A placebo-controlled, multicenter, randomized, double-blinded study to evaluate the efficacy of IE prophylaxis in patients who undergo a dental, GI, or GU tract procedure has not been done. Such a study would require a large number of patients per treatment group and standardization of the specific invasive procedures and the patient populations. This type of study would be necessary to definitively answer long-standing unresolved questions regarding the efficacy of IE prophylaxis. The Committee hopes that this revised document will stimulate additional studies on the prevention of IE. Future published data will be reviewed carefully by the AHA, the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, and other societies, and further revisions to the present document will be based on relevant studies. Pathogenesis of IE The development of IE is the net result of the complex interaction between the bloodstream pathogen with matrix molecules and platelets at sites of endocardial cell damage. In addition, many of the clinical manifestations of IE emanate from the host s immune response to the infecting microor- ganism. The following sequence of events is thought to result in IE: formation of nonbacterial thrombotic endocarditis (NBTE) on the surface of a cardiac valve or elsewhere that endothelial damage occurs, bacteremia, adherence of the bacteria in the bloodstream to NBTE, and proliferation of bacteria within a vegetation. Formation of NBTE Turbulent blood flow produced by certain types of congenital or acquired heart disease, such as flow from a high- to a low-pressure chamber or across a narrowed orifice, trauma- tizes the endothelium. This creates a predisposition for deposition of platelets and fibrin on the surface of the endothelium, which results in NBTE. Invasion of the blood- stream with a microbial species that has the pathogenic potential to colonize this site can then result in IE. 