Faculty peer reviewed
While the journals and media continue to focus on the H1N1 virus, an article published in The Journal of the American Medical Association (JAMA) sparked a good deal of controversy. In fact, the New York Times referenced the study in an article entitled, “F.D.A to Seek New Standards on Human Tests (1).” Dhruva et al set out to study the premarket approval process for medical devices and the quality of the evidence used during that process (2). They performed a systematic review of 123 studies used in 78 premarket approvals for high-risk cardiovascular devices between January 2000 and December 2007. The approval process for these devices is the “most stringent type of device marketing application required by the FDA.” In their review they found the mean number of studies used to support an approval was 1.6 with 65% of approvals supported by only a single study. In the 123 studies, 27% were randomized, 14% were blinded, 96% were multi-centered, and study sizes ranged from 23-1548 with a mean of 308 subjects. The New York Times interviewed Dr. Jeffrey Shuren, the acting director of The Center for Devices and Radiological Health at the FDA. He stated that there will be changes in what the FDA will require for device approval, and the studies will require more sharply defined end points. In an unusual move, the FDA will release their own study which found that 40% of studies used to approve cardiovascular devices lacked “high-quality” data. Dr. Shuren went on to say that while changes have already been made since 2007, more are likely on the way.
Another controversial study, by a group from the National Institute of Health (NIH), was in the Archives of Internal Medicine this week (3). This study pointed out that the risk of radiation from Computed Tomographic (CT) scans might be worse than we originally thought. The researchers used health insurance data to estimate the number of CT scans performed each year. They estimated that 72 million CT scans were performed during 2007. They excluded CT scans performed during the last 5 years of life, leaving 57 million CT scans that would put patients at risk for the development of cancer. Using dosing from established protocols and cancer rates amongst patients with prior radiation exposure (much from the Japanese atomic bomb survivors), they estimated that these 2007 CT scans will cause 29,000 future cancers secondary to radiation exposure. While CT scans have become a mainstay in medicine and are often crucial in diagnosis, we must acknowledge that the scans are not completely benign and health professionals must become more prudent in patient selection for these scans.
In other journals, Circulation released more results from the BARI-2D study (4), further clarifying the optimal treatment for diabetics with coronary artery disease. The original BARI-2D study found that in diabetic (type 2) patients with stable ischemic coronary artery disease no decrease in all-cause death was noted when randomized to percutaneous coronary intervention (PCI) compared to optimal medical therapy. The study this week examined the secondary outcomes of BARI-2D, including cardiac death and myocardial infarction. The study design first had physicians decide if CABG or PCI would be the recommended revascularization procedure. The subjects were then randomized to that procedure plus intensive medical therapy or intensive medical therapy alone. The study also randomized subjects to insulin provision or insulin sensitization therapy in a 2×2 factorial design. Overall there was no difference between all-cause death, cardiac death, or MI between the revascularization group and medical therapy group. In subjects who physicians decided PCI would be the optimal procedure, the group randomized to PCI did not differ in overall death, cardiac death, or MI compared with the medical therapy group. In the group where physicians decided CABG would be the treatment of choice, there was no difference in death or cardiac death between the group receiving the CABG and the medical therapy alone group (8.0% cardiac death in CABG group vs. 9.0% in medical therapy group). However the CABG group had fewer MIs compared to the medical therapy group (10% 5-year rate of MI in the CABG group vs. 17% in medical therapy group; p-value 0.003). Additionally, there was no difference between the group randomized to insulin sensitization compared with the insulin provision group for any of the outcomes. This data supports that diabetic patients with stable coronary artery disease who would not undergo CABG receive no benefit from revascularization by PCI. However interpreting the CABG data is not as clear. The decrease in MIs did not relate to changes in mortality. The benefit may be obscured by the fact that the majority of MIs in the CABG group were procedural related, and those subjects who had MIs had a much higher risk of subsequent death during the follow up period.
Finally in this week’s New England Journal of Medicine there is a nice review of activated protein C use in severe sepsis, addressing several controversies surrounding its use (5). The review explains the pathophysiology behind activated protein C, including its anticoagulant activity and inhibition of the systemic inflammatory response during sepsis. The review goes on to explain the evidence behind the drug’s use in sepsis. The PROWESS trial (6) was the original study which showed a decrease in mortality from 30.8% in the placebo group to 24.7% in the activated protein C group. Analyses from that trial showed the majority of the effect occurred in subjects with severe sepsis (APACHE score > 25). Subsequent data has shown that there is no benefit in those with APACHE scores < 25 or only single organ dysfunction (ADDRESS trial (7)), as well as no benefit in children (8). Much controversy has surrounded the fact that the PROWESS trial was sponsored by Eli Lilly, (makers or recombinant human activated protein C (drotrecogin alfa); Xigris) and after just the single trial the Surviving Sepsis Campaign, also heavily supported by Eli Lilly stated in their position statement that they recommend using Xigris in subjects with severe sepsis. Critics charged that the Surviving Sepsis guidelines were really just an extension of Eli Lily’s marketing. In response to these charges the group changed the recommendation the following year to “we suggest.” Further in response, Eli Lilly has started another trial analyzing Xigris’ use in severe sepsis with APACHE scores > 25. Nevertheless, despite all the controversy, the authors of this review support Xigris’ use in subjects with severe sepsis (APACHE score > 25) and evidence of multi-organ dysfunction.
As we usher in a new year, we have time to look back at the biggest stories in medicine from 2009. Health care reform took center stage in politics, new recommendations for mammography sparked almost as much controversy, a mother gave birth to octuplets, and a strain of influenza terrified a nation. Nature’s year in review provided some interesting numbers to think about (9): The estimated death rate of the 1918 influenza pandemic was 2%, while H1N1 has a death rate of 0.007-0.045%. There are 6,250 deaths from H1N1 through November, while 250,000-500,000 people die every year from seasonal flu. Life expectancy has risen to 78 years in the US, while in Sierra Leone the life expectancy is 40 years. Death rate of uninsured emergency room patients is 5.7% while insured patients have a death rate of 3.3%. On a more uplifting note, the cost of sequencing a human genome dropped from $300 million in 2003 to $4,400 in 2009.
Dr. Hastings is a 2nd year resident in internal medicine at NYU Medical Center.
Peer reviewed by Neil Shapiro MD, Editor in Chief, Clinical Correlations.
1. Meier B. F.D.A to Seek New Standards on Human Tests. The New York Times. 2009 December 30, 2009;Sect. B1.
2. Dhruva SS, Bero LA, Redberg RF. Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices.
3. Berrington de Gonzalez A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, Land C. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med2009 Dec 14;169(22):2071-7.
4. Chaitman BR, Hardison RM, Adler D, Gebhart S, Grogan M, Ocampo S, Sopko G, Ramires JA, Schneider D, Frye RL. The bypass angioplasty revascularization investigation 2 diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation2009 Dec 22;120(25):2529-40.
5. Toussaint S, Gerlach H. Activated protein C for sepsis. N Engl J Med2009 Dec 31;361(27):2646-52.
6. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med2001 Mar 8;344(10):699-709.
7. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med2005 Sep 29;353(13):1332-41.
8. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet2007 Mar 10;369(9564):836-43.
9. 2009 by the numbers. Nature Medicine2009 12/2009;15(12):1351-2.