Primecuts: This Week In The Journals

August 9, 2010

By Caprice Cadacio, MD

Faculty Peer Reviewed

Last month my fellow interns and I were enveloped by the fury that is known as July, the month infamous for shocking young interns into realizing they are now doctors.  I was fortunate to have started on Ambulatory Care meaning my evenings and weekends were still mine to enjoy and in the midst of this August elective, I continue to hold on to my summer.  In a few weeks, however, I will say goodbye as I am literally escorted into the night when I begin a night float rotation.  Until then, I can share my summer reading with you.

In local news, outrage erupted in lower Manhattan this week when the New York City Landmarks Preservation Commission made room to build a mosque near Ground Zero (1).  Interestingly, the structure that the Commission denied landmark status already houses a Muslim prayer site.  Moving west, a federal judge overturned California’s controversial Proposition 8, giving many Golden Staters a reason to rejoice (2).  It seems that America continues to struggle with issues of civil liberties and rights.  We still have a long way to go, America.

World politics is going to get interesting as musician Wyclef Jean declared his candidacy for Haitian president (3).  Speaking of politics, a few politicians’ children made some noteworthy headlines this week.  Rudolph Guliani’s daughter, Caroline, was caught shoplifting in the Upper East Side (4).  Bristol Palin and Levi Johnson called off their engagement again (5).  And Chelsea Clinton wed in Rhinebeck, New York (6).

Lastly, BP is fairly confident that it has the Deepwater Horizon oil rig permanently under control after engineers poured thousands of barrels of mud and cement into the oil well (7).  Amen.

Now onto some medical headlines…

The Annals of Internal Medicine featured CARDIA, a prospective study showing that individuals aged 18-30 with suboptimal LDL levels (>100 as defined by ATP III) had a greater risk of developing coronary calcium, an early marker of coronary artery disease, 15 to 20 years later (prevalence of 44% with LDL scores >160 compared to 8% with LDL scores <70, p<0.001) (8, 9).  Putting the two extremes head-to-head would of course show a hefty difference in coronary calcium levels but there was an increase in odds ratio and proportion of patients with coronary calcium as cumulative LDL scores increased.  Thus, aggressive lifestyle modification early on for patients with suboptimal but not high LDL (100 to 159) has utility in promoting future coronary health.  This study also highlights the discrepancy between ATP III and USPSTF lipid screening guidelines.  ATP recommends starting screening at age 20 while USPSTF recommends starting at 35 for men unless a patient has risk factors (9, 10).  Maybe the CARDIA study will sway some physicians towards using the ATP III guidelines.  The Lancet featured more on lipids, specifically HDL, with Ridker et al’s study using the population and data from the JUPITER trial (11).  HDL is known to be cardioprotective and Ridker et al confirmed that low HDL is a risk factor for vascular events in the placebo group.  This inverse relationship, however, was not observed in the rosuvastatin treatment group.  The authors daresay that residual risk of vascular events even after aggressive statin therapy may not be attributable to low HDL.  Does this mean patients with optimal LDL on statins but low HDL levels should not receive adjunct HDL promoting therapy?  Unlikely.  This study seems to suggest that a patient’s baseline HDL before statin therapy is a better predictor of cardiovascular risk.

Type II diabetes has made major news in the last few weeks with Avandia but let us shift our attention from medication to the role of nutrition in treating diabetes.  Diet modifications are known to improve and slow the progression of diabetes.  The LOADD study in BMJ, examined the effect of intensive nutrition counseling on diabetics with A1Cs over 7% who were already on optimized medication regimens (12).  93 patients were enrolled and randomized to either routine care or routine care with nutritional intervention over 6 months.  After six months the intervention group showed a 0.4% decrease in A1C while the control group showed no change (p = 0.007).  The absolute reduction in A1C may have been even greater with more follow up time.  Thus, let us not be afraid to refer our patients to nutritionists or counsel on nutrition more aggressively when A1Cs won’t budge.

Speaking of diet we turn to the age old debate of low carbohydrate versus low fat diets for weight loss.  The Annals of Internal Medicine featured a study that randomized 307 obese patients to abide by either a low carbohydrate or low fat diet (13).  The primary endpoint was weight loss after 2 years on the assigned diet regimen and group behavioral treatment including self monitoring and relapse management.  After two years there was no significant difference in weight loss between the low carbohydrate and the low fat diet arm, -7.37 (-9.10 to -5.63) and -6.34 (-8.06 to -4.63) respectively (p=0.41).  Although there was an overall weight reduction in both treatment arms, weight loss peaked at 6 months and both groups gained some weight back in the latter part of the study.  In summary, when patients ask about one macronutrient driven diet over the other for weight loss, we can say the debate is still out but there continues to be no proven difference.

This week’s NEJM featured three articles on the treatment of hereditary angioedema (HAE).  About 1 in 50,000 individual are affected by this condition, characterized by low or nonfunctioning C1 inhibitor, a complement pathway inhibitors (14).  Clinical manifestations include painful attacks of mucosal swelling in the skin, GI tract, and upper airway.  For acute HAE attacks, C1 inhibitors have been available in Europe for years now but have only recently been available in the US since 2009 with the drug Berinert.  Cinryze, also a C1 inhibitor, was approved for HAE prophylaxis in 2008 but Zuraw et al. wanted to examine Cinryze’s utility as an agent for acute HAE attacks (15).  In their placebo controlled trial, 68 patients were randomized to receive either placebo or 1000U of C1 inhibitor during an acute attack.  The median onset of relief in the placebo group was over 4 hours compared to 2 hours in the treatment group (p=0.02) but 40% of the treatment group did NOT have relief within 4 hours.  More robust data is likely needed to convince the FDA to bestow another clinical indication upon Cinryze.

Androgens and anti-fibrinolytics were the only available short and long term prophylactic agents for HAE in the US until 2008 when Cinryze was approved.  Zuraw et al included a second set of data from a crossover study confirming the efficacy of C1 inhibitors as prophylaxis for HAE.  The treatment arm received injections of 1000U of C1 inhibitor every three to four days for 12 weeks.  Participants crossed over and received the treatment from the other study arm for another 12 weeks.  Average normalized attack rates for the C1 inhibitor group during both 12 weeks periods were 6.26 compared to 12.73 for the placebo group, (p<0.001).  One caveat against C1 inhibitors: they are expensive. C1 inhibitors may not be cost effective first line agents for long term HAE prophylaxis.

Briefly, icatibant and ecallantide for acute HAE attacks were discussed in two separate articles.  To better understand the effects of these drugs, we can very lightly touch upon the mechanism behind HAE’s clinical manifestations. C1 inhibitor plays a regulatory role in several pathways including the complement, coagulation, fibrinolytic and kallikein-kinin pathways (16).  All of these pathways are interconnected and their relationship ultimately leads to the release of bradykinin.  Bradykinin, the true culprit, mediates pain and leads to vasodilatation and vessel permeability causing the edema of HAE.  In the FAST-2 trial, Cicardi et al showed that icatibant, a bradykinin B2 receptor antagonist, significantly reduced the median time to clinically significant relief compared to tranexamic acid, an anti-fibrinolytic agent (p<0.001).  In the FAST-1 trail, however, Cicardi et al showed that there was an insignificant reduction in median relief time from icatibant versus placebo (p=0.14).  Icatibant is currently only available in Europe but with no significant benefit over placebo, icatibant may not fly in the US unless more placebo-controlled data becomes available.  Wrapping up this discussion on acute HAE treatment, Cicardi et al’s EDEMA 3 study showed that ecallantide, a kallikren inhibitor, had significantly better median treatment outcome scores than placebo at four hours (p=0.004), (14).  Ecallantide received its FDA nod in December 2009 but it was slapped with a black box warning regarding the risk of anaphylaxis.  EDEMA 3, a follow up to EDEMA 1 and 2, reported no anaphylaxis in their participants.

Expect to see more HAE treatment data in the future as the FDA continues to review follow-up studies.  This is great news for sufferers of this rare but debilitating condition.  Future research can focus on self-administration of C1 inhibitors for acute attacks as well as comparing the different treatment modalities to one another.

Ending with some local medical news, 3 cases of the West Nile Virus were confirmed in the NYC area (17).  All three were hospitalized and over the age of 45 and one individual had meningitis.  The war continues against the vector of this virus: those pesky mosquitoes.

Dr. Cadacio is a first year resident at NYU Langone Medical Center

Peer reviewed by Barbara Porter, MD, Section Editor, Clinical Correlations

Picture of Static Kill released by Coast Guard Unified Command, courtesy Wikimedia Commons

References:

1.  http://cityroom.blogs.nytimes.com/2010/08/03/mosque-near-ground-zero-clears-key-hurdle/?scp=1&sq=mosque&st=cse

2.  http://www.nytimes.com/2010/08/05/us/05prop.html?hp

3.  http://blogs.wsj.com/speakeasy/2010/08/04/wyclef-jean-on-his-decision-to-run-for-the-presidency-of-haiti/

4.  http://www.nytimes.com/2010/08/05/nyregion/05giuliani.html?hp

5.  http://www.npr.org/templates/story/story.php?storyId=128960758

6.  http://www.nytimes.com/2010/08/01/nyregion/01chelsea.html?scp=4&sq=clinton&st=cse

7.  http://www.nytimes.com/2010/08/06/us/06spill.html?scp=2&sq=bp&st=cse (BP oil) (BP oil)

8.  Pletcher MJ, Bibbins-Domingo K,  Liu K, Sidney S, Lin F, Vittinghoff E, Hulley S. Nonoptimal Lipids Commonly Present in Young Adults and Coronary Calcium Later in Life: The CARDIA (Coronary Artery Risk Development in Young Adults) Study. Ann of Int Med. 2010 August 3;153(3): 137-146.  http://www.annals.org/content/153/3/137.abstract

9.  http://www.nhlbi.nih.gov/guidelines/cholesterol/atp_iii.htm

10.  http://www.ahrq.gov/clinic/uspstf/uspschol.htm

11.  Ridker PM, Genset J, Boekholdt, SM, Libby P, Gotto AM, Norestgaard BG, Mora S, MagFadyen JG, Glynn RJ, Kastelein JJP. 2010 July 31. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. The Lancet. 2010 July 31. 376 (9738): 333 – 339.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960713-1/abstract

12.  Coppell KJ, Kataoka M, Williams SM, Chisholm AW, Vorgers SM, Mann JI. Nutritional intervention in patients with type 2 diabetes who are hyperglycaemic despite optimised drug treatment-Lifestyle Over and Above Drugs in Diabetes (LOADD) study:randomised controlled trial. BMJ. 2010 July 20. 341:3337.  http://www.bmj.com/cgi/search?fulltext=loadd&sortspec=date&x=0&y=0

13.  Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill B, Stein RI, Mohammed BS, Miller B, Rader DJ, Zemel B, Wadden TA, Tenhave T, Newcomb CW, Klein S. Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet A Randomized Trial. Ann of Int Med. 2010 August 3;153(3): 147-157.s  http://www.annals.org/content/153/3/147.abstract

14.  Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, Horn PT, Pullman WE. Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema. N Engl J Med. 2010 August 5. 363:523-531.  http://www.nejm.org/doi/full/10.1056/NEJMoa0905079

15.  Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, Bielory L Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM. Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. N Engl J Med. 2010 August 5.363:513-522  http://www.nejm.org/doi/full/10.1056/NEJMoa0805538

16.  Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann K, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anné S, Björkander J, Bouillet L, Cillari E, Hurewitz D, Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hébert J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Fernández Romero DS, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Wing-Tze Fan WT. Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema. N Engl J Med. 2010 August 5.363:532-541.  http://www.nejm.org/doi/full/10.1056/NEJMoa0906393

17.  http://www.nytimes.com/2010/08/07/nyregion/07nile.html?_r=1&scp=1&sq=west%20nile&st=cse

Image courtesy of Wikimedia Commons.

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