The effect was similar to that obtained when thiazides are used as a single agent .
Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug .
This means that the BP lowering effect of thiazides is additive .
Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose .
Because of the short duration of the trials and lack of reporting of adverse events , this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug
BACKGROUND Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug .
Therefore , it is essential to determine the effects of diuretics on blood pressure ( BP ) , heart rate and withdrawals due to adverse effects ( WDAEs ) when given as a second-line drug .
Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study
Context Hypertension is a recognized risk factor for the development of congestive heart failure ( CHF ) . By measuring blood pressure , however , we have not yet been able to underst and the significance of pulse pressure as a contributor to CHF in middle-aged men and women . Contribution Using data from the Framingham Heart Study , the authors found that although elevations of systolic , diastolic , and pulse pressure were all related to the risk for CHF , the relation was strongest for systolic and pulse pressure . Caution s Underst and ing the relationships between systolic , diastolic , and pulse pressure and risk for CHF is helpful ; however , they do not help determine the increased risk faced by a person with systolic hypertension who also has increased pulse pressure . The Editors Hypertension is the most common risk factor for congestive heart failure ( CHF ) . It confers a twofold risk for the occurrence of CHF and also carries the highest population attributable risk among all risk factors for CHF ( 1 , 2 ) . Placebo-controlled clinical trials in patients with hypertension have demonstrated a consistent reduction in risk for CHF attributable to the lowering of elevated blood pressure ( 3 - 6 ) . The causal role of hypertension in the pathogenesis of CHF underscores the need to identify high-risk patients because early treatment may prevent or delay the occurrence of CHF ( 2 , 7 ) . The prognostic significance of systolic and diastolic blood pressure in CHF has been reported . However , blood pressure may also be divided into two other components : steady ( mean arterial pressure ) and pulsatile ( pulse arterial pressure ) ( 8 - 10 ) . Pulse pressure , a simple correlate of conduit vessel stiffness , is associated with left ventricular hypertrophy ( 11 ) . Increased pulse pressure has also been implicated in the development and progression of large-vessel atherosclerosis and small-vessel disease ( 12 - 14 ) . Accumulating evidence indicates that pulse pressure ( defined as the difference between systolic and diastolic blood pressure ) may be an important predictor of cardiovascular events ( 15 - 18 ) . Pulse pressure predicts the risk for CHF in elderly persons ( 19 , 20 ) ; however , the association of pulse pressure with CHF in middle-aged men and women has not been examined . The Framingham Heart Study provides an opportunity to examine the long-term associations of systolic , diastolic , and pulse pressure with the new onset of  CHF in middle-aged and elderly men and women .  Blood pressure and traditional risk factors have been measured repeatedly at serial examinations in this community-based cohort with long-term follow-up . We examined systolic blood pressure , diastolic blood pressure , and pulse pressure as predictors of risk for CHF in the Framingham Heart Study . Methods The Framingham Heart Study , which began in 1948 , has followed 5209 participants ( 28 to 62 years of age at entry to the study ) as part of a prospect i ve epidemiologic study of cardiovascular disease . Enrollment criteria and study design have been published previously ( 21 ) . Biennial follow-up visits included a medical history , physical examination , blood pressure measurements , 12-lead electrocardiography , and laboratory tests . Eligibility requirements for inclusion in our study were as follows : Participants had to be free of coronary heart disease and CHF and not be receiving antihypertensive therapy at Framingham Heart Study clinic baseline examinations 10 , 11 , or 12 ( 1968 to 1973 ) . Participants were followed for onset of CHF through mid-1994 . We obtained data for selected risk factors from the baseline examination . Methods for assessing risk factors have been published previously ( 21 , 22 ) . Risk factors , including age , sex , cigarette smoking , heart rate , antihypertensive medication use , and total and high-density lipoprotein cholesterol levels , were assessed .  Sitting systolic and diastolic blood pressure were measured twice by the examining physician ( using a mercury column sphygmomanometer ) and averaged . We used body mass index ( kg/m2 ) as a measure of obesity . Participants were categorized as smokers if they smoked cigarettes regularly within the 1-year period before the baseline examination . Electrocardiography revealed left ventricular hypertrophy when increased voltage was associated with major ST-T repolarization changes ( strain pattern ) ( 22 ) . Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L ( > 140 mg/dL ) , two r and om nonfasting blood glucose levels greater than 11.10 mmol/L ( > 200 mg/dL ) , or the use of insulin or an oral hypoglycemic agent . Diagnostic criteria for CHF have been described previously ( 21 , 22 ) . At each clinic examination , a history of interim hospitalizations and symptoms of CHF were obtained . Outside medical records of participants who did not attend an examination were evaluated for incident CHF . All suspected interim events were review ed by a panel of three physicians who evaluated relevant Framingham Heart Study clinic notes , outside physician reports , and hospitalization records . Congestive heart failure was diagnosed when at least two major or one major and two minor criteria were present . Minor criteria were considered only if their presence could not be attributed to another disease process . Major criteria were paroxysmal nocturnal dyspnea , pulmonary rales , distended jugular veins , enlarging heart size on chest radiography , acute pulmonary edema , hepatojugular reflux , third heart sound , jugular venous pressure of 16 cm or greater , and weight loss of 4.5 kg or greater in response to diuresis . Major criteria also included pulmonary edema , visceral congestion , or cardiomegaly on autopsy . Minor criteria were bilateral ankle edema , nocturnal cough , shortness of breath on ordinary exertion , hepatomegaly , pleural effusion , decrease in vital capacity by one third from the previous maximum recorded value , and heart rate of 120 beats/min or more . Statistical Analysis We used multivariable Cox proportional-hazards regression models to examine the relations of systolic , diastolic , and pulse pressure with CHF . After accounting for age and sex and using a P value less than 0.15 as the selection criterion , we determined covariates by stepwise selection from the following list : body mass index , diabetes , smoking status , total cholesterol level , high-density lipoprotein ( HDL ) cholesterol level , totalHDL cholesterol ratio , left ventricular hypertrophy , and heart rate . Only total cholesterol level and totalHDL cholesterol ratio did not enter the model . After accounting for relevant covariates , we used Cox proportional-hazards models to obtain hazard ratio estimates with 95 % CIs for st and ardized values of systolic , diastolic , and pulse pressure . These estimates were obtained individually and pairwise by using SAS software ( SAS Institute , Inc. , Cary , North Carolina ) ( 23 ) . We repeated analyses for participants stratified according to hypertension status and sex . Because blood pressure and age are correlated , we conducted separate analyses for participants younger than 60 years of age and 60 years of age and older . To examine constancy of effects over time , follow-up was divided into early and late periods ( < 10 years , 10 years ) , and hazard ratios were calculated separately for early and late follow-up . In addition , we analyzed blood pressure as a time-varying covariate and assessed the effect of antihypertensive treatment after the baseline blood pressure measurements . We used the KaplanMeier method to plot age- and sex-st and ardized cumulative incidence rates for CHF as a function of pulse pressure tertile at baseline . Descriptive data are presented as percentages or means ( SD ) . A P value less than 0.05 was considered statistically significant . Role of the Funding Sources The funding sources had no role in the design , conduct , analyses , and reporting of the study or in the decision to su bmi t the manuscript for publication . Results A total of 894 men and 1146 women , age 50 to 79 years , fulfilled criteria for inclusion in our study . Table 1 presents baseline clinical characteristics for these persons . During 35 497 person-years of follow-up ( mean , 17.4 years [ range , 0.06 to 24 years ] ) , CHF developed in 234 ( 11.8 % ) persons . Myocardial infa rct ion preceded CHF in 59 ( 25 % ) persons . Table 1 . Baseline Clinical Characteristics of the Study Participants Increments of 1 SD in systolic pressure , pulse pressure , and diastolic pressure were associated with hazard ratios for congestive failure of 1.56 , 1.55 , and 1.24 , respectively , after adjustment for age , sex , smoking , left ventricular hypertrophy , body mass index , diabetes mellitus , HDL cholesterol level , and heart rate ( Table 2 ) . When blood pressure tertiles were used , similar associations were observed among various components of blood pressure and CHF . No threshold effect or J-shaped association was documented ( Table 2 ) . The cumulative incidence of CHF according to tertiles of baseline pulse pressure is plotted in the Figure . Table 2 . Risk FactorAdjusted Association of Blood Pressure with Congestive Heart Failure Figure . Cumulative incidence of congestive heart failure according to pulse pressure tertiles at the baseline examination . The joint influences of different blood pressure components were also examined , with adjustment for the covariates mentioned previously . Of note , correlations among the blood pressure variables ranged from modest to very high ( r = 0.20 for diastolic and pulse pressure , r = 0.65 for diastolic and systolic pressure , and r = 0.88 for systolic and pulse pressure ) . Diastolic pressure was not significant ( hazard ratio , 1.12 [ CI , 0.98 to 1.29 ] ) in conjunction with pulse pressure ( hazard ratio , 1.51 [ CI , 1.33 to 1.72 ] ) . Likewise , diastolic pressure was not significant ( hazard ratio , 0.86 [ CI , 0.72 to 1.03 ] ) in conjunction with systolic pressure ( hazard ratio , 1.71 [ CI , 1.45 to 2.01 ] ) , but joint estimates were less stable than those obtained for individual pressure variables . Finally
The effect was similar to that obtained when thiazides are used as a single agent .
Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug .
This means that the BP lowering effect of thiazides is additive .
Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose .
Because of the short duration of the trials and lack of reporting of adverse events , this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug
BACKGROUND Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug .
Therefore , it is essential to determine the effects of diuretics on blood pressure ( BP ) , heart rate and withdrawals due to adverse effects ( WDAEs ) when given as a second-line drug .