Fluid Matters in Choosing Antihypertensive
Assuming that blood pressure is lowered equivalently, diuretics are more effective than angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and α-adrenergic receptor blockers (α-blockers) at preventing heart failure, and they are more effective than ACEIs and α-blockers at preventing strokes. Compared with β-adrenergic receptor blockers (β-blockers) and ACEIs, CCBs are less effective at reducing myocardial infarcts and heart failure. There is currently no conceptual framework by which to organize data indicating that some antihypertensive medications are better than others at preventing cardiovascular diseases. The thesis of this article is that the fluid reduction or fluid retention attributable to antihypertensive medications, either alone or in combination, provides a basis for ranking these medications. Diuretics have a theoretical advantage compared with other antihypertensive medications because they reduce total body fluid more than other agents. Therefore, they are the preferred drugs for treating hypertension. The other antihypertensive agents that promote fluid reduction, ACEIs and angiotensin receptor blockers (ARBs), are next in preference, ranking a close second to diuretics. Because β-blockers have a neutral effect on total body fluid, they rank on a third tier of preference, after ACEIs and ARBs. CCBs and α-blockers are the least preferred medications for treating hypertension because they promote fluid retention.
Provided that blood pressure is lowered comparably, diuretics have been demonstrated to be more effective than angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and α-adrenergic receptor blockers (α-blockers) at preventing heart failure, and diuretics have been found to be more effective than ACEIs and α-blockers at preventing stokes. Diuretics offer no advantage over ACEIs, CCBs, or α-blockers in preventing fatal coronary heart disease, preventing nonfatal myocardial infarcts, or lowering all-cause mortality, and diuretics offer no advantage over CCBs in preventing strokes. Compared with β-adrenergic receptor blockers (β-blockers) and ACEIs, CCBs are less effective at reducing myocardial infarcts and heart failure.
Although the preponderance of the evidence favors using diuretics as first line pharmacological therapy for the treatment of hypertension, the research data do not uniformly support this conclusion. The Second Australian National Blood Pressure (ANBP2) study demonstrated that, particularly in men, there were fewer cardiovascular events and fewer deaths from any cause in the group treated with ACEIs than in the group treated with hydrochlorothiazide (HCTZ). The favorable results for the ACEI in ANBP2 may reflect, in part, the predominance of white persons in the study population. Several studies have documented that the nondihydropyridine CCBs diltiazem and verapamil are equivalent to, and in some instances better than, diuretics and β-blockers in preventing some cardiovascular diseases. The second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension-2) trial found no difference in long-term cardiovascular outcomes between subjects taking diuretics and β-blockers and subjects taking ACEIs and CCBs. The Captopril Prevention Project (CAPPP) compared captopril with diuretics and β-blockers and found that subjects treated with captopril were less likely to die from cardiovascular causes, but subjects in the captopril group were more likely to develop strokes. One might argue that β-blockers potentially diluted the benefit of the diuretics in the STOP-Hypertension-2 and CAPPP trials, but in the Metoprolol Atherosclerosis Prevention in Hypertension (MAPHY) study, metoprolol was found to be superior to diuretics in terms of preventing sudden cardiovascular deaths.
Of course, there are limitations in comparing the results of different antihypertensive trials. One limitation is that demographic differences such as age, gender, race, and ethnicity may confound the comparisons. Another limitation is that not all antihypertensive trials achieved equivalency in blood pressure reduction. For example, subjects in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) study assigned to diuretic treatment had lower systolic blood pressures than subjects assigned to ACEI, CCB, or α-blocker treatment, and subjects in the CCB group had lower diastolic blood pressures than subjects in the diuretic group. Even though the ALLHAT investigators made appropriate adjustments for the differences in blood pressures, these differences cloud the interpretation of the results.
This article proposes that, apart from blood pressure lowering itself, the fluid reduction or fluid retention property of each antihypertensive medication helps explain its relative merit in preventing cardiovascular diseases. The benefit of diuretics compared with other antihypertensive medications lies in the ability of diuretics to lessen total body fluid-total body fluid being the sum of the intravascular fluid, the intracellular fluid, the interstitial fluid, and fluid that is third-spaced (pleural effusions or ascites). That ACEIs are sometimes superior to diuretics in terms of cardiovascular outcomes lies in the fluid reduction properties of ACEIs. On the other hand, compared with diuretics, β-blockers, ACEIs, and clonidine, the relative inferiority of CCBs in reducing myocardial infarcts and heart failure is the result of fluid retention. Finally, nondihydropyridine CCBs result in less fluid retention than do dihydropyridine CCBs. This may explain why some studies found no cardiovascular outcome differences when nondihydropyridine CCBs were compared with diuretics and β-blockers. This article will use the term "diuretic" to refer to thiazide medications such as HCTZ or chlorthalidone.
There is no method to directly and readily measure total body fluid. Weight gain or loss is used as a surrogate marker for total body fluid increases or decreases. Based on the presence or absence of leg edema, it is possible to gauge whether the amount of interstitial fluid is increased or not. Based on the presence or absence of jugular venous distension, hepatojugular reflux, or an S3 or S4 cardiac murmur, it is possible to gauge whether the amount of intravascular fluid is increased or not, and based on the presence or absence of ascites or a pleural effusion, it is possible to gauge whether fluid is third-spaced or not. In general, if there is increased interstitial fluid, increased intravascular fluid, or increased third-spaced fluid, then there is increased total body fluid.
If total body fluid determines the relative merits of antihypertensive medications, it is unclear why, but intravascular volume is probably a factor. When there is excess interstitial fluid in the form of leg edema, increased cardiovascular pathology may result from repetitive, transient changes in the fluid volume of the intravascular compartment that results from fluid shifting to dependent parts of the body, via the blood vessels and lymphatics, depending on whether people are recumbent or upright.
Table 1 lists a number of different antihypertensive medications and the rates of edema that have been reported with each one. Only trials involving hypertensive subjects without diabetes are included.
Assuming that blood pressure is lowered equivalently, diuretics are more effective than angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and α-adrenergic receptor blockers (α-blockers) at preventing heart failure, and they are more effective than ACEIs and α-blockers at preventing strokes. Compared with β-adrenergic receptor blockers (β-blockers) and ACEIs, CCBs are less effective at reducing myocardial infarcts and heart failure. There is currently no conceptual framework by which to organize data indicating that some antihypertensive medications are better than others at preventing cardiovascular diseases. The thesis of this article is that the fluid reduction or fluid retention attributable to antihypertensive medications, either alone or in combination, provides a basis for ranking these medications. Diuretics have a theoretical advantage compared with other antihypertensive medications because they reduce total body fluid more than other agents. Therefore, they are the preferred drugs for treating hypertension. The other antihypertensive agents that promote fluid reduction, ACEIs and angiotensin receptor blockers (ARBs), are next in preference, ranking a close second to diuretics. Because β-blockers have a neutral effect on total body fluid, they rank on a third tier of preference, after ACEIs and ARBs. CCBs and α-blockers are the least preferred medications for treating hypertension because they promote fluid retention.
Provided that blood pressure is lowered comparably, diuretics have been demonstrated to be more effective than angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and α-adrenergic receptor blockers (α-blockers) at preventing heart failure, and diuretics have been found to be more effective than ACEIs and α-blockers at preventing stokes. Diuretics offer no advantage over ACEIs, CCBs, or α-blockers in preventing fatal coronary heart disease, preventing nonfatal myocardial infarcts, or lowering all-cause mortality, and diuretics offer no advantage over CCBs in preventing strokes. Compared with β-adrenergic receptor blockers (β-blockers) and ACEIs, CCBs are less effective at reducing myocardial infarcts and heart failure.
Although the preponderance of the evidence favors using diuretics as first line pharmacological therapy for the treatment of hypertension, the research data do not uniformly support this conclusion. The Second Australian National Blood Pressure (ANBP2) study demonstrated that, particularly in men, there were fewer cardiovascular events and fewer deaths from any cause in the group treated with ACEIs than in the group treated with hydrochlorothiazide (HCTZ). The favorable results for the ACEI in ANBP2 may reflect, in part, the predominance of white persons in the study population. Several studies have documented that the nondihydropyridine CCBs diltiazem and verapamil are equivalent to, and in some instances better than, diuretics and β-blockers in preventing some cardiovascular diseases. The second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension-2) trial found no difference in long-term cardiovascular outcomes between subjects taking diuretics and β-blockers and subjects taking ACEIs and CCBs. The Captopril Prevention Project (CAPPP) compared captopril with diuretics and β-blockers and found that subjects treated with captopril were less likely to die from cardiovascular causes, but subjects in the captopril group were more likely to develop strokes. One might argue that β-blockers potentially diluted the benefit of the diuretics in the STOP-Hypertension-2 and CAPPP trials, but in the Metoprolol Atherosclerosis Prevention in Hypertension (MAPHY) study, metoprolol was found to be superior to diuretics in terms of preventing sudden cardiovascular deaths.
Of course, there are limitations in comparing the results of different antihypertensive trials. One limitation is that demographic differences such as age, gender, race, and ethnicity may confound the comparisons. Another limitation is that not all antihypertensive trials achieved equivalency in blood pressure reduction. For example, subjects in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) study assigned to diuretic treatment had lower systolic blood pressures than subjects assigned to ACEI, CCB, or α-blocker treatment, and subjects in the CCB group had lower diastolic blood pressures than subjects in the diuretic group. Even though the ALLHAT investigators made appropriate adjustments for the differences in blood pressures, these differences cloud the interpretation of the results.
This article proposes that, apart from blood pressure lowering itself, the fluid reduction or fluid retention property of each antihypertensive medication helps explain its relative merit in preventing cardiovascular diseases. The benefit of diuretics compared with other antihypertensive medications lies in the ability of diuretics to lessen total body fluid-total body fluid being the sum of the intravascular fluid, the intracellular fluid, the interstitial fluid, and fluid that is third-spaced (pleural effusions or ascites). That ACEIs are sometimes superior to diuretics in terms of cardiovascular outcomes lies in the fluid reduction properties of ACEIs. On the other hand, compared with diuretics, β-blockers, ACEIs, and clonidine, the relative inferiority of CCBs in reducing myocardial infarcts and heart failure is the result of fluid retention. Finally, nondihydropyridine CCBs result in less fluid retention than do dihydropyridine CCBs. This may explain why some studies found no cardiovascular outcome differences when nondihydropyridine CCBs were compared with diuretics and β-blockers. This article will use the term "diuretic" to refer to thiazide medications such as HCTZ or chlorthalidone.
There is no method to directly and readily measure total body fluid. Weight gain or loss is used as a surrogate marker for total body fluid increases or decreases. Based on the presence or absence of leg edema, it is possible to gauge whether the amount of interstitial fluid is increased or not. Based on the presence or absence of jugular venous distension, hepatojugular reflux, or an S3 or S4 cardiac murmur, it is possible to gauge whether the amount of intravascular fluid is increased or not, and based on the presence or absence of ascites or a pleural effusion, it is possible to gauge whether fluid is third-spaced or not. In general, if there is increased interstitial fluid, increased intravascular fluid, or increased third-spaced fluid, then there is increased total body fluid.
If total body fluid determines the relative merits of antihypertensive medications, it is unclear why, but intravascular volume is probably a factor. When there is excess interstitial fluid in the form of leg edema, increased cardiovascular pathology may result from repetitive, transient changes in the fluid volume of the intravascular compartment that results from fluid shifting to dependent parts of the body, via the blood vessels and lymphatics, depending on whether people are recumbent or upright.
Table 1 lists a number of different antihypertensive medications and the rates of edema that have been reported with each one. Only trials involving hypertensive subjects without diabetes are included.