistance, this may prove to be an important adjunctive therapy for our liver patients to reduce morbidity and hospitalization.  Caution advised:  Salix Pharmaceuticals was involved in study, patients who have Transjugular intrahepatic porto-systemic shunt were excluded and no mention was made of ongoing alcohol use (4).

Also in this week’s issue of NEJM, Peterson and colleagues shared their discovery of a possible genetic basis for nonalcoholic fatty liver disease (NAFLD).  Taking notice of the association between hepatic insulin resistance, type 2 diabetes mellitus and NAFLD, and the concept of an association between hypertriglyceridemia and two single nuclear polypmorphisms (SNPs) in the gene that encodes apolipoprotein C3 gene (APOC3), a cohort study was created.  The cohort was of Asian-Indian men, a group known to have a high prevalence of NAFLD.  The investigators found that carriers of the apoc3 variant alleles c-482T and t455c had a 30% increase in fasting plasma apolipoprotein c3 versus those homozygous for the wild type.  The variants also had a 60% increase in fasting triglyceride levels.  The NAFLD prevalence was 38% in the variant versus 0% in the wild-type (5).  While this information is not yet ready for translation to our clinical practice, it is exciting to have insight into the molecular basis of NAFLD, which will likely continue to be prevalent as our population remains obese.

Ray and colleagues this week in the Annals present data from a retrospective cohort of patients hospitalized for acute myocardial infarction, unstable angina or percutaneous coronary intervention who were given clopidogrel between 1999 and 2005.  They set out to shed light on the ongoing controversy of concurrent proton pump inhibitor (PPI) and clopidogrel use, surrounding  the knowledge that clopidogrel requires hepatic  cytochrome (CYP) P450 2C19 to become the active drug and that all PPIs are substrates of this CYP.  They found the hazard ratio for the combined endpoint of all serious cardiovascular outcomes was 0.99 but the 95% confidence interval spanned 0.82 to 1.19, therefore PPI use may be associated with increased cardiovascular problems.  They also reported a HR of 0.5 (95% CI 0.39-0.65) for gastrointestinal bleeds requiring hospitalization (6)  The jury is still out on this, but I think that we have enough evidence to avoid that PPI in those not at high risk for GI bleed and choose an alternative agent.   Look for an upcoming  post on Clinical Correlations thoroughly reviewing this issue.

My last picks illustrate the importance of continued self-evaluation in practice, from global health to the bedside.  On Thursday March 18th the World Health Organization (WHO) published an update to their 2008 report on Multidrug Resistant Tuberculosis (MDR-TB) and Extensively Drug Resistant Tuberculosis (XDR-TB).  It concludes that we have reason to be “cautiously optimistic that drug-resistant TB can be controlled. (7)” Newsflash: 3.6% of global incident cases of TB that are reported are MDR-TB and 50% of those cases are in China and India.  In 2008 TB caused 150,000 deaths worldwide.  Between 5.4-10% of MDR cases are XDR-TB.  Those grim numbers are countered with data from Russia showing that MDR-TB can be effectively treated.  Overall the success rate for treatment is 60% for MDR TB and the drugs alone are between 5 to 200 times the prices than that for TB (7).  This report reminds me that without the world-wide efforts at reporting cases of TB, tracking the treatment of TB patients, and funding of the team that is needed to treat TB we would not be able to control the epidemic.

The New York Times this Friday March 26th published a story examining the FDA’s press release  which announced that the FDA had ordered Glenmark Generics Ltd. and Konec, Inc. to stop making sublingual nitroglycerin (8).  I will now think twice when typing (or writing) a prescription for nitro because pharmacies around the nation can fill bottles with nitroglycerin tablets that have not been approved by the FDA.  The reason is “Many makers of various drugs, not only nitroglycerin tablets, have long contended that their medications did not require F.D.A. review because they were grandfathered as pre-1938 drugs. (9)” The FDA was created in 1938. Pfizer makes 80% of the US’s sublingual nitroglycerin and it is the only company whose nitro is actually approved by the FDA (9).

Thanks for stopping by PrimeCuts. This week we’ve entered a new era of health care delivery in the US, taken a double-take on safety of a PPI-clopidogrel combination and of our national supply of nitro, been inspired by bench work in NAFLD, acquired a new tool to help keep our liver patients out of the hospital, and in a reminder of the global epidemic of MDR-TB been inspired by a success story of curtailing its spread.

Kara Greenwald is a second year internal medicine resident at NYU Medical Center

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

[1] MDR-TB or multidrug resistant tuberculosis is defined as that resistant to at least isoniazid and rifampin. XDR-TB or extremely drug resistant tuberculosis is MDR plus resistance to at least one second line injectable medication (amikacin, kanamycin and/or capreomycin) (7).

References

(1)    Organizing for America. Twitter.com/Whitehouse. 3-23-2010 http://twitter.com/BARACKOBAMA

(2)    The Whitehouse. Putting Americans in control of their health care. [Internet] Washington DC. [cited 2010 Mar 27] Available from  http://www.whitehouse.gov/health-care-meeting/proposal

(3)    Food and drug administration. FDA: Press announcements page “FDA approves new use of Xifaxin for patients with live disease” [Internet]. Sliver Spring (MD): FDA; 2010 Mar 26 [updated 2010 Mar 26; cited 2010 Mar 27]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/.

(4)    Bass et al. Rifaximin treatment in hepatic encephalopathy. NEJM [Internet]. 2010 Mar 25 [cited 2010 Mar 27]; 362(12):1071-81. Available from: http://content.nejm.org/cgi/content/short/362/12/1071.

(5)    Peterson et al. Apolipoprotein C3 gene variants in the nonalcoholic fatty liver disease. NEJM [Internet]. 2010 Mar 25 [cited 2010 Mar 27];362(12):1082-89. Available from: http://content.nejm.org/cgi/content/short/362/12/1082

(6)    Ray et al. Outcomes with concurrent use of clopidogrel and proton pump inhibitors: a cohort study. Ann Intern Med. [Internet]. 2010 Mar 16 [cited 2010 Mar 27]; 152(6):337-45. Available from: http://www.annals.org/content/152/6/337.abstract

(7)    World Health Organization. Multidrug and extensively drug resistant TB (M/XDR-TB) : 2010 Global report on surveillance and response [Internet]. France: World Health Organization; 2010 March [cited 2010 Mar 26]. 71p. Available from: http://www.who.int/tb/publications/2010/978924599191/en/index.html . France.

(8)    Food and drug administration. FDA: Press announcements page ” FDA orders 2 companies to stop marketing unapproved nitroglycerin tablets” [Internet]. Sliver Spring (MD): FDA; 2010 Mar 16 [updated 2010 Mar 26; cited 2010 Mar 26]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/

(9)    Singer, Natasha. F.D.A. says millions got unapproved heart pills. New York Times [Internet].2010 Mar 26 [cited 2010 Mar 27] Available from: http://www.nytimes.com/2010/03/27/business/27nitro.html


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