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Fluid Matters in Choosing Antihypertensive Therapy: a Hypothesis That the Data Speak Volumes

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Fluid Matters in Choosing Antihypertensive Therapy: a Hypothesis That the Data Speak Volumes J Am Board Fam Pract: first published as 10.3122/jabfm.18.2.113 on 29 March 2005. Downloaded from Fluid Matters in Choosing Antihypertensive Therapy: A Hypothesis That the Data Speak Volumes Robert P. Blankfield, MD, MS Assuming that blood pressure is lowered equivalently, diuretics are more effective than angiotensin- converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and ␣-adrenergic receptor blockers (␣-blockers) at preventing heart failure, and they are more effective than ACEIs and ␣-block- ers at preventing strokes. Compared with ␤-adrenergic receptor blockers (␤-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 antihyper- tensive 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 reduc- tion, ACEIs and angiotensin receptor blockers (ARBs), are next in preference, ranking a close second to diuretics. Because ␤-blockers have a neutral effect on total body fluid, they rank on a third tier of pref- erence, after ACEIs and ARBs. CCBs and ␣-blockers are the least preferred medications for treating hy- pertension because they promote fluid retention. (J Am Board Fam Pract 2005;18:113–24.) Provided that blood pressure is lowered compara- research data do not uniformly support this con- bly, diuretics have been demonstrated to be more clusion. The Second Australian National Blood effective than angiotensin-converting enzyme in- Pressure (ANBP2) study demonstrated that, partic- hibitors (ACEIs), calcium channel blockers (CCBs), ularly in men, there were fewer cardiovascular ␣ ␣ and -adrenergic receptor blockers ( -blockers) at events and fewer deaths from any cause in the http://www.jabfm.org/ preventing heart failure, and diuretics have been group treated with ACEIs than in the group treated found to be more effective than ACEIs and with hydrochlorothiazide (HCTZ).7 The favorable ␣ 1–5 -blockers at preventing stokes. Diuretics offer results for the ACEI in ANBP2 may reflect, in part, ␣ no advantage over ACEIs, CCBs, or -blockers in the predominance of white persons in the study preventing fatal coronary heart disease, preventing population. Several studies have documented that nonfatal myocardial infarcts, or lowering all-cause the nondihydropyridine CCBs diltiazem and vera- on 26 September 2021 by guest. Protected copyright. mortality, and diuretics offer no advantage over pamil are equivalent to, and in some instances bet- CCBs in preventing strokes.3,4 Compared with ter than, diuretics and ␤-blockers in preventing ␤-adrenergic receptor blockers (␤-blockers) and some cardiovascular diseases.8–10 The second ACEIs, CCBs are less effective at reducing myo- Swedish Trial in Old Patients with Hypertension cardial infarcts and heart failure.1,2 (STOP-Hypertension-2) trial found no difference Although the preponderance of the evidence fa- in long-term cardiovascular outcomes between vors using diuretics as first line pharmacological ␤ therapy for the treatment of hypertension,6 the subjects taking diuretics and -blockers and sub- jects taking ACEIs and CCBs.11 The Captopril Prevention Project (CAPPP) compared captopril Submitted, revised, 13 December 2004. with diuretics and ␤-blockers and found that sub- From the Department of Family Medicine, Case Western Reserve University, School of Medicine, Cleveland, OH. jects treated with captopril were less likely to die Address correspondence to Robert P. Blankfield, MD, MS, from cardiovascular causes, but subjects in the cap- Berea Health Center, University Hospitals Primary Care 12 Physician Practice, 201 Front Street, Suite 101, Berea, OH topril group were more likely to develop strokes. 44017 (e-mail: blankfi[email protected]). One might argue that ␤-blockers potentially di- http://www.jabfp.org Fluid Matters in Antihypertensive Therapy 113 J Am Board Fam Pract: first published as 10.3122/jabfm.18.2.113 on 29 March 2005. Downloaded from luted the benefit of the diuretics in the STOP- a surrogate marker for total body fluid increases or Hypertension-2 and CAPPP trials, but in the decreases. Based on the presence or absence of leg Metoprolol Atherosclerosis Prevention in Hyper- edema, it is possible to gauge whether the amount tension (MAPHY) study, metoprolol was found to of interstitial fluid is increased or not. Based on the be superior to diuretics in terms of preventing sud- presence or absence of jugular venous distension, den cardiovascular deaths.13 hepatojugular reflux, or an S3 or S4 cardiac mur- Of course, there are limitations in comparing mur, it is possible to gauge whether the amount of the results of different antihypertensive trials. intravascular fluid is increased or not, and based on One limitation is that demographic differences the presence or absence of ascites or a pleural such as age, gender, race, and ethnicity may con- effusion, it is possible to gauge whether fluid is found the comparisons. Another limitation is that third-spaced or not. In general, if there is increased not all antihypertensive trials achieved equiva- interstitial fluid, increased intravascular fluid, or lency in blood pressure reduction. For example, increased third-spaced fluid, then there is increased subjects in the Antihypertensive and Lipid-Low- total body fluid. ering Treatment to Prevent Heart Attack (ALL- If total body fluid determines the relative mer- HAT) study assigned to diuretic treatment had its of antihypertensive medications, it is unclear lower systolic blood pressures than subjects as- why, but intravascular volume is probably a fac- signed to ACEI, CCB, or ␣-blocker treatment, tor. When there is excess interstitial fluid in the and subjects in the CCB group had lower dia- form of leg edema, increased cardiovascular pa- stolic blood pressures than subjects in the di- thology may result from repetitive, transient uretic group.3,4 Even though the ALLHAT in- changes in the fluid volume of the intravascular vestigators made appropriate adjustments for the compartment that results from fluid shifting to differences in blood pressures, these differences dependent parts of the body, via the blood vessels cloud the interpretation of the results.14 and lymphatics, depending on whether people This article proposes that, apart from blood are recumbent or upright. pressure lowering itself, the fluid reduction or fluid Table 1 lists a number of different antihyperten- retention property of each antihypertensive medi- sive medications and the rates of edema that have cation helps explain its relative merit in preventing been reported with each one. Only trials involving cardiovascular diseases. The benefit of diuretics hypertensive subjects without diabetes are in- compared with other antihypertensive medications cluded. http://www.jabfm.org/ lies in the ability of diuretics to lessen total body fluid–total body fluid being the sum of the intra- Calcium Channel Blockers vascular fluid, the intracellular fluid, the interstitial Leg edema is a common dose- dependent side ef- fluid, and fluid that is third-spaced (pleural effu- fect of the CCBs. Edema formation occurs even sions or ascites). That ACEIs are sometimes supe- though CCBs increase renal sodium excretion (na- rior to diuretics in terms of cardiovascular out- triuresis).15,16 In the case of nifedipine, the edema comes lies in the fluid reduction properties of occurs simultaneously with the natriuresis.17 on 26 September 2021 by guest. Protected copyright. ACEIs. On the other hand, compared with diuret- CCBs increase renal blood flow by selectively ics, ␤-blockers, ACEIs, and clonidine, the relative dilating the renal afferent arterioles, thereby result- inferiority of CCBs in reducing myocardial infarcts ing in natriuresis and diuresis.18 The initial diuretic and heart failure1 is the result of fluid retention. and natriuretic effects of most CCBs probably per- Finally, nondihydropyridine CCBs result in less sist with long-term usage,19,20 but the natriuresis fluid retention than do dihydropyridine CCBs. resulting from nifedipine may be transient.21 This may explain why some studies found no car- Edema occurs with CCBs because of vasodila- diovascular outcome differences when nondihydro- tion in the distal arterioles, thereby leading to in- pyridine CCBs were compared with diuretics and creased intravascular capillary pressures and in- ␤-blockers. This article will use the term “diuretic” creased venous pressures, at least in the lower to refer to thiazide medications such as HCTZ or extremities,22 and eventually leakage of fluid into chlorthalidone. the extracellular space. There is no method to directly and readily mea- In placebo-controlled studies, the rate of edema sure total body fluid. Weight gain or loss is used as was 11% in a group treated with nifedipine, 14% in 114 JABFP March–April 2005 Vol. 18 No. 2 http://www.jabfp.org J Am Board Fam Pract: first published as 10.3122/jabfm.18.2.113 on 29 March 2005. Downloaded from Table 1. Frequency of Edema in Controlled and Uncontrolled Trials of Different Antihypertensive Medications
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