At Last, Something of Life-Saving Potential for Severe Sepsis

At Last, Something of Life-Saving Potential for Severe Sepsis

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Mar-Apr 02	Rank Last Period Jan-Feb 02
1	B.J. Druker, et al. "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia," New Engl. J. Med., 344(14):5 April 2001. [Oregon Hlth. Sci. U., Portland; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ; U. Calif., Los Angeles] *417XH	45	1
2	D.M. Herrington, et al., "Effects of estrogen replacement on the progression of coronary-artery atherosclerosis," New Engl. J. Med., 343(8):522-9, 24 August 2000. [6 U.S. institutions] *346QM	41	9
3	B.J. Druker, et al., "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome," New Engl. J. Med., 344(14):1038-42, 5 April 2001. [Oregon Hlth. Sci. U., Portland; Univ. Calif., Los Angeles; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ] *417XH	39	5
4	G.R. Bernard, et al., "Efficacy and safety of recombinant human activated protein C for severe sepsis," New Engl. J. Med., 344(10):699-709, 8 March 2001. [9 institutions worldwide] *408AX	37	†
5	F.E. Silverstein, et al., "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial," JAMA-J. Amer. Med. Assn., 284(10):1247-55, 13 September 2000. [12 U.S. institutions] *350WL	36	3
6	C. Bombardier, et al., "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis," New Engl. J. Med., 343(21):1520-8, 23 November 2000. [14 institutions worldwide] *375PR	34	2
7	D.J. Slamon, et al., "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2," New Engl. J. Med., 344(11):783-92, 15 March 2001. [9 institutions worldwide] *410LA	32	6
8	A.M.J. Shapiro, et al., "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen," New Engl. J. Med., 343(4):230-8, 27 July 2000. [U. Alberta, Edmonton, Canada] 337QC	29	†
9	G. Steinbach, et al., "The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis," New Engl. J. Med., 342(26):1946-52, 29 June 2000. [U. Texas, M.D. Anderson Cancer Ctr., Houston; ICRF, St. Marks Hosp., London, U.K.; NCI, Bethesda, MD; G.D. Searle & Co., Skokie, IL] *328TZ	28	†
10	P.E. Lipsky, et al., "Infliximab and methotrexate in the treatment of rheumatoid arthritis," New Engl. J. Med., 343(22):1594-1602, 30 November 2000. [11 institutions worldwide] *377JT	28	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

he granting of approval to a new therapy by the U.S. Food and Drug Administration is not always accompanied by congratulatory messages from the FDA and the Secretary for Health and Human Services. However, there was a touch of euphoria in the announcement, on November 21, 2001, that drotrecogin alfa (activated) had been approved for severe sepsis in adults. (Sepsis, as some non-medical Science Watch readers may need to note, is a far more serious condition than the mere bacterial infection that dictionaries and the wide availability of non-prescription antiseptic products might suggest.) Roughly 30% of the up to 750,000 cases of sepsis seen in the United States every year are fatal despite measures such as intravenous antibiotics and intensive care. When illness becomes as serious as this, we are seeing the effects of different responses to infection potentially affecting several organs. In these inflammatory, thrombotic, and fibrinolytic responses, a natural substance called activated protein C has an important modulating role. Also, circulating concentrations of this protein are reduced in patients with sepsis. The ability to manufacture activated protein C by recombinant methods has led to clinical studies of the product drotrecogin alfa (Xigris, Eli Lilly), and the placebo-controlled trial conducted by the international PROWESS study group contributed much of the evidence behind the FDAs approval (the report is currently at #4, having previously appeared at #5 in the May/June 2002 issue). Enrollment in the trial, planned to include 2,280 patients, was stopped when an interim analysis revealed a significant positive effect for the new drug on mortality, and the data reported cover 1,690 patients. On enrollment, over two-fifths of these patients with severe bacterial or fungal infections already had three or more dysfunctional organs or body systems, and more than 70% were on mechanical ventilation. Four-fifths had protein C deficiency.

The key result is the mortality 28 days after the infusion, 30.8% in placebo group and 24.7% in the active-drug group (p = 0.005). With this agent, which is contraindicated in patients with hemorrhagic disorders, serious bleeding might be expected to be among the complications of therapy. This happened in 3.5% of patients given drotrecogin alfa and in 2.0% of those on placebo but the opposite, thrombotic events were if anything reduced (3.0% and 2.0%).

With a clinical result such as this, we hardly need biological markers of efficacy, but there was laboratory confirmation that the new drug was working in the expected way. The fall in plasma D-dimer concentrations and the reduction in circulating levels of interleukin-6 confirmed that the procoagulant and inflammatory effects of sepsis, respectively, were being affected in the expected direction.

So many treatments aimed at preventing death in severe sepsis have failed that clinicians could be forgiven for thinking that once sepsis is manifest, organ damage is already irreversible, and medicine is powerless. Dr. Gordon R. Bernard from the Vanderbilt University School of Medicine, Nashville, Tennessee, the lead investigator in the PROWESS study, foresees a shift in emphasis as a result of this paper. The study "has put sepsis on the map as a major public health problem," he tells Science Watch. "I never realized how much easier the task of stimulating interest in the demographics, epidemiology, and current sepsis therapy as well as investigating new therapies would become once a specific agent becomes available for clinical use." Drotrecogin alfa is not licensed for less severe sepsis or for children, and in PROWESS one in four patients given the new drug died, so there is plenty for this altered perception of the disease to work on.

Mr. David W. Sharp, M.A. (Cambridge), is a contributing editor to The Lancet, London, U.K.

Science Watch^Ž, September/October 2002, Vol. 13, No. 5
Citing URL: http://www.sciencewatch.com/sept-oct2002/sw_sept-oct2002_page7.htm