Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. 1.1.2. Risk Factor Interactions Data from the Framingham Heart Study have provided evi- dence of a predictive role of hypertension, dyslipidemia, glucose intolerance, cigarette smoking, and left ventricular (LV) hypertrophy in CVD.21 These 5 primary risk factors are the most important modifiable determinants of CVD risk and appear to operate independently of one another. This has led to the idea that the threshold at which a patient should be treated for hypertension should be determined by a patient s burden of CVD risk factors, which in turn deter- mine the level of CVD risk. In the guidelines developed by the National Kidney Foundation,22 this principle has been followed for patients with albuminuria and even modest chronic renal insufficiency, for which the BP threshold for the initiation of antihypertensive therapy is 130/80 mm Hg. The American Diabetes Association has based its recom- mendation on age: People with diabetes mellitus should be treated to a BP of <140/80 mm Hg, except that lower systolic targets, such as <130 mm Hg, may be appropri- ate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. 